Pet imaging of breast cancer via sigma-2 receptors

Research Corner

Abstracts of Funded NationalInstitutes of Health Grants

The following abstracts of diagnostic radiology research and training grants funded by the National Institutes of Health (NIH)were awarded to principal investigators (PIs) whose primary appointments are in medical school departments of radiology.These abstracts are listed on the NIH Web page (http://www-commons.cit.nih.gov/crisp/) and are printed here verbatim.

The grant identification number (eg, 1RO1AI12345-01) contains a three-digit activity code (in the previous example, RO1)that identifies a specific category of extramural activity. All current NIH activity code titles and definitions can be ob-tained at the NIH Web page http://silk.nih.gov/silk/brownbooks/actcod.

IRG (Internal Review Group) refers to the study section that reviewed the application. ICD (Institute, Center, Division) re-fers to the NIH funding source.

The abstracts of the funded grants are printed alphabetically by author according to the funding institute or center.

National Center For ResearchResources

PET IMAGING OF BREAST CANCER VIASIGMA-2 RECEPTORS

Grant Number: 1R21CA102869-01PI Name: Mach, Robert H.

Abstract: Description (provided by applicant): The earlydetection of breast tumors at a stage when it is most treat-able represents the most important issue in the clinical man-agement of breast cancer. Although screening mammographyis widely accepted as the best procedure for this purpose,there are a number conditions (i.e., women with dense breasttissue, breast implants, or scar tissue for an earlier biopsystudy) that interfere with the identification of abnormalitiesthat may be caused by breast tumors. In addition, anothermajor problem in the clinical management of breast cancer isthe identification of an appropriate treatment strategy oncethe disease has been correctly diagnosed. Therefore, a nonin-vasive imaging procedure that can detect breast tumors inpatients that are problematic for mammography, and provideinsight into identifying an appropriate strategy for treatingthis disease, would be an important tool in the clinical man-agement of breast cancer. The goal of the research describedin this application is to develop sigma-2 (sigma2) receptor-based radiotracers for imaging breast tumors with the nonin-vasive imaging technique PET. The choice of this receptoras a target for imaging is based on published reports that
human breast tumors possess a high density of sigma2 recep-
tors versus surrounding normal tissue. Therefore, a sigma2receptor-based imaging agent should be useful in detectingbreast tumors is patients that are problematic for mammogra-phy. A second reason for focusing on this receptor is ourpublished data demonstrating that sigma2 receptors are ex-pressed in approximately 10-fold higher density in prolifera-tive mouse mammary adenocarcinoma cells versus the non-proliferative or quiescent cell population under both in vitro(cell culture) and in vivo (tumor xenografts) conditions.Therefore, a sigma2 receptor PET radiotracer has the poten-tial to provide information regarding the proliferative statusof breast cancer. An in vivo imaging procedure that can pro-vide information about the proliferative status of primarybreast tumors would represent a significant improvementover current methods used in making this assessment. Ourpreliminary data also indicate that sigma2-selective radiotrac-ers are predicted to have a better tumor: background ratiothan other agents, such as FDG and the DNA precursors,currently used to assess proliferation in PET oncology stud-ies. Consequently, a major goal of this R21/R33 grant appli-cation is to conduct the necessary in vivo studies needed tovalidate this novel, receptor-based imaging approach for de-termining the proliferative status of breast tumors. A seriesof studies are also proposed to compare our imaging proce-dure with that of [18F]FLT, a substrate of thymidine kinase1 which was recently introduced as a potential proliferation-based radiotracer. We propose to compare our receptor-basedapproach to the [18F]FLT method, and compare the resultsof these studies to proliferative status of the tumor deter-mined by flow cytometry of the BUdR labeled DNA. Fi-nally, a series of microPET imaging studies (using the Con-corde Microsystems microPET R4 and Focus PET scanners)
will be conducted in order to determine if the sigma2 recep-
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Academic Radiology, Vol xx, No x, Month 2005

tor imaging approach can be used to monitor a positive re-sponse to antiestrogen and Herceptin therapy in estrogen re-ceptor (�) and Her2/neu receptor (�) human breast tumorxenografts.

Thesaurus Terms: breast neoplasm, neuropeptide receptor,noninvasive diagnosis, positron emission tomography, radio-tracer, receptor expression, technology/technique develop-ment adenocarcinoma, cell proliferation, chemical synthesis,ligand, tumor progression athymic mouse, bioimaging/bio-medical imaging, clinical research, flow cytometry, heterolo-gous transplantation

Institution: Washington UniversityLindell And Skinker BlvdSt. Louis, MO 63130

Fiscal Year: 2003Department: RadiologyProject Start: 15-Aug-2003Project End: 31-Jul-2004ICD: National Cancer InstituteIRG: ZRG1

IMAGING THE RESPONSE OF LOCALLYADVANCED BREAST CANCER

Grant Number: 5R01CA072064-09PI Name: Mankoff, David A.

Abstract: Description (provided by applicant): In this com-petitive renewal application, we will investigate specific as-pects of the biology of locally advanced breast caners(LABCs) that were uncovered by our initial set of studies.Our previous specific aims were to (1) measure the responseof LABC to neo-adjuvant chemotherapy using [Tc-99m]-sestamibi (MIBI) and [F-181]-fluorodeoxyglucose (FDG)PET and (2) to characterize the physiology of tumor re-sponse using MIBI, FDG, and [0-15]-water with the goal ofidentifying mechanisms of resistance. Our studies establishedserial MIBI imaging as an accurate toll for measuring re-sponse and indicated the accuracy of FDG PET for initialLABC staging and determining the extent of viable tumorpost-therapy. In addition, we found a very striding set offindings regarding the physiology of responding tumors: (1)Tumors with a high rate of glycolysis (high FDG uptake)pre-therapy responded poorly to chemotherapy. (2) Patientswho ultimately achieved a complete macroscopic response totherapy (CP) had a drop in tumor blood flow after twomonths of therapy, while all others had no change or an in-crease in blood flow; this pattern did not hold for the changein FDG uptake. Our studies also suggested that MIBI uptakeis largely determined by blood flow and that neither pre-therapy MIBI uptake nor washout is a reliable predictor ofchemotherapy resistance. Recent analysis has shown that the
ratio of pre-therapy glycolysis to blood flow and the level of
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residual blood flow and MIBI uptake post-therapy predictdisease-free survival. We now focus on mechanisms of tu-mor response and treatment resistance suggested by our firstset of studies. By comparing PET measurements of tumorphysiology to response and to in vitro assays of tumor bio-logic properties, we will investigate (1) the mechanisms un-derlying the apparent chemotherapy resistance of highly gly-colytic LABC, in particular tumor hypoxia, (2) methods tomeasure response early in the course of therapy using PETcell proliferation tracers, and (3) the kinetic properties ofMIBI using the positron-emitter [Tc-94m]-sestamibi to moreprecisely determine the effect of blood flow and efflux pumpexpression on MIBI uptake and washout. Our studies willincrease the understanding of resistance and response to che-motherapy in advanced breast cancer and generate new ap-proaches to individualizing patient treatment to optimize re-sponse. In this amended application, we focus on recentprogress that has strengthened our preliminary data and fur-ther supports our proposed investigations of the biology ofadvanced breast cancer and its relationship to therapeuticresponse.

Thesaurus Terms: antineoplastic, breast neoplasm, breastneoplasm/cancer diagnosis, drug resistance, human therapyevaluation, neoplasm/cancer chemotherapy, positron emissiontomography, radiopharmacology, technetium drug metabo-lism, glucose metabolism, neoplasm/cancer blood supply,prognosis bioimaging/biomedical imaging, clinical research,human subject, patient oriented research, radiotracer

Institution: University Of WashingtonOffice Of Sponsored ProgramsSeattle, WA 98105

Fiscal Year: 2005Department: RadiologyProject Start: 01-Aug-1996Project End: 31-Mar-2007ICD: National Cancer InstituteIRG: RNM

DIAGNOSIS OF IM NODAL METASTASESIN BREAST CANCER

Grant Number: 5R01CA090771-04PI Name: Mankoff, David A.

Abstract: Description (Verbatim from the Applicant’s Ab-stract): Two recent randomized prospective studies, includinga study at the British Columbia (BC) Cancer Agency, haveshown that adjuvant irradiation of the chest wall and nodalbeds draining the breast improves survival, even in patientswith as few as 1-3 axillary Iymph node metastases. Althoughthis approach included treatment to the internal mammarynodal (IMN) chain, the importance of IMN irradiation is un-
known, and the inclusion of IMN radiotherapy in post-surgi-


cal radiotherapy remain controversial. This is due to the factthat (1) only a subset of patients who are candidates for ad-juvant nodal bed radiotherapy actually have IMN metastasesand (2) IMN radiotherapy carries potential cardiac, lung, andmediastinal toxicity. Current clinical practice does not in-clude IMN biopsy, in part due to the morbidity of undirectedIMN sampling. FDG PET is a non-invasive imaging methodwith high sensitivity for axillary lymph node metastases. Ourpreliminary studies suggest that it is highly accurate in de-tecting IMN metastases as well. Our recent work has alsoshown that lymphatic mapping with peri-lesional injectionand lymphoscintigraphy can determine which tumors drain tothe IMN. We hypothesize that a stepwise approach to IMNmetastasis diagnosis using FDG PET to identify macrometas-tases and lymphoscintigraphy to identify drainage to theIMN can select patients for IMN biopsy and radiotherapy.Once validated this approach would rationally select patientsfor IMN radiation therapy and would require IMN biopsy inonly a subset of patients. We propose a diagnostic studywhich will be a joint project between University of Wash-ington and the BC Cancer Agency as an extension of an es-tablished collaboration. In this study we will (1) develop therole of FDG PET and lymphoscintigraphy in identifyingIMN metastases, (2) identify tumor features that predict ahigher risk for IMN metastases, and (3) develop methods forusing FDG PET to help plan radiotherapy. This diagnosticstudy will provide important data to direct future internalmammary radiotherapy trials.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, diagnosis design/evaluation, lymph node neo-plasm, metastasis deoxyglucose, noninvasive diagnosis, auto-radiography, clinical research, computed axial tomography,female, human subject, positron emission tomography, wom-en’s health

Institution: University Of WashingtonOffice Of Sponsored ProgramsSeattle, WA 98105

Fiscal Year: 2004Department: RadiologyProject Start: 25-Jul-2001Project End: 30-Apr-2006ICD: National Cancer InstituteIRG: RNM

INDIRECT LYMPHOSONOGRAPHY FORSENTINEL NODE LOCALIZATION

Grant Number: 5R21CA110164-02PI Name: Mattrey, Robert F.

Abstract: Description (provided by applicant) The P.I. hashad a long-term relationship with Alliance Pharmaceutical
scientists in San Diego. We have collaborated on many dis-
coveries made by the P.I. or Alliance that were translatedfrom concept to the clinic. Two of these are now commercialproducts. All of these agents were perfluorocarbon-based thatconstitute the core technology of Alliance and the expertiseof my laboratory. Alliance is now focused on the oxygentransport indications and divested its ultrasound contrastagent (USCA) (Imagent) in June 2003 to Photogen Technol-ogies, Inc. who in turn created a new division, IMCOR Phar-maceuticals, Inc., based in San Diego and employs about 30people all of whom were scientists or support staff at Alli-ance assigned to the contrast media effort. IMCOR is dedi-cated to the clinical and commercial development of spe-cialty imaging agents, and is currently focused on contrastagents for ultrasound and x-ray CT in cardiology and oncol-ogy. Capitalizing on the expertise of IMCOR scientists andthe interest of IMCOR to commercialize contrast agents, andour expertise in contrast research should lead to synergisticdiscoveries and clinical translation. The long-term objectiveof the project proposed here is to commercialize an USCAfor indirect lymphography to detect the sentinel lymph node(SLN) for resection. If the project is successful we should beable to trace the lymph duct from the tumor to every SLNdraining the site regardless of location and needle-localizethe node pre-operatively. The benefits will be to minimizetissue dissection by guiding the surgeon directly to the SLN.If the node is accessible, resection could potentially be doneunder local anesthesia or by use of a percutaneous resectiondevice. This would allow the pathologist to study the noderigorously with all appropriate stains rather than the currenthurried assessment that is done while the patient is anesthe-tized. We plan to manipulate microbubble size, aggregationpotential, surface charge and shell properties to produce anagent that is optimized for efficient entry into the lymphduct, visualization of maximal length of the duct, fillingdraining node and enhancing them intensely and be able todo so repeatedly by re-massaging the depot from the sameinjection. Further, we will optimize the agent to be resistantto ultrasound pressure and be trapped at least in part by thedraining node. We have optimized a reproducible animalmodel that would allow us to study these characteristics andcompare one agent to the other as we optimize the formula-tion.

Thesaurus Terms: contrast media, lymphatic system, radi-ography, technology/technique development X ray, blood/lymphatic neoplasm, cardiography, lymph node, oncology,oxygen transport, ultrasound imaging/scanning bioimaging/biomedical imaging, laboratory rabbit

Institution: University Of California San DiegoLa Jolla, CA 920930934

Fiscal Year: 2005Department: RadiologyProject Start: 01-Sep-2004
Project End: 31-Aug-2006
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ICD: National Cancer InstituteIRG: ZCA1

LUNG IMAGE DATABASE

Grant Number: 5U01CA091099-03PI Name: Meyer, Charles R.

Abstract: Description: (provided by applicant) This proposalis a response to RFA CA-01-001, Lung Image Database Re-source for Imaging Research. Herein we propose to partici-pate in formulating the multi-institutional lung imaging data-base acquisition and quality control specification, and begincollecting cases and populating a local database according tothe specification resulting from the multi-institutional con-sensus guidelines. The database will be served for publicsharing either through direct Internet access from our lab, orvia NIH centralized resources as determined later. We be-lieve that there are multiple reasons why we should be cho-sen as one of the institutions to participate in this project. 1)We have been participants, at times leaders, in the fields ofimage processing that this database is designed to advance.These fields include computer assisted diagnosis (CAD) ofcancer from mammograms and now applied to CT scans,detection of metastatic and primary cancer changes in re-sponse to chemo and radiation therapy via registration andsubtraction of interval CT exams, and the use of CT sideinformation to reduce PET?s overall system point spreadfunction to improve quantitative analysis of lesions smallerthan 1 cm. Such prior expertise will insure that database ac-quisition specifications contain nearly all necessary elementsrequired for future use. 2) The clinical collaborators on thisproject have already had significant experience recruitinglung patients for another lung database project, the NationalEmphysema Treatment Trials (NETT). In this project Michi-gan ranked second in the number of patients screened for thestudy, and first in the enrollment of patients that passed thescreen. 3) The design of patient research database construc-tion methodology that safely cleans patient identifiers fromthe data has already been completed for a pending POl ap-plication. 4) The Department of Radiology and the Univer-sity Hospitals are already committed to the acquisition ofnew generation CT and PET scanners within the next 2years.

Thesaurus Terms: cancer information system, computedaxial tomography, computer system design/evaluation, lungneoplasm, positron emission tomography cooperative study,deoxyglucose clinical research, human subject

Institution: University Of Michigan At Ann ArborAnn Arbor, MI 481091274

Fiscal Year: 2003Department: Radiology
Project Start: 17-Aug-2001
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Project End: 31-Jul-2006ICD: National Cancer InstituteIRG: ZCA1

AUTOMATIC 3D REGISTRATION FORENHANCED CANCER MANAGEMENT

Grant Number: 5P01CA087634-04PI Name: Meyer, Charles R.

Abstract: Description (provided by applicant) Driven bytechnology development, the oncologist/radiologist is cur-rently under assault by increasing quantities of higher resolu-tion anatomical and functional imaging data. The new Light-Speed CT scanner by GE is but one typical example of suchnew acquisition devices. It is imperative that new image pro-cessing tools be developed to help specialists filter throughthe massive amounts of data in order to maintain or evenimprove their sensitivity and specificity in detecting neoplas-tic changes. We believe that this grant is a significant step inthis important direction and represents the best efforts of atruly multidisciplinary team. Automatic 3D Registration forEnhanced Cancer Management is a proposal to support lim-ited, preclinical testing of the ability of advanced image pro-cessing techniques to improve the management of cancer byroutinely culling more and earlier information for the clini-cian from existing diagnostic modalities. This programproject grant includes a)the use of fMRI for pre (neuro)surgi-cal planning focused on patients with movement disordersassociated with lesions near the motor strip who could neverremain sufficiently motionless for current fMRI techniques,b) support for lesion change detection and quantificationfrom repeated, interval CT and ultrasound exams in order tomonitor and potentially modify therapy plans based on indi-vidual patient response, c) automation in defining organs inradiation therapy treatment planning using noncontrast CTdata sets, and d) the development of a method using regis-tered CT and PET for reducing false positive nodes calledon CT-only chest exams.

Thesaurus Terms: image processing, imaging/visualization/scanning, method development, neoplasm/cancer diagnosis,neoplasm/cancer therapy, neoplastic growth, statistics/biome-try bioimaging/biomedical imaging, clinical research


Fiscal Year: 2005Department: RadiologyProject Start: 15-Jul-2002Project End: 30-Jun-2007ICD: National Cancer Institute
IRG: ZCA1


POSITION EMISSION TOMOGRAPHY INCERVICAL CANCER

Grant Number: 5R01CA085797-04PI Name: Miller, Tom R.

Abstract: Description (Verbatim from the Applicant’s Ab-stract): The overall goal of this project is improved radio-therapy treatment of patients with cervical cancer with use ofpositron emission tomography (PET). PET with F-18 fluoro-deoxyglucose (FDG) will be used to provide three-dimen-sional definition of the primary tumor volume and regionalspread of disease to more accurately administer brachyther-apy. PET-based prognostic indicators will be developed. Thefirst step will be verification of the ability of PET to accu-rately define tumor volume and to differentiate recurrent tu-mor from radiation-induced inflammation. Tumor size andextent of disease will be correlated with the results of mag-netic resonance imaging in patients receiving radiotherapywith evaluation of FDG uptake before, during and after ra-diotherapy. Techniques will be developed to accurately de-termine the position of the brachytherapy applicator in rela-tion to the tumor volume. FDG-PET images showing theprimary tumor and regional spread of disease will-be spa-tially registered with the position of the brachytherapy appli-cator after placement of the applicator in the patient, thuspermitting modification of the source loading in the future tooptimize the dose to the tumor while minimizing radiation ofthe adjacent normal structures. The dose to the tumor andnormal structures will be evaluated and follow-up will beperformed to assess the rate of recurrence and complicationsin relation to the calculated doses the patients actually re-ceived. The potential impact of PET-guided alterations insource loading and treatment duration will be evaluated. Todetermine the prognostic value of PET, the volume of theprimary tumor and the tracer uptake and heterogeneity ofuptake within the tumor, obtained from FDG-PET images,will be correlated with the rate of tumor recurrence to deter-mine PET markers that will identify patients at high risk forearly recurrence who may need more aggressive initial treat-ment.

Thesaurus Terms: cervix neoplasm, diagnosis design/evalu-ation, neoplasm/cancer diagnosis, positron emission tomogra-phy, prognosis deoxyglucose, fluorine, inflammation, methoddevelopment, neoplasm/cancer radiation therapy, neoplasm/cancer relapse/recurrence, radiobiology, radionuclide clinicalresearch, female, human subject, magnetic resonance imag-ing, women’s health


Fiscal Year: 2004Department: Radiology
Project Start: 03-Apr-2001
Project End: 31-Mar-2005ICD: National Cancer InstituteIRG: RNM

POSITRON EMISSION TOMOGRAPHY INPROSTATE CANCER

Grant Number: 1R01CA101734-01PI Name: Miller, Tom R.

Abstract: Description (provided by applicant): The primarygoal of this project is determination of the value of positronemission tomography employing the radiopharmaceuticalC-11 acetate (AC-PET) in patients with medium- and high-risk prostate cancer who are candidates for treatment withcurative intent by radical prostatectomy or radiation therapybecause the standard clinical and imaging evaluation wasnegative for tumor spread beyond the prostate. The followingspecific aims will be pursued: 1. Determine the role of AC-PET in changing initial patient management; 2. Determinethe value of AC-PET in predicting recurrence; 3. Assess theperformance of AC-PET for detection of lymph nodes bycomparison with biopsy. Study Design: The study includes atotal of 285 patients in two groups who are scheduled fortreatment with curative intent, both of whom will undergoAC-PET imaging prior to treatment. For the surgery group,if the PET examination is negative for disease outside theprostate gland, the treatment will proceed and the patientwill be followed for evidence of recurrence. If the PET ex-amination is positive, the referring physician will be encour-aged to undertake confirmatory studies, which may lead to achange in therapy. All patients in the radiation therapy groupwill undergo the standard treatment, and they will then befollowed for evidence of recurrence. The lymph node biopsyresults in the surgery patients will be correlated with thePET findings to compute the positive and negative predictivevalues of AC-PET. Anticipated Results: AC-PET will lead tocancellation of radical prostatectomy in at least 10% of thesurgical patients. It is also expected that AC-PET will signif-icantly improve the prediction of recurrence compared withconventional methods based on clinical stage, PSA and Glea-son score. The predictive value of AC-PET should be highwhen correlated with the pathological data. Health Rele-vance: If this project is successful, it will have a significantimpact on the management of patients with moderate- andhigh-risk prostate cancer who are candidates for curativetreatment. In some of these patients, a positive PET scanwill lead to cancellation of planned surgery, sparing thesemen the morbidity of radical surgery while permitting someof them to receive more appropriate hormonal treatment.PET may also contribute significant prognostic informationthat may affect the decision to administer early adjuvant
therapy to delay or prevent recurrence.
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Thesaurus Terms: patient care management, positron emis-sion tomography, prostate neoplasm acetate, carbon, lymphnode, metastasis, neoplasm/cancer radiation therapy, neo-plasm/cancer radiodiagnosis, neoplasm/cancer relapse/recur-rence, prognosis, prostate surgery, radionuclide bioimaging/biomedical imaging, biopsy, clinical research, human subject,laparoscopy, male, patient oriented research


Fiscal Year: 2003Department: RadiologyProject Start: 01-Sep-2003Project End: 31-Aug-2008ICD: National Cancer InstituteIRG: RNM

BIOLOGICALLY SIGNIFICANT DAMAGEIN DNA

Grant Number: 5R01CA046295-15PI Name: Milligan, Jamie R.

Abstract: Description (Provided By Applicant):The uniqueaspect of the biologically significant DNA damage associatedwith ionizing radiation is that this damage is clustered. It istherefore qualitatively distinct from that produced by UVradiation, or chemicals such as alkylating agents. The long-term goals of this work are to clarify the radiation chemicalmechanisms by which DNA damage is introduced by ioniz-ing radiation and by which it may be processed, modified, orrepaired. This provides a means to evaluate the ability ofcellular systems to cope with this damage. Applications tohuman health include defining the causes of individual varia-tion in radiosensitivity (for example the role of anti-oxidantsin protecting against radiation damage) and the developmentof mechanistic models for risk estimation of cancer etiologyby low dose and low dose rate exposures. Our approach usesmodel systems in which DNA damage is detected as singlestrand breaks, double strand breaks, various base damages,and by its effect on the transformation efficiency of bacteria.The DNA substrates are plasmids and the SV4O minichro-mosome. The ionizing radiations include 7-rays and a-parti-cles. To assess DNA damage, we will employ three newmodel systems that we have developed. These systems havebeen designed with the intention of concentrating upon thedirect effect (ionization of the DNA itself), because this pro-cess is poorly understood in comparison with the indirecteffect (DNA damage by solvent radicals). These model sys-tems involve the use of DNA in the form of partially hy-drated films, the reaction of DNA with one-electron oxi-dants, and the use of DNA in a highly associated form. Be-
cause the DNA damage is produced under well-defined
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conditions, a quantitative description of it can be made interms of rate constants, lifetimes, and cluster sizes. The re-sult will be an improved understanding of the mechanismsby which damage is introduced by energy deposition, is clus-tered and modified, leads to permanent products, and ulti-mately leads to biological and physiological endpoints.

Thesaurus Terms: DNA damage, DNA repair, nucleic acidstructure, radiation genetics, radiation sensitivity alpha ben-zopyrone, bacterial protein, endonuclease, free radical scav-enger, hydroxyl radical, iodine, ionizing radiation, poly-amine, temperature, virus DNA, virus genetics Xenopus oo-cyte, electron spin resonance spectroscopy, plasmid, simianvirus 40


Fiscal Year: 2005Department: RadiologyProject Start: 15-Dec-1988Project End: 30-Jun-2007ICD: National Cancer InstituteIRG: RAD

TUMOR UPTAKE OF GA-67 BYPHOTODEGRADED NIFEDIPINE

Grant Number: 7R01CA077574-08PI Name: Morton, Kathryn A.

Abstract: Description (Provided by Applicant): This pro-posal is the first competing renewal of a 3-year RO1 grant toimprove the uptake of gallium-67 for tumor imaging. Uptakeof Ga-67 by tumors has traditionally thought to be mediatedby transferrin (Tf) and Tf receptor-dependent mechanisms.We have found that uptake of Ga-67 by cells and tumors isalso mediated by a Tf-independent process, which appearsmore important in tumors than normal tissues. More signifi-cantly, we have shown that the Tf-independent uptake of GAin cells and tumors can be regulated. It can be specificallyinduced in tumors by administration of compound, which wehave named “nitrosipine,” which is produced when nifedi-pine, a commonly used dihyropyridine calcium channelblocker, is exposed to fluorescent or UV light. We have gen-erated evidence that nitrosipine may also enhance a varietyof other metal cations as well. This may expand the utility ofnitrosipine for gamma scintigraphy, PET imaging and radio-therapy. We propose to apply the knowledge gained duringthe last funding cycle to the following 6 specific aims: 1. Todefine the molecular features of nitrosipine that are necessaryfor promoting uptake of Ga-67. 2. To confirm and define thenature of the binding of nitrosipine (or other active deriva-tives) to metal cations. 3. To define the biological mecha-nism by which nitrosipine enhances the cellular Ga-67 up-
take. 4. To define the in vivo kinetics and optimal method


for dosing to maximize the visualization of tumors. 5. Totest how broadly effective nitrosipine, and similar active de-rivatives, are in promoting uptake of GA-67 in tumors of awide variety of histologic types in a murine tumor models.6. To explore the potential for nitrosipine or active deriva-tives, to enhance the uptake of Cu-64.

Thesaurus Terms: biological transport, gallium, methoddevelopment, neoplasm/cancer radionuclide diagnosis, nifedi-pine, photoactivation, radionuclide, radionuclide imaging/scanning calcium channel, chemical binding, chemical kinet-ics, copper, dosage, radiopharmacology, transferrin receptorCHO cell, bioimaging/biomedical imaging, fluorescencespectrometry, gas chromatography mass spectrometry, highperformance liquid chromatography, laboratory mouse, neo-plasm/cancer transplantation, nuclear magnetic resonancespectroscopy, tissue/cell culture, ultraviolet spectrometry

Institution: University Of UtahSalt Lake CITY, UT 84102

Fiscal Year: 2004Department: RadiologyProject Start: 12-Feb-1999Project End: 31-Jul-2006ICD: National Cancer InstituteIRG: ZRG1

COMBINED MR-DIFFUSE OPTICS FORFUNCTIONAL IMAGING

Grant Number: 1R21CA101139-01A1PI Name: Nalcioglu, Orhan

Abstract: Description (provided by applicant): MagneticResonance Imaging and Spectroscopy (MRI, MRS) can beused to obtain detailed physiologic and metabolic informa-tion regarding tumors. Diffuse Optical Spectroscopy and To-mography (DOS, DOT � SDOT) can provide unique andcomplementary information regarding tumor physiology andmetabolism. Simultaneous employment of both MR and opti-cal modalities may offer new insight that is unavailable byuse of either of these techniques alone. During the past twoyears, based on funding under an NCI Pre-ICMIC grant, wehave built a broadband frequency domain photon migrationprobe (FDPM) that is compatible with high magnetic fields,operates inside a 4 Tesla MR system, and provides simulta-neous optical/MR measurements in small animals. Beforesuch a system can be widely used in clinical cancer studies,we believe it is essential to validate our measurements anddevelop a detailed understanding of the factors that influenceMRI-optics co-registration. One of the limitations for under-taking such a study is the fact that nontomographic opticalmeasurement techniques have poor spatial localization that isdue to their broad point spread function and ambiguity in the
origin of the detected signals. Consequently, there is a great
need to understand the underlying relationship between opti-cal and MR signals. Once this relationship is clarified, thespatial localization of optical measurements can be improvedand functional information can be accurately assigned to dis-crete tumor tissue structures. The long-term goal of thisproject is to construct an MR-compatible optical spectro-scopic tomography system for improved spatial localizationof optical measurements and accurate opticaI-MRI co-regis-tration. Such a system can be scaled up for human studies ofcancer. During the R21 phase (Year 01) we will expand thecurrent single transmitter/receiver optical system to an MRcompatible multi-wavelength, multi-detector system and opti-mize its performance for SDOT. During this process, differ-ent geometries, detectors, data acquisition techniques, andimage inversion strategies will be explored. In the subse-quent R33 phase (Years 02-04) of the application, we willpursue the following aims: 1) design and construct a fullscale small animal MR-SDOT system, 2) using the con-structed system investigate the relationship between MRI/MRS and optical measurements to improve the spatial local-ization in SDOT, 3) employ the developed dual imaging sys-tem for combined dynamic contrast enhanced functionalimaging of tumors in animal models.

Thesaurus Terms: image processing, nuclear magnetic reso-nance spectroscopy, optical tomography, optics, spectrome-try, technology/technique development adenocarcinoma, bio-medical equipment development, breast neoplasm, data col-lection methodology/evaluation, magnetic resonance imaging,melanoma, neoplastic growth, phantom model, photonicsbioengineering/biomedical engineering, bioimaging/biomedi-cal imaging, laboratory mouse, laboratory rat

Institution: University Of California IrvineIrvine, CA 926977600

Fiscal Year: 2004Department: Radiological SciencesProject Start: 16-Apr-2004Project End: 31-Mar-2005ICD: National Cancer InstituteIRG: ZCA1

PROGNOSIS OF METASTATIC DISEASEIN EARLY BREAST CANCER

Grant Number: 5R01CA090437-05PI Name: Nalcioglu, Orhan

Abstract: Description (Provided by applicant): We proposeto investigate the angiogenesis status in stage I and II inva-sive ductal carcinoma (IDC) of the breast by immunohisto-chemistry (IHC) and magnetic resonance imaging (MRI).Angiogenesis is the formation of new blood vessels withintumors, which is essential for the growth and spread of can-
cer. Because angiogenesis is thought to be a very early event
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in cancer pathogenesis, a better characterization of its statusmay aid in appropriate management of disease by adminis-tering the most appropriate treatment protocol. Supportingevidence has indicated that the angiogenesis is associatedwith the aggressiveness of the primary cancer. The long-termgoal is to predict the risk of future relapse and metastasis.The angiogenic molecular markers, including mutant p53,thrombospondin-1 (TSP-1), CD31 (vascular marker) and CD-105 (neovascular marker) vessel density, and VEGF (Vascu-lar Endothelial Growth Factor), can be quantitatively mea-sured with IHC analysis. These markers have been shown tobe good prognostic indicators. However, since the study isperformed from a thin slide of a cancer, the inadequate sam-pling may result in values that are not representative of thewhole tumor. New vessel formation results in a higher vas-cularity and a leakier structure, which can be detected bydynamic contrast enhanced MRI. This technique has beenshown as a non-invasive means to measure the vascularcharacteristics in tumors. The enhancement kinetics can beanalyzed with pharmacokinetic models to derive the vascularvolume and vascular permeability parameters. The former isrelated to the blood flow supplied to the tumor, and the latteris related to the leakage status (or, maturity) of vessels,which are two important properties of a tumor. Therefore,MRI can be used to measure the vascularity from a thoroughsampling of the entire tumor, thus may provide supplemen-tary information to the IHC markers for the assessment ofangiogenesis more accurately. In this study we will applyIHC and dynamic MRI to characterize the angiogenic statusof early breast cancer (invasive ductal carcinoma, stage I andII). The patients with suspected malignant breast lesions willbe first studied with MRI. Then surgical biopsy will be per-formed, and the specimen will be sent for pathological ex-amination and IHC. The patients will be followed closely forlymphatic involvement and developments of recurrence andmetastasis. After the studies are completed, we will deter-mine the predictive value of MRI, IHC, and a combinationof MRI � IHC for their association with the initial lymphnode involvement. If a strong correlation can be established,the painful procedure of lymph node dissection may beaborted. The successful outcome of the current proposal shouldenhance the accuracy of the prognostic factors and reduce thetreatment-associated morbidity while also reducing the long-term mortality by selecting the “correct treatment.”

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, diagnosis design/evaluation, metastasis, prognosisCD antigen, angiogenesis, biomarker, lymph node neoplasm,mathematical model, neoplasm/cancer relapse/recurrence,noninvasive diagnosis, p53 gene/protein, pharmacokinetics,thrombospondin, vascular endothelial growth factor clinicalresearch, female, human subject, immunocytochemistry,magnetic resonance imaging, women’s health

Institution: University Of California Irvine
Irvine, CA 926977600
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Fiscal Year: 2005Department: Radiological SciencesProject Start: 01-Apr-2001Project End: 31-Mar-2006ICD: National Cancer InstituteIRG: ZRG1

TOOLS FOR IMPROVED RADIATIONTREATMENT USING MRSI

Grant Number: 5R21CA110171-02PI Name: Nelson, Sarah J.

Abstract: Description (provided by applicant) The objectiveof this study is to combine the efforts of MR scientists andradiation oncologists at the University of California at SanFrancisco (UCSF) with engineers at General Electric Medi-cal Systems (GEMS) in developing data acquisition, recon-struction and post-processing capabilities for integratingMagnetic Resonance Spectroscopic Imaging (MRSI) datainto radiation treatment planning for cancer patients. Themotivation for this translational research has come from re-cent improvements in radiation treatment delivery systemsthat are able to conform dose very precisely to irregularlyshaped 3-D targets. MRSI research studies at UCSF haveshown that the spatial extent of the metabolic abnormality isoften significantly different from the lesion observed withconventional MR imaging and that this is likely to have amajor impact upon target definition. As a result of the stud-ies at UCSF and supporting data from other institutions, theRadiation Therapy Oncology Group (RTOG) has proposed amulti-center clinical trial of the value of MRSI in targetinggliomas. A prerequisite for performing this study is thetranslation of the technology into robust tools that are avail-able on clinical MR scanners and that integrate MRSI intothe treatment planning process in a timely and efficient man-ner. This requires active participation from the manufacturerof the MR scanner. The scientists and clinicians at UCSFhave already demonstrated the ability to form a partnershipwith GEMS in developing MRSI packages. This experiencewill now be directed towards a developing a prototype pack-age for integrating MRSI into radiation treatment planning ofbrain tumors. Although this R21 project will focus on a sin-gle tumor site, the package will be constructed in a modularfashion so that the tools developed can be adapted to othertypes of tumors and used in conjunction with multiple imag-ing and treatment platforms.

Thesaurus Terms: automated data processing, computerassisted medical decision making, computer system design/evaluation, glioma, image guided surgery/therapy, neoplasm/cancer radiation therapy, neuroimaging, nuclear magneticresonance spectroscopy, patient care planning bioimaging/
biomedical imaging, clinical research, human subject


Institution: University Of California SanFrancisco

3333 California Street, Suite 315San Francisco, CA 941430962

Fiscal Year: 2005Department: RadiologyProject Start: 06-Aug-2004Project End: 31-Jul-2006ICD: National Cancer InstituteIRG: ZCA1

RESPONSE TO FRACTIONATEDRADIATION THERAPY BY MRSI

Grant Number: 5R01CA059880-10PI Name: Nelson, Sarah J.

Abstract: Description (provided by applicant): MagneticResonance Spectroscopic Imaging (MRSI) is an in vivo mo-lecular imaging technique that has been proposed for defin-ing tumor burden for patients with gliomas. The currentfunding cycle has demonstrated that MRSI is superior toconventional MR imaging for predicting outcome and fol-lowing response to Gamma Knife Radiosurgery (GK-RS) inrecurrent gliomas. The objective in the next funding cycle isto make this technology more generally applicable by inves-tigating the application of MRSI to the evaluation of frac-tionated radiation therapy. This treatment is used as a fol-low-up to surgical resection for almost all newly diagnosedmalignant gliomas. New approaches such as Intensity Modu-lated Radiation Therapy (IMRT) have made it possible totreat irregular 3-D volumes accurately and reproducibly in ahighly conformal manner. Critical factors for realizing thepotential of IMRT and for understanding its limitations arethe ability to determine whether treatment failure is due toinadequate targeting or to an intrinsic lack of sensitivity toradiation. This represents a complex problem in gliomas be-cause of the heterogeneity of the lesion and the spatial varia-tions in radiation dose to the tumor and surrounding braintissue. Specific Aim 1 will address the optimization of dataacquisition and reconstruction parameters. This will includethe investigation of the use of a 3T MR scanner rather thestandard 1.5T clinical system for obtaining the anatomic andmetabolic data. Specific Aim 2 will involve the developmentof algorithms for quantitative analysis of the MRSI data andcorrelation with serial MR images. The final Specific Aimwill apply the new technology to the serial evaluation of 60patients with malignant gliomas who are being treated atUCSF with fractionated radiation therapy. Using the MRSIdata to guide and evaluate such focal therapy is expected tohave a major impact upon treatment effectiveness and ulti-
mately upon patient outcome.
Thesaurus Terms: glioma, human therapy evaluation, imageprocessing, magnetic resonance imaging, neoplasm/cancerradiation therapy brain disorder chemotherapy, diagnosis de-sign/evaluation, lactate, lipid, neoplasm/cancer radiodiagno-sis, neoplasm/cancer surgery, radiation dosage, radiologybioimaging/biomedical imaging, biopsy, clinical research,computed axial tomography, human subject, patient orientedresearch



Fiscal Year: 2004Department: RadiologyProject Start: 15-May-1993Project End: 31-Jul-2008ICD: National Cancer InstituteIRG: RNM

HIGH RESOLUTION CONE BEAMVOLUME CT FOR BREAST IMAGING

Grant Number: 5R33CA094300-03PI Name: Ning, Ruola

Abstract: Description (provided by applicant): The longterm goal of this project is to develop a novel cone beamvolume computed tomography breast imaging (CBVCTBI)technique to provide clinically useful three-dimensional (3D)high resolution tomographic images for breast cancer detec-tion. CBVCTBI will require only a single fast volume scan-ning (4.8-9.6 seconds) to provide true 3D description ofbreast anatomy with 2.0-5.0 1p/mm isotropic resolution andwill provide adequate low contrast resolution and high con-trast spatial resolution for breast cancer detection.The clinicalsignificance of CBVCTBI is that it will improve the sensitiv-ity of breast cancer detection due to its much better low con-trast resolution, compared to conventional mammography.CBVCTBI with high resolution volume of interest (VOI)reconstruction mode for target imaging, will also better char-acterize breast tumors three-dimensionally; conventionalmammography does not provide 3D information of breastcancer. CBVCTBI will be developed and validated throughcomputer simulation, phantom and specimen studies per-formed on a specially designed DBVCTBI prototype systemthat uses a flat panel detector (FPD) and cone beam tomo-graphic acquisition geometry. This is an R21-R33 combinedproject. Specific aims of the R21project include: 1) Performphantom studies to determine the required total exposurelevel (absorbed patient dose) for breast cancer imaging task,2) Implement and optimize a fast cone beam reconstructionalgorithm on a dual processor PC workstation, 3) Perform a
comparison study of breast coverage near the chest wall be-
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tween a conventional mammography system and a slightlymodified standard stereotactic biopsy table (which will beused for the prototype CBVCTBI scanner) to provide evi-dence for appropriate coverage of the breast near the chestwall. 4) Obtain institutional review boar (IRB) approval toimage breast specimens in the R33 project period. Specificaims for the R33 project period include: 1) Estimate glandu-lar radiation dose for CBVCTBI technique, 2) Implementand optimize the cone beam reconstruction algorithms basedon the different new volume scan schemes, 3) Develop theFPD-based prototype system, 4) Evaluate the prototype sys-tem, 5) Perform phantom and specimen studies to validatethe CBVCTBI technique and optimize the system perfor-mance.

Thesaurus Terms: breast neoplasm/cancer diagnosis, com-puted axial tomography, technology/technique development,three dimensional imaging/topography early diagnosis, imageenhancement, mammography, phantom model, radiation dos-age X ray, bioimaging/biomedical imaging, clinical research,female, human subject, women’s health

Institution: University Of Rochester517 Hylan Bldg., Box 270140Rochester, NY 14627

Fiscal Year: 2005Department: RadiologyProject Start: 03-Jun-2003Project End: 31-May-2007ICD: National Cancer InstituteIRG: ZCA1

IMPROVING THE SOFTCOPY READINGOF MAMMOGRAMS USING CAD

Grant Number: 5R01CA102337-02PI Name: Nishikawa, Robert M.

Abstract: Description (provided by applicant): As in allother areas of radiology, mammography will become film-less. Full-field digital mammography (FFDM) is necessaryfor this to happen. There are additional advantages to wideclinical implementation of FFDM. Most important is the pos-sibility of improving the accuracy of mammography throughthe development of advance techniques such as tomosynthe-sis and computer-aided diagnosis (CAD). One of the majorroadblocks to FFDM is the reluctance of radiologists to em-ploy softcopy reading, principally because the current gener-ation of mammography workstations is cumbersome to use.We believe that softcopy will eventually allow radiologiststo become more efficient and thereby more productive. Thelong-term goal of our research is to improve the utility ofsoftcopy reading so as to facilitate the wide clinical use offull-field digital mammography. The goal of this project is to
show that by using a computer-aided detection scheme, radi-
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ologists do not have to zoom the image to search for micro-calcifications. Our hypothesis is that by employing CAD thatradiologists will take less time to read an image on softcopyand that this can be done without a decrease in performance.To test this hypothesis, we will compare two reading condi-tions: (1) zoom without computer aid, and (2) no zoomingwith aid available. The specific aims are: 1. Collect 365cases of mammograms: 275 normal, 70 with a malignantcluster of calcifications, and 20 with a malignant mass ordistortion or asymmetry. 2. Modify an existing high-resolu-tion workstation to mimic a clinical mammography worksta-tion. 3. Conduct an observer study to test hypothesis. Webelieve that FFDM and related technologies have the poten-tial to greatly improve the accuracy of mammography byreducing the miss rate and reducing the callback rate and thebenign biopsy rate. Improving the softcopy display is onestep to realizing this potential.

Thesaurus Terms: computer assisted diagnosis, digital im-aging, health care personnel performance, image processing,mammography, method development bioimaging/biomedicalimaging, cancer information system, clinical research, humandata

Institution: University Of Chicago5801 S Ellis AveChicago, IL 60637

Fiscal Year: 2004Department: RadiologyProject Start: 01-Jun-2003Project End: 31-May-2006ICD: National Cancer InstituteIRG: ZRG1

COMPUTERIZED LESION DETECTION INBREAST TOMOSYNTHESIS

Grant Number: 1R21CA109963-01PI Name: Nishikawa, Robert M.

Abstract: Description (provided by applicant): Breast tomo-synthesis is a promising new technique that produces a 3-di-mensional image set. Initial clinical results indicate that thetechnique can overcome the major problem with conven-tional mammography. A conventional mammography, be-cause it produces a 2-D image, suffers from the problem ofoverlapping tissue either obscuring a cancer (false negative)or mimicking a cancer (false positive). While the techniquedemonstrates much promise, it has not yet been properlyoptimized. Our long-term goal is to optimize fully breasttomosynthesis. As part of that optimization, we believe thatcomputer-aided diagnosis will play an important role inbreast tomosynthesis, because each patient will have up to80 images of each breast. Our goal for this proposal is to
develop computer-aided detection (CADe) schemes for


breast tomosynthesis. The specific aims are (1-3 are for R21and 4-7 for R33): 1. To develop a database of clinical breasttomosynthesis cases; 2. To develop CADe schemes (clus-tered calcifications and masses) using projection images; 3.To develop a comprehensive model of breast tomosynthesissystem to produce synthetic tomosynthesis images. 4. Tostudy the effect of image acquisition on the performance ofCADe schemes; 5. Use CADe results on projection imagesto improve reconstructed image set; 6. Develop CADeschemes using reconstructed image set; 7. Pilot observerstudy comparing tomosynthesis with and without CAD. Ifwe are successful, tomosynthesis will have greater clinicalutility and, therefore, acceptability. This should improve thedetection of breast cancer - improved sensitivity and speci-ficity - resulting in a reduction in breast cancer mortality andmorbidity.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, computer assisted diagnosis, diagnosis design/evaluation, diagnostic test, mammography computed axialtomography, digital imaging, image guided surgery/therapy,image processing, imaging/visualization/scanning, three di-mensional imaging/topography bioimaging/biomedical imag-ing, clinical research, human tissue

Institution: University Of Chicago5801 S Ellis AveChicago, IL 60637


23NAMRI OF BREAST CANCER

Grant Number: 5R21CA095907-02PI Name: Ouwerkerk, Ronald

Abstract: Description (provided by applicant): The aim ofthis project is to develop a multi nuclei Magnetic Resonance(MRI) Imaging breast examination with enough sensitivityand specificity for tumor grading, which would result in areduction of the need for needle biopsies. Current MRI tech-niques have good sensitivity, but the specificity is inadequateto allow an evaluation of tumor malignancy. This would im-prove if one of the parameters measured in the MRI examwere a tumor specific metabolic marker. An elevated [Na]ias a result of the altered changed Na exchange kinetics typi-cal of proliferating cells, is an excellent metabolic marker fortumor malignancy. With 23Na MRI the tissue sodium con-centration (TSC) can be quantified, but in breast lesions theTSC contains a large component from the extracellular vol-
ume fraction (EVF), masking intracellular changes that may
correlate with tumor malignancy. We propose to use a com-bination of 23Na MRI and dynamic contrast enhancement1H MR imaging (1H MRI) to improve the specificity of theMRI exam for evaluating tumor malignancy. This will beachieved through using the sensitivity of 23Na MRI for[Na]i in tumors together with the sensitivity of dynamic con-trast enhanced 1H MRI for the extracellular volume fraction(EVF). This is the first proposed method to extract informa-tion on [Na]i without sacrificing signal to noise ratio (SNR)or resolution, and this is accomplished by using an indepen-dent measurement of the EVF. Although washout kinetics ofGd contrast agent are particularly sensitive to EVF, high res-olution three dimensional coverage of the breast prohibitsaccurate determination of EVF. The time course of Gd con-trast enhancement also depends on microvascular permeabil-ity. Therefore dynamic contrast enhancement 1H MR dataand 23Na MRI measurement of TSC in tumors will be usedto create a single parameter combining the best features of23Na MRI and dynamic contrast enhancement studies. Byeffectively adding a measure for [Na]i, to state of the artdynamic contrast enhancement studies the specificity of tu-mor grading with MRI methods will be improved to a pointwhere the need for needle biopsies may be reduced.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, diagnosis design/evaluation, radionuclide, sodium,tumor progression diagnosis quality/standard, hydrogen ion,image enhancement clinical research, computer program/software, human subject, magnetic resonance imaging, statis-tics/biometry, women’s health

Institution: Johns Hopkins University3400 N Charles StBaltimore, MD 21218

Fiscal Year: 2004Department: RadiologyProject Start: 15-Sep-2003Project End: 31-Aug-2005ICD: National Cancer InstituteIRG: ZRG1

ADVANCED TECHNIQUES FOR CANCERIMAGING

Grant Number: 2T32CA009695-11PI Name: Pelc, Norbert J.

Abstract: Description (provided by applicant): This applica-tion is for the continuation of our training program Ad-vanced Techniques in Cancer Imaging. The goal of this pro-gram is to provide postdoctoral students and medical fellowswith rigorous training towards a career in cancer imagingand academic radiology. The need for such a program isdriven by the degree to which diagnostic imaging has be-
come technology-intensive and the rapid pace at which it has
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been evolving since the successful introduction of computer-ized tomography in the 1970’s. The program in Radiology atStanford is rooted in the close and unique juxtaposition ofimaging scientists, clinicians and educators and excellentresources across the School of Medicine, including RadiationOncology, Electrical Engineering, Molecular PharmacologyHealth Policy and Research, and the Program in Cancer Bi-ology. Since the program was originated in January 1993,we have successfully graduated 10 M.D. and Ph.D. trainees.They were extremely productive during their tenure in theprogram, and many continue academic activity in cancer im-aging today. The six current trainees are pursuing research inMR imaging of breast cancer adrenal masses, and MR fluo-roscopy, for example, and all are considered to be highlycompetitive for academic radiology appointments for FY 02and FY 03 when they complete the program. With outstand-ing faculty, superb facilities and instrumentation resources,and substantial grant support including a P41 center grant toserve as a national research resource in advanced MR tech-nology and a P20 Pre-ICMIC in molecular imaging and neo-plastic disease, we are committed to continuing this trainingprogram with a total of 12 new trainees, each with a trainingperiod of two years per trainee. The training program willcontinue to be directed by Dr. Gary Glazer, Professor andChairman of the Department of Radiology, and will beserved by fourteen outstanding preceptors and three distin-guished program advisors. As in the initial funding period,trainees will participate in courses in clinical cancer and im-aging sciences, biostatistics and medical ethics, in seminarsand conferences, and will be required to complete original,independent research. Trainees will be selected by the commit-tee of preceptors on the basis of a written application whichincludes transcripts, letters of reference, and a statement aboutcareer goals in cancer imaging and academic radiology. Everyeffort will be made to select men and women from diversebackgrounds who have exceptional potential for success.

Thesaurus Terms: There are no thesaurus terms on file forthis project.

Institution: Stanford University1215 Welch Road, Mod BStanford, CA 943055402

Fiscal Year: 2003Department: RadiologyProject Start: 01-Feb-1993Project End: 31-Jan-2008ICD: National Cancer InstituteIRG: NCI

MAMMOGRAPHIC DENSITY ANDINVASIVE BREAST CANCER

Grant Number: 5R01CA105007-02
PI Name: Pisano, Etta D.
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Abstract: Description (provided by applicant): Results fromthe recently published Women’s Health Initiative (WHI)clinical trial have unequivocally confirmed previous epidemi-ologic data, which suggested that, combined hormone ther-apy with estrogen and progestin (EPT) increases risk ofbreast cancer. Although the magnitude of the risk increase isrelatively modest, given the high prevalence of EPT use, theattributable number of cases affected is likely to be large.Because the overall risk increase is relatively modest, it islikely that some women are more susceptible to the carcino-genic effect of EPT than others. It would thus be useful tohave a clinical biomarker that could be used to identify thosehigh-risk EPT users. The ideal biomarker would be measur-able early enough in the course of EPT to allow cessationbefore elevated risk is expressed as frank disease. Mammo-graphic density (MD) change is a promising candidate forsuch a marker. Using the infrastructure for film digitizationand density measurement developed under a previous WHIancillary protocol, mammograms from all cases of invasivebreast cancer within the EPT arm of the WHI trial will becollected along with 3 controls from the same population,matched by treatment assignment (EPT or placebo), clinicalcenter, and ethnicity. Density changes over the initial base-line mammogram and the first follow-up mammogram afterrandomization for each participant will be measured. Mea-surements of MD and risk assessment will be made by fourexperienced human readers and an automated computer pro-gram. The primary aims of this project are to estimate therelative risk for breast cancer associated with a change inMD, to determine whether the increased breast cancer riskassociated with MD change is independent of baseline MD,to determine the proportion of breast cancer cases attribut-able to MD change among women assigned to EPT, and, todetermine whether post-EPT MD change explains the in-creased breast cancer risk associated with EPT within theentire study population. The secondary aims of this projectare to measure the difference in relative risk of breast cancerusing MD measurements made by four experienced observ-ers and to determine whether relative risk of breast cancerusing MD change assessed by an experimental automatedcomputer procedure is comparable to that estimated by fourexperienced assessors using established thresholding tech-niques.

Thesaurus Terms: breast neoplasm, cancer risk, density,hormone therapy, mammography, neoplasm/cancer invasive-ness biomarker, digital imaging, estrogen, hormone regula-tion/control mechanism, longitudinal human study, progestin,clinical research, female, human subject, women’s health

Institution: University Of North Carolina ChapelHill

Aob 104 Airport Drive Cb#1350Chapel Hill, NC 27599

Fiscal Year: 2005


Department: RadiologyProject Start: 12-Mar-2004Project End: 28-Feb-2007ICD: National Cancer InstituteIRG: ZRG1

SOC FOR MOLECULAR IMAGING 3RDANNUAL INTERNATIONAL MTG

Grant Number: 1R13CA112680-01PI Name: Piwnica-Worms, David R.

Abstract: Description (provided by applicant): The Societyfor Molecular Imaging Third Annual International Meetingwill be held from Sept 9 - Sept 12, 2004, in St. Louis. Themeeting is being organized by a group at Washington Uni-versity. The Organizing Committee is David Piwnica-Worms, Michael J. Welch and Joseph J.H. Ackerman. Thefield of in vivo cellular and molecular imaging is explodingwith new approaches that reveal aspects of biology in theliving body, including cancer, that were until recently inac-cessible to investigation. The rapidly evolving imaging tech-nologies to be described at the Third Annual Meeting of theSociety for Molecular Imaging are designed to reveal biolog-ical changes in vivo, and thus can be used to improve thestudy of biology and disease, accelerate the development ofnew therapeutic approaches and expand the use of thesetechnologies to a wide range of disciplines. The meeting en-vironment will be one where we discuss imaging broadly,and will include talks and discussion in areas of biology,chemistry, clinical imaging, genomics, technical advance-ments and industrial applications that address central issuesin the mapping of molecular functions in vivo through imag-ing. New insights into mammalian biology that have beenrealized through imaging will be a key focus of the meeting.The number of participants is expected to be approximately800 including invited speakers, discussion leaders, and par-ticipants. This proposal requests funds to provide partial sup-port for travel and subsistence expenses for invited partici-pants, minority faculty and young investigators from NorthAmerica and overseas.

Thesaurus Terms: imaging/visualization/scanning, meeting/conference/symposium, molecular biology bioimaging/bio-medical imaging, travel

Institution: Washington UniversityLindell and Skinker BlvdSt. Louis, MO 63130

Fiscal Year: 2004Department: RadiologyProject Start: 01-Sep-2004Project End: 31-Aug-2005ICD: National Cancer Institute
IRG: ZCA1
Grant Number: 5P50CA094056-03PI Name: Piwnica-Worms, David R.

Abstract: Description (provided by applicant): WashingtonUniversity Medical School’s concept of an In Vivo Cellularand Molecular Imaging Center (ICMIC) envisions a processthat will permit the Center to become the focal point for thedevelopment of novel in vivo molecular imaging initiativeson campus. This involves further expanding and reinforcingcollaborations and enhancing the productivity of multidisci-plinary programs in basic cancer cell biology and molecularimaging research. The ultimate objective of the proposedP50 Program is to combine the institutional expertise ofWashington University in the basic sciences of molecularoncology, immunology, molecular genetics and signal trans-duction with our well developed infrastructure in medicalimaging under the formal configuration of an ICMIC. Weare strategically positioned to focus the majority of our IC-MIC resources on the advancement of novel interactive andcollaborative oncologic molecular imaging projects. To meetthese goals, an organizational structure with three molecularimaging cores, four multidisciplinary ICMIC researchprojects, four developmental research projects, an educa-tional program and a training/career development programare proposed. The four projects, representing innovative andexciting new initiatives on campus are: 1) In Vivo Imagingof Gene Expression in Prostate Cancer, 2) Non-InvasiveMonitoring of T Cell-Mediated Tumor Ablation, 3) ImagingCancer Viruses with Tat Transducible Peptides, 4) ImagingMDRI P-glycoprotein Transport Activity In Vivo withTc-94m-Sestamibi PET to Predict Response to Chemo-therapy in Extensive Stage Small Cell Lung Cancer. Anorganizational structure for an ICMIC has been estab-lished and all milestones achieved with our active P20planning grant. The P50 Center grant will now promoteexcellence in molecular imaging in cancer research byproviding a formal conduit for interdisciplinary multi-mo-dality collaborations.

Thesaurus Terms: human therapy evaluation, magnetic res-onance imaging, neoplasm/cancer chemotherapy, positronemission tomography, prognosis, bioimaging/biomedical im-aging, clinical research, human subject


Fiscal Year: 2004Department: RadiologyProject Start: 31-May-2002Project End: 31-Mar-2007ICD: National Cancer Institute
IRG: ZCA1
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INTERDISCIPLINARY SMALL ANIMALIMAGING FOR ONCOLOGY

Grant Number: 5R24CA092871-05PI Name: Pomper, Martin G.

Abstract: The goal of this application is to expand our inter-disciplinary small animal imaging program to include comple-mentary imaging capabilities that will increase our understand-ing of cancer. MR-based functional and metabolic imaging isthe backbone of our current effort, which has been formalizedinto the Johns Hopkins pre-ICMIC. We now intend to balancethat effort with a program that incorporates a strong nuclearimaging component. We intend to obtain a dedicated small ani-mal PET device and undertake the development of a biplanex-ray/gamma scintigraphy system that will enable us to study awider array of physiologic processes. We are also initiating acollaboration to enhance our optical imaging potential. We in-tend to focus on three broad areas relevant to the diagnosis andtreatment of cancer: new technology development, includingdrug development, in-depth analysis of the tumor microenviron-ment, and quantification of gene expression, primarily in cellsand tissues expressing the malignant phenotype. We will pursuethese aims by coordinating efforts in 3 core resource facilities:(I) technology development, (II) molecular biology and (III)chemistry, all of which will support the central imaging core. Aquantitative subcore will also support the imaging core. Amongthe 12 base grants are one center grant (the pre-ICMIC) and 3program project grants, all of which address important questionsin cancer biology and/or therapy and will be greatly enhancedby an imaging component. The combined expertise of JohnsHopkins University (JHU), the University of Virginia and theNIH will create an SAIRP with strong molecular imaging capa-bilities accessible to researchers in the Mid-Atlantic region.

Thesaurus Terms: Animalia, imaging/visualization/scanninginterdisciplinary collaboration, technology/technique develop-ment bioimaging/biomedical imaging

Institution: Johns Hopkins University3400 N Charles StBaltimore, MD 21218

Fiscal Year: 2005Department: RadiologyProject Start: 27-Aug-2001Project End: 31-Dec-2006ICD: National Cancer InstituteIRG: ZCA1

MR SPECTROSCROPY AND IMAGING INHEAD AND NECK TUMORS

Grant Number: 5R01CA102756-02
PI Name: Poptani, Harish
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Abstract: Description (provided by applicant): More than55,000 Americans will develop cancer of the head andneck (HN) this year accounting for nearly 3% of all can-cers in the United States. These cancers are more commonin men and in people over age 50. More than 85% ofthese cancers are related to tobacco and alcohol consump-tion. Despite aggressive surgery and radiotherapy (RT),which may result in significant functional loss, the sur-vival rate of patients with head and neck cancer has re-mained relatively unchanged over the past three decades.The predictive indices based on tumor morphology orclinical characteristics are generally less accurate in defin-ing outcome of response. Hence, there is an urgent needfor a reliable predictor of early response in these tumors.Magnetic resonance spectroscopy (MRS) and imaging(MRI) can non-invasively identify specific metabolic pat-terns and tissue physiology that may be used as markersfor predicting and monitoring early treatment response.Preliminary studies on 41 cases of non-Hodgkins Lym-phomas and 12 cases of HN tumors indicate that 31pMRS can predict response prior to initiation of therapy.1H MRS and MRI provides higher sensitivity and spatialresolution than 31p MRS and would thus facilitate study-ing smaller tumors and investigating heterogeneous tumorresponse. The overall goal for this proposal is to test thehypothesis that NMR spectroscopy and imaging can pre-dict and monitor early response to treatment of head andneck tumors. This hypothesis will be tested with the fol-lowing specific aims: Aim 1: To evaluate the utility of thePME/13 NTP ratio in predicting and detecting treatmentresponse by 31p MRS, Aim 2: To determine if total cho-line (Cho) and lactate (Lac) levels can predict and moni-tor treatment response and Aim 3: To use physiologicalMRI parameters (T2, ADC and DCE) as predictors/moni-tors of local tumor response to chemotherapy and radia-tion therapy of HN tumors. 31p MRS studies will be per-formed using proton decoupled and NOE enhanced 3DCSI sequence. 1H MRS studies will be performed by im-plementing a selective multi-quantum coherence transferpulse sequence (Sel-MQC), for detection of lactate (Lac)and total choline (TCho) on the clinical scanner. StandardMRI pulse sequences for implementing dynamic contrastenhanced (DCE), diffusion weighted imaging (DWI) andT2 weighted imaging (T2WI) imaging will be streamlinedso that a complete examination consisting of 31p MRS or1H MRS combined with DCE, DWI and T2WI can beimplemented on human HN patients within one hour.

Thesaurus Terms: head/neck neoplasm, human therapyevaluation, magnetic resonance imaging, neoplasm/cancerdiagnosis, noninvasive diagnosis, nuclear magnetic resonancespectroscopy, prognosis choline, image enhancement, lactate,neoplasm/cancer chemotherapy, neoplastic process, outcomesresearch bioimaging/biomedical imaging, clinical research,
human subject, patient oriented research


Institution: University Of Pennsylvania3451 Walnut StreetPhiladelphia, PA 19104

Fiscal Year: 2005Department: RadiologyProject Start: 01-Jun-2004Project End: 31-May-2008ICD: National Cancer InstituteIRG: RNM

MULTIDISCIPLINARY RESEARCHTRAINING IN CANCER IMAGING

Grant Number: 5R25CA092043-03PI Name: Price, Ronald R.

Abstract: Description (provided by applicant): This applica-tion proposes to establish a unique training program in can-cer imaging research. The program is designed to train bothmedical post-doctoral candidates with extensive experienceIn medical imaging, oncology or cancer biology, and basic-science post-doctoral candidates with extensive experience inimaging technology or cancer biology who desire to becomeindependent investigators. Trainees will utilize the wide vari-ety of imaging resources available through the Departmentsof Radiology at Vanderbilt University Medical Center andMeharry Medical College, The Vanderbilt In-Vive ImagingCenter and The Vanderbilt/Keck Free Electron Laser Facil-ity. Individual trainee research projects will be Integratedwith ongoing projects in the cancer laboratories of theVanderbilt/Meharry Alliance with special emphasis on theprojects of The Vanderbilt-lngram Cancer Center and theConsortium for Mouse Models of Human Cancer. Eachtrainee will be assigned two or more mentors representingboth the imaging sciences and cancer biology disciplines.The specialized curriculum provided by this training programwill establish two new courses, a new cancer imaging semi-nar and a new cancer imaging Journal club. The curriculumis also supplemented through existing courses offered by thecooperating departments: Biomedical Engineering, ElectricalEngineering/Computer Sciences, Cell/Cancer Biology, Math-ematics, Physics, Biochemistry and Clinical Investigation.The program leadership will consist of three co-directorsreflecting the multidisciplinary nature of the training pro-gram. Ronald R. Price, Ph.D. will coordinate the specializedcurriculum components specific to training in the imagingsciences. Lynn Matrisian, Ph.D. will coordinate the curricu-lum components specific to training in the biological sci-ences. Charles DePriest, M.D. will direct minority recruit-ment and will coordinate training components specific topost-doctoral physician scientists with prior experience inmedical imaging. The training program is designed to pro-vide a two or three year (dependent upon trainee back-
ground) intensive research experience using imaging meth-
ods and technology which when successfully completed, willprepare individuals to become active participants in a multi-disciplinary team of cancer researchers.

Thesaurus Terms: diagnosis design/evaluation, educationevaluation/planning, imaging/visualization/scanning, neo-plasm/cancer diagnosis, neoplasm/cancer education career,curriculum, postgraduate education, training Animalia, bio-imaging/biomedical imaging, clinical research, human sub-ject

Institution: Vanderbilt University3319 West End Ave.Nashville, TN 372036869

Fiscal Year: 2003Department: Radiology & Radiological ScisProject Start: 16-Jul-2001Project End: 30-Jun-2006ICD: National Cancer InstituteIRG: NCI

A POSITRON EMISSION MAMMOGRAPHY/TOMOGRAPHY BIOPSY DEVICE

Grant Number: 5R01CA094196-03PI Name: Raylman, Raymond R.

Abstract: Description (provided by applicant): Detection ofcancer in the dense breast is a significant challenge for x-raymammography. Similarities between the density of lesionsand surrounding breast tissue, in addition to x-ray opacity,limit effective detection of small to medium sized tumors inthese patients. To address this concern, nuclear medicine-based imaging techniques, such as positron emission tomog-raphy (PET) used with 18F-Fluorodeoxyglucose (FDG), havebeen applied with some success to breast imaging. Thesemethods rely upon differences in metabolic activity betweentumor and normal tissue, instead of density contrasts for cre-ating images. Although these techniques have demonstratedsome potential in detecting breast lesions in dense breasts,their limited spatial resolution and specificity does not war-rant their sole use for making diagnoses. The most effectivemethod for diagnosis remains histological evaluation of tis-sue samples acquired from biopsy. In many cases stereotacticcore biopsy of suspicious lesions guided by x-ray mammog-raphy is an effective and minimally-invasive method for per-forming these procedures. In the case of lesions optimallydetected in a dense breast with PET, however, x-ray tech-niques may not be optimal for biopsy guidance. In responseto this need, we propose the construction of a device thatwill be capable of acquiring high resolution images of thebreast using PET techniques. These images will then be usedto assess radiotracer uptake and guide the placement of abiopsy needle into suspicious lesions. Image-based verifica-
tion of needle positioning will be accomplished by acquiring
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a set of stereotactic planar, positron emission mammography(PEM) images. This dual modality system called, PEM-PET,will be capable of performing three main tasks: lesion detec-tion, radiotracer quantitation and lesion localization. The ap-paratus will consist of two sets of rotating, large-area planarpixelated scintillator arrays. The use of rotating planar detec-tors was adopted (instead of the more intuitive ring geome-try) to facilitate access to the breast during biopsy proce-dures, while permitting acquisition of PEM and PET images.The choices of scintillator material (Lutetium Oxyorthosili-cate) and detector pixel size were based on computer simula-tion studies and model observer studies. Development of thesystem will include the construction of the detector units,and the creation of tomopraphic and planar image recon-struction methods. The PEM-PET system will be optimizedand evaluated with task-dependent metrics obtained frommodel and human observer studies, and a pre-clincal trial. Atthe completion of this project an apparatus for the effectivedetection and diagnosis of lesions for use in the subgroup ofwomen with difficult to image breasts will have been devel-oped and evaluated.

Thesaurus Terms: biopsy, breast neoplasm, diagnosis de-sign/evaluation, mammography, positron emission tomogra-phy, technology/technique development diagnosis quality/standard, mathematics, radiotracer bioimaging/biomedicalimaging, clinical research, human subject, stereotaxic tech-nique

Institution: West Virginia UniversityP. O. Box 6845Morgantown, WV 265066845

Fiscal Year: 2005Department: RadiologyProject Start: 01-Sep-2003Project End: 31-Aug-2007ICD: National Cancer InstituteIRG: DMG

BRAIN TUMOR THERAPEUTIC EFFICACYBY QUANTITATIVE MR

Grant Number: 5P01CA085878-04PI Name: Ross, Brian D.

Abstract: Description (provided by applicant): Among thecauses of death due to cancer, brain tumors are ranked sec-ond in the pediatric age group and fourth in middle-agedman and malignant gliomas are uniformly fatal with only 50percent of patients surviving one year from initial diagnosis.These stark statistics underscore the urgent need for im-proved therapies along with capabilities that would providefor early therapeutic assessment of efficacy in these patients.A sensitive and early predictor of therapeutic outcome for
patients would provide for improved care and the opportu-
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nity to individualize and adjust the treatment to each patient.The central hypothesis of this project is that the effectivenessof therapeutic interventions can be determined prior to tumorshrinkage using quantitative MR diffusion, perfusion and 1Hspectroscopic methods. Both animal and human brain tumorswill be evaluated using MR following therapeutic interven-tion including chemotherapy, radiation, gene, nanoparticlesand antiangiogenic therapies. This research program will pro-vide new mechanistic insights into: The use of MRI/S forthe early detection of brain tumor response to therapy andthe effects of neovascularization on therapy (Project 1); Thesensitivity and resolution of MRI/S for the detection of ther-apeutic transgene delivery, function and therapeutic efficacyin brain tumors (Project 2); The capability of using Nano-Platforms for the delivery of image contrast agents and po-tentially therapeutic drugs to brain tumors (Project 3); andThe predictiveness of MRI for the early assessment of hu-man brain tumor response to therapy (Project 4). This re-search plan is an outgrowth of the progress made with previ-ous NCI support. Four interactive projects and four cores areproposed. The Administrative Core A provides administra-tive support along with internal and external review for allprojects. The Animal MR Imaging Core B provides the nec-essary MRI/S services for Projects 1-3. The Digital ImageProcessing Core C provides a centralized and high-through-put capability for the digital post processing of all acquiredMR data for all projects (Projects 1-4). The BiostatisticalCore D provides statistical support to all projects.

Thesaurus Terms: brain neoplasm, magnetic resonance im-aging, neoplasm/cancer therapy


Fiscal Year: 2004Department: RadiologyProject Start: 05-Sep-2001Project End: 31-Aug-2006ICD: National Cancer InstituteIRG: NCI

MICHIGAN SMALL ANIMAL IMAGINGRESOURCE (MSAIR)

Grant Number: 5R24CA083099-07PI Name: Ross, Brian D.

Abstract: Description (provided by applicant): The establish-ment of the Michigan Small Animal Imaging Resource(MSAIR) four years ago at the University of Michigan hasproved extremely successful. During this time, the MSAIR fa-cility has doubled in overall space and is scheduled to double insize again with a concurrent move to the new Biomedical Sci-ence Research Building which will be the focal point of the
University of Michigan Medical School. This is part of an ex-


panding Life Sciences Initiative within Michigan which empha-sizes collaborative, intellectual innovation and multidisciplinaryresearch. This facility will also house a state-of-the-art vivariumthat has been planned to be integrated together with theMSAIR. Furthermore, the number and types of imaging modali-ties available for users has dramatically increased during theinitial funding of the MSAIR. This includes the addition of ahorizontal bore 9.4 tesla MRI system with microgradient coils,addition of two in vivo bioluminescent imaging systems, addi-tion of two microPET systems available for imaging of rodentsand monkeys, addition of a fluorescent imaging system andfinally, inclusion of a MicroCT system. The number of cancerinvestigators who have utilized the MSAIR during the initialfunding period has also seen remarkable growth (5-fold), thusmaking an important impact in cancer research. The objectivesof this current proposal are to: 1) Acquire a combinedSPECT/CT device capable of scanning both mice and rats. 2)Recruit a radiochemist to the MSAIR for synthesis of customPET/SPECT probes. The addition of a radiochemist dedicatedto assisting MSAIR users with labeled probes for both PET andSPECT will fulfill a need expressed by many investigators. 3)Provide Core services in molecular biology for the productionof custom recombinant protein probes and recombinant celllines. 4) Initiate a training laboratory and lecture workshop fortraining investigators in the use of imaging technologies forcancer research. The overall focus of this proposal is to providea shared resource and the tools which allow cancer researchersto incorporate state-of-the-art imaging technologies into theirindividual research interests. Moreover, the MSAIR has becomea central, diverse and dynamic resource facility wherein ex-change of techniques and ideas can occur, which fosters pro-ductive interdisciplinary collaborations in cancer research.

Thesaurus Terms: Rodentia, bioimaging/biomedical imag-ing, biomedical equipment resource, biomedical resource,neoplasm/cancer computed axial tomography, magnetic reso-nance imaging, molecular biology, molecular probe, positronemission tomography, single photon emission computed to-mography, training


Fiscal Year: 2005Department: RadiologyProject Start: 01-Sep-1999Project End: 31-Aug-2009ICD: National Cancer InstituteIRG: ZCA1

ROLE OF HER4 AS DIFFERENTIATIONFACTOR IN BREAST CANCER

Grant Number: 5K08CA083753-05
PI Name: Sartor, Carolyn I.
Abstract: Description (Applicant’s Description): Candidate:The proposed research plan will explore the function ofHER4 as a potential differentiation factor in human breastcancer. The training that Dr. Sartor will receive under thedirect supervision of Dr. H. Shelton Earp during the awardperiod will significantly enhance her development in basicscience methodology critical to the success of an indepen-dent investigator. Dr. Sartor’s long-term career goals are tobecome an academic radiation oncologist who can combinemultidisciplinary breast cancer patient care with a study ofthe biology of human breast cancer. Her ultimate goal is todetermine the significance of the epidermal growth factorreceptor family of receptors in human breast cancer withregard to prognosis, treatment response, recurrence, and todevelop new therapeutic strategies that target EGFR familymembers. Funding of the requested award would ensure theprotected time away from clinical responsibilities necessaryto ensure further lab training in molecular oncogenesis re-search. Environment: Support from this proposal comes fromthe UNC Lineberger Comprehensive Cancer Center and theDepartrnent of Radiation Oncology. Dr. Sartor is providedspace in Dr. Earp’s laboratory as well as use of the core fa-cilities of the Cancer Center and the UNC Breast CancerSPORE. Support will include equipment, reagents, and con-sumables for the project. Funding of this proposal will en-sure that 75 percent of the candidate’s time will be devotedto the proposed research. Research: Our preliminary studies,as well as those of others, demonstrate that ligands that acti-vate HER4 can cause differentiation and decrease prolifera-tion of human breast cancer cells. However, HER4 has notbeen proven to have a direct and causal role in differentia-tion. Therefore, we propose a series of experiments usingstably expressed HER4, EGFR:HER4 chimera and dominantnegative HER4 mutants to determine whether activation ofHER4 causes differentiation. We will define the contest inwhich HER4 is involved in a differentiation signal, payingparticular attention to partnership with other EGFR familymembers, studied under the influence of EFG family memberligands which activate HER4. We will then explore thedownstream signal transduction pathways of HER4 involvedin differentiation. These avenues of investigation of HER4will help us to understand more about the complex and criti-cally important EGFR family members in breast cancer, andmay lead to the discovery of HER4 as an important prognos-tic factor and potential target for novel therapeutics.

Thesaurus Terms: biological signal transduction, breastneoplasm, epidermal growth factor, growth factor receptor,oncoprotein chimeric protein, enzyme activity, heregulin,ligand, mitogen activated protein kinase, mutant, phosphati-dylinositol 3 kinase, protein tyrosine kinase, tumor suppres-sor protein immunoprecipitation, tissue/cell culture

Institution: University Of North Carolina Chapel HillAob 104 Airport Drive Cb#1350
Chapel Hill, NC 27599
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Fiscal Year: 2005Department: RadiologyProject Start: 21-Jun-2001Project End: 31-May-2006ICD: National Cancer InstituteIRG: NCI

MRI CONTRAST AGENT METHODS OFASSESS TUMOR ANGIOGENESIS

Grant Number: 5R01CA082500-05PI Name: Schmainda, Kathleen M.

Abstract: Description (provided by applicant): Patients withbrain tumors are in desperate need of new therapies, such asthose that inhibit new vessel formation (angiogenesis). Re-cent clinical testing of angiogenesis inhibitors has accentu-ated the need for non-invasive measures of tumor vascula-ture. Therefore, the long-term goal of this first-time competi-tive renewal application is to develop MRI contrast agentmethods that efficiently evaluate the clinical potential of an-ti-angiogenic therapies. The general hypothesis is that MRcontrast-agent methods will provide relevant markers of tu-mor angiogenesis if the biophysical relationships underlyingthese methods are well characterized. Excellent progress hasbeen made in this regard, especially considering that the ini-tial 5 year proposal was awarded 3 years of funding. Simula-tions and experiments, made in a rat brain tumor model, us-ing contrast-agent T1 methods demonstrate that an accuratemeasurement of tissue blood volume fraction depends pro-foundly on the choice of imaging sequence and parameters.Studies to characterize the susceptibility-based blood volumemeasurements have shown that the susceptibility calibrationfactor is different for tumor and normal brain tissue, a newfinding that may be due to the differences in vascular geom-etry. Treatment of the rat 9L gliosarcoma with the steroiddexamethasone demonstrated a vessel-size selective effect,which may parallel the balance of angiogenic factors. Usinga novel GE(gradient-echo)/SE(spin-echo) imaging methodwe demonstrated that dynamic susceptibility contrast (DSC)measures of total and microvascular rCBV (relative cerebralblood volume), along with vessel size information could beobtained from patients with brain tumors. Total rCBV andvessel diameter information ware found to be statisticallydifferent between low and high-grade tumors. Discerning thisdifference depends on the proper consideration of contrastagent extravasation effects. The specific aims are logical andexciting extensions of the initial aims. We will continue todevelop and validate the susceptibility contrast methods formeasuring blood volume and vessel diameter with i. the de-velopment of a novel tumor-specific simulation model and ii.MRI and histology measurements made in a rat 9L gliosar-coma model (Aim 1). The usefulness of these methods to
track changes with therapy will be evaluated (Aim 2). Tu-
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mor-appropriate methods to measure cerebral blood flow(CBF) will be developed and validated (Aim 3). The opti-mized CBV, CBF methods will be applied to brain tumorpatients and correlated with relevant immunohistochemicalmarkers (Aim 4). Significance: Completion of these studiesshould move us closer to the ultimate goal of dramaticallyimproving the diagnosis and management of patients withvascular tumors such as gliomas. Novelty: A key uniquecomponent of the proposed studies is the characterization ofthe biophysical relationships underlying the proposed meth-ods. This will not only aid in assessing the accuracy of thetechniques, but will also help us to exploit the wealth of in-formation that can be derived from such measurements.

Thesaurus Terms: angiogenesis, contrast media, glioma,magnetic resonance imaging, method development, neo-plasm/cancer blood supply blood vessel, blood volume, cere-brovascular imaging/visualization, gadolinium, medical com-plication, morphology, noninvasive diagnosis, vascular endo-thelial growth factor bioimaging/biomedical imaging, clinicalresearch, computer simulation, human subject, immunocyto-chemistry, laboratory rat, statistics/biometry

Institution: Medical College Of WisconsinPo Box 26509Milwaukee, WI 532260509

Fiscal Year: 2004Department: RadiologyProject Start: 01-Mar-2000Project End: 31-Mar-2007ICD: National Cancer InstituteIRG: RNM

EVALUATION OF MULTI MODALITYBREAST IMAGING

Grant Number: 5P01CA085424-04PI Name: Schnall, Mitchell D.

Abstract: More than 175,000 American women are diag-nosed with breast cancer each year and approximately50,000 of these women will die of their disease. The bestchance for a cure of this disease is early detection of breastcancer tumors. X-ray mammography has so far been shownto be an important component of any breast cancer screeningprogram., play a critical role in the detection, diagnosis andlocal staging of breast cancer tumors. X-ray mammographyhas so far been shown to be an important component of anybreast cancer screening program., playing a critical role inthe detection, diagnosis and local staging of breast cancer.Over the past 15 years there has been an explosion of medi-cal imaging technology, resulting in a variety of possibleimaging resources for research and clinical uses. In the lastseveral years, there have been intense efforts to apply vari-
ous imaging modalities to improve the detection, diagnosis


and local staging of breast cancer. The major goal of thisproject is to develop an understanding of the relative perfor-mance of the of the new generation of breast imaging mo-dalities. The results obtained from this program will be usedto guide appropriate clinical implementation of advancedbreast imaging technology and will provide the critical datanecessary to plan proper phase 3 trials to establish clear clin-ical roles of this technology. In order to accomplish thisgoal, 3 interrelated clinical trials will be performed, eachtargeted at a particular clinical implementation of breast im-aging: lesion characterization, local cancer staging, andscreening. Each of these trials will employ state-of-the-arttechnology in FFDM, MRI, PET, ultrasound, and opticalimaging. They will each employ a clinically- relevant patientpopulation. In addition to these 3 clinical projects evaluatingthe performance of the different modalities to perform thedifferent clinical implementations, a fourth project willmodel the cost and outcome of these models. These will thenbe utilized to develop cost-effective strategies for clinicalapplications of multi-modality breast imaging.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, diagnosis design/evaluation, imaging/visualization/scanning bioimaging/biomedical imaging


Fiscal Year: 2004Department: RadiologyProject Start: 17-Sep-2001Project End: 31-Aug-2006ICD: National Cancer InstituteIRG: NCI

DOPPLER VASCULARITY/SONOGRAPHY–BREAST CANCER DIAGNOSIS

Grant Number: 5R01CA087526-04PI Name: Sehgal, Chandra M.

Abstract: Our previous studies suggest that gray-scale ultra-sound and Doppler imaging complement one another. Whilegray-scale imaging can characterize masses with high speci-ficity, Doppler imaging has high sensitivity. This applicationproposes an innovative integration of the two modes suchthat both high sensitivity and specificity can be achieved. Anintense 5-year multidisciplinary program encompassing threespecific goals is proposed. In Aim 1 color-Doppler, power-Doppler and gray- scale images will be acquired from 300patients with suspicious breast masses. All modes of imagingwill be conducted on the same patients and on the same day.The issues related to optimal imaging will be emphasized bycareful control of experimental conditions. Among other
things, this will include regular image calibration and moni-
toring of progesterone levels in the patients to account forvariations in blood flow during the normal menstrual cycleas well as for variations due to hormonal therapy. In Aim 2we introduce new approaches for deriving quantitative fea-tures from Doppler and gray-scale images. The emphasiswill be on quantifying features that physicians use in evalu-ating images. In Aim 3 these features will be supplementedwith qualitative assessments to develop a multifactorialmodel for a comprehensive diagnosis of breast lesions.Novel approaches based on advanced nonlinear methods,including neural networks, will be developed to formulate adecision tree for cancer diagnosis. Each strategy will beevaluated by ROC analysis. This approach will provide ob-jective measures to demonstrate the importance of sono-graphic and Doppler features and how they can be used opti-mally to accurately diagnose breast cancers. Taken together,this program takes advantage of unique breadth of clinicalexperience and basic sciences at the University of Pennsyl-vania. An integrated approach in which one mode representstissue property and the other its function will result in a sys-tematic and comprehensive diagnosis of breast cancers.

Thesaurus Terms: breast neoplasm, breast neoplasm/cancerdiagnosis, computer assisted diagnosis, diagnosis design/evaluation, ultrasound blood flow measurement, neoplasm/cancer blood supply, noninvasive diagnosis, phantom model,progesterone, bioimaging/biomedical imaging, clinical re-search, female, human subject, women’s health


Fiscal Year: 2004Department: RadiologyProject Start: 01-Mar-2001Project End: 28-Feb-2006ICD: National Cancer InstituteIRG: RNM

TRANSDUCIBLE MOLECULAR PROBESFOR IMAGING TUMORS

Grant Number: 1K08CA102158-01PI Name: Sirlin, Claude B.

Abstract: Description (provided by applicant): Candidate:Dr. Claude Sirlin, M.D., is an assistant professor in radi-ology with a strong background in clinical imaging andimaging research. His long-term career goal is to becomea clinical scientist and independent investigator develop-ing novel imaging probes to improve the non-invasivedetection and characterization of human tumors. His im-mediate objective is to pursue an intense period of scien-tific training and development in molecular biology and
small animal imaging. He has designed a phased career
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development plan that emphasizes hands-on research butalso incorporates course work and other structured didac-tic learning activities. Environment: The rich and interdis-ciplinary environment at the University of California, SanDiego is ideal for the candidate’s short- and long-termsuccess. Dr. Sirlin will be mentored by Dr. StevenDowdy, Ph.D., an accomplished molecular biologist andHoward Hughes investigator who has developed a focusedinterest in using protein transduction to develop novelmolecular probes for tumor therapy. Dr. Sirlin will adaptthis technology for imaging. The candidate will also bementored by Dr. Robert Mattrey, M.D., a successful clini-cal imaging scientist with expertise in contrast media andsmall animal imaging who is the principal investigator ona P20 grant aimed at developing an In Vivo Cellular andMolecular Imaging Center at UCSD. Through both of hismentors, Dr. Sirlin will also have the opportunity to formnumerous contacts and long-term collaborations with otheroutstanding investigators in the UCSD School of Medicineand affiliated institutes. UCSD has all the necessary re-search and imaging resources for Dr. Sirlin to accomplishhis goals. Research: Imaging cellular and molecular pro-cesses is the new horizon for diagnostic imaging. Dr. Sir-lin will focus on protein transduction as a powerful solu-tion to drug delivery limitations for many intracellulartargeting paradigms. He will construct molecular probesconsisting of one or more protein transduction domainsfor intracellular delivery, targeting domains to trap theprobes in the cells of interest, and three different imagingreporters to permit PET, scintigraphic, and MR imagingof tumors in live mice. Agents will be tested and opti-mized in vitro and then tested in vivo. Dr. Sirlin’s pro-posed research integrates different aspects of molecularbiology, reporter probe design, synthetic chemistry, ani-mal tumor models, and multimodality small animal imag-ing and therefore provides a good fit with his training ob-jectives and serves as logical mechanism for his careerdevelopment.

Thesaurus Terms: genetic transduction, imaging/visualiza-tion/scanning, intracellular transport, nucleic acid probe, pro-tein localization, technology/technique development, argi-nine, autoradiography, chimeric protein, hypoxia, misonida-zole, nuclear magnetic resonance spectroscopy, positronemission tomography, reporter gene bioimaging/biomedicalimaging, laboratory mouse


IRG: NCI
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HR-MAS-PATHOLOGIC CORRELATION OFPROSTATE TISSUE MARKERS

Grant Number: 5K01CA096618-03PI Name: Swanson, Mark G.

Abstract: Description (provided by applicant): This pro-posed research career award builds on the principal investi-gator’s work as an NIH fellow involving the use of magneticresonance spectroscopy for the improved characterization ofprostate cancer. Prostate cancer is a disease that afflicts onein five American men; however, it is difficult to predictthose cancers that will spread (metastasize) and become lifethreatening from those that will remain indolent. CombinedMagnetic Resonance Imaging and Spectroscopic Imaging(MRI/3D-MRSI) has demonstrated the ability to: improvethe localization of prostate cancer within the gland; assessthe extracapsular spread of the disease; and provide a mea-sure of therapeutic response. As an NIH postdoctoral fellow,the principal investigator used MRI/3D-MRSI to study themetabolic effects of hormone ablation therapy in prostatecancer patients, and developed high resolution magic anglespinning (HR-MAS) techniques for the analysis of ex vivoprostate cancer tissues. The goal of this study is to bettercharacterize the metabolic changes observed in vivo byMRSI and ex vivo by HR-MAS by improving their correla-tion with the underlying biochemical, morphologic, and ge-netic changes associated with the disease. To achieve thesegoals, we will use multidimensional HR-MAS techniques toidentify new metabolic markers which can be exploited invivo, and diffusion based experiments to learn more aboutthe intracellular vs. extracellular distribution of prostate me-tabolites. Further, we will combine our HR-MAS findingswith improved pathologic analysis to more accurately corre-late specific metabolic profiles with prostate tissue type. Im-munohistochemical assays will be performed to correlatemetabolic profiles with other markers for cellular prolifera-tion and apoptosis. We will also investigate the impact ofzinc changes on citrate metabolism by assaying zinc levelsin prostate tissues by atomic absorption spectrophotometryand zinc transporter gene expression using real-time reverse-transcriptase polymerase chain reaction analysis. These meth-ods will then be used to learn more about changes in citratemetabolism under hormone dependent and independent con-ditions, using the transgenic adenocarcinoma of the mouseprostate (TRAMP) model. The completion of the specificaims of this study will provide the principal investigator withthe additional tools needed to develop his own independentcancer imaging research program. UCSF is a leading prostatecancer research center, with an NCI-designated comprehen-sive cancer center and prostate SPORE program. This excel-lent research environment combined with the extensive re-search experience of the mentor will greatly facilitate the
completion of the goals set out in this proposal.


Thesaurus Terms: biomarker, metabolism, nuclear magneticresonance spectroscopy, pathologic process, prostate neo-plasm, urinary tract imaging/visualization adenocarcinoma,androgen, apoptosis, cell proliferation, citrate, disease/disor-der model, gene expression, hormone related neoplasm/can-cer, neoplasm/cancer classification/staging, zinc atomic ab-sorption spectrometry, bioimaging/biomedical imaging, clini-cal research, genetically modified animal, histopathology,human subject, immunocytochemistry, laboratory mouse,male, patient oriented research



Fiscal Year: 2004Department: RadiologyProject Start: 01-Aug-2002Project End: 31-Jul-2007ICD: National Cancer InstituteIRG: NCI

A NOVEL DEVICE TO ALLOW ZOOM-INIMAGING FOR PET SCANNERS

Grant Number: 4R33CA110011-02PI Name: Tai, Yuan-Chuan

Abstract: Description (provided by applicant): Positronemission tomography (PET) has been widely accepted forclinical imaging for oncologic, cardiac and neurological ap-plications. The current trend of design favors high-efficiencymedian-resolution scanners to minimize the scan time forwhole body imaging protocols. The smallest object detect-able and the quantitative accuracy of PET imaging are di-rectly related to the scanner resolution. The emerging field ofmolecular imaging to study disease models, pharmacokinet-ics of new drugs, and gene expression using small laboratoryanimals via in vivo imaging has shown promising results.The techniques and models developed from laboratory ani-mal studies will soon require clinical trials to provide valida-tion and further development for human applications. Thesuccess of such translation relies on high-resolution humanPET systems to advance the molecular imaging research toclinical applications. The goal of this project is to developthe technology required to provide high-resolution PET im-ages of the organs of interest at a fraction of the cost of adedicated high-resolution PET scanner. The proposed designis a detector insert that can be attached to a whole-body PETscanner to provide high-resolution images within a smallerfield of view, a concept similar to the use of surface coils inMRI to improve its image resolution. Since the device isdesigned as an accessory detector, its cost is significantly
lower than a complete system. The image resolution within
the regions of interest can be as low as 3 mm FWHM orsmaller, depending on the design of the detectors, the dimen-sion of the insert, and the original system resolution. Thesensitivity of such a device may be more than twofold of astand-alone high resolution system using the same detectors.The R21 phase of this project provides feasibility study ofthe design, while the R33 phase is to implement a prototypedevice for an existing PET scanner. The specific aims of theR21 phase are (1) develop APD-based high-resolution PETdetector, (2) validate the image resolution and sensitivity ofthe proposed device via simulation and experiment, and (3)evaluate the effect of scatter from the device and develop arejection technique. The specific aims of the R33 phase are:(1) Construct the device, (2) integrate the device to an exist-ing PET scanner, (3) develop image reconstruction algo-rithms for the special geometry, and (4) test the device andevaluate its performance. The immediate applications of theprototype device include high-resolution imaging for headand neck tumors and lymph nodes, brain tumors, and brainfunctions. The design earl be extended to develop specialinserts to image cancers involving breasts, lungs, and pros-tate. The outcome of this project will make a significant ad-vancement in high resolution human PET imaging for bothclinical and research applications.

Thesaurus Terms: biomedical equipment development, clin-ical biomedical equipment, computed axial tomography, im-age enhancement, positron emission tomography, computersimulation, electromagnetic radiation, evaluation/testing, lightscattering, method development, whole body imaging/scan-ning bioimaging/biomedical imaging, clinical research, hu-man subject, patient oriented research


Fiscal Year: 2005Department: RadiologyProject Start: 01-Sep-2004Project End: 30-Jun-2008ICD: National Cancer InstituteIRG: ZCA1

SPORE IN GASTROINTESTINAL CANCER

Grant Number: 1P50CA106991-01PI Name: Tepper, Joel E.

Abstract: Description (provided by applicant): UNC GICancer SPORE’s unique goals emphasize multidisciplinarytranslational research that spans and links the population,clinical, and basic sciences. To decrease the burden of colo-rectal cancer on the patient population at large we will: (1)determine the clinical importance of new and existing targets
on the colorectal cancer population (2) define the relation-
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ship of these molecular abnormalities to racial disparities (3)evaluate how best to manipulate these molecular targets fortherapy, and (4) verify the target manipulation and effect ina group of colorectal cancer patients. To decrease colorectalcancer mortality a better understanding of the relationship oflaboratory discoveries in signaling, oncogenesis and othermolecular changes to the clinical setting is needed. We havedeveloped projects that will allow us to accomplish thesegoals through the strong multi-disciplinary collaboration thatalready exists between clinical, laboratory and population-based scientists in the UNC Lineberger Comprehensive Can-cer Center. The UNC GI Cancer SPORE’s five projects andtheir translational objectives are: Project 1: Prognostic andPredictive Factors in Outcomes of Patients with ColorectalCancer: A Population-Based Study. Determine which patient,treatment and molecular characteristics of colon cancer pa-tients and their tumors will be predictive of prognosis, re-sponse to therapy and survival. Project 2: Molecular Changesin the NF-KappaB Pathway in Response to ChemoradiationTherapy in Rectal Cancer. Define in a clinical trial the NF-KappaB-related molecular responses of tumors and normaltissue during treatment compared to pre-treatment, the corre-lation of these responses with clinical outcome and the abil-ity of proteasome inhibitors to modify this response to ther-apy. Using a variety of experimental models, determine ifmore specific approaches to NFkappaB inhibition will im-prove current regimens of colorectal cancer therapy. Project3: Investigation of ERBB signaling in Colorectal Cancersduring Liver Metastasis. To characterize, using patients withliver metastasis of colorectal cancer as a model, ERBB re-ceptor activation, downstream signaling patterns and alter-ations in mRNA expression profiles of patients treated with asmall molecule, dual kinase inhibitor in order to identifymarkers of response to ERBB directed therapy, to definereasons for treatment failure, and to correlate patient re-sponses with the mouse model results. Project 4: Targetingthe RAS�ERK Pathway for Colorectal Cancer Treatment.Determine whether a prospective group of patients withcolorectal carcinomas that harbor mutated Ras show geneexpression profiles that will predict their sensitivity to anti-Ras and anti-Raf or anti-MEK therapeutic strategies and todefine the mechanisms for response or resistance. Project 5:Determination of the Role of Fucosyltransferases in Colorec-tal Cancer Initiation and Progression. To identify mutationsand differential expression of human fucosyltransferases as-sociated with the development of colorectal carcinoma, de-termine their potential interactions with NSAID use, apopto-sis, diet and other genotypes, using samples from population-based databases. Core Resources in Administration,Genomics, Biostatistics and Bioinformatics, and Tissue Pro-curement and Analysis will enhance the specialized researchof the SPORE. Career and Developmental Research Pro-grams are also included.

Thesaurus Terms: biomarker, colorectal neoplasm, gastroin-
testinal neoplasm, gene expression, neoplasm/cancer epide-
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miology, neoplasm/cancer genetics, neoplasm/cancer therapyclinical research

Institution: University Of North Carolina ChapelHill

AOB 104 Airport Drive Cb#1350Chapel Hill, NC 27599


A HIGH PERFORMANCE PET AND CTTOMOGRAPH

Grant Number: 5R33CA094317-04PI Name: Townsend, David W.

Abstract: Description (provided by applicant): To addressthe difficulties encountered by fusion software in retrospec-tively co-registering anatomical and functional images forregions of the body other than the brain, we have recentlytaken a more hardware-oriented approach by directly fusingthe technologies of CT and PET. This combined PET/CTprototype has demonstrated in over 250 cancer patient stud-ies the important advantages of routinely performing co-reg-istered anatomical and functional imaging. The studies withthe prototype have stimulated commercial development ofcombined PET/CT scanners and at least two designs thatcomprise a clinical CT scanner placed in tandem with a clin-ical PET scanner are now available. While currently avail-able PET technology has demonstrated broad applicability indiagnostic cancer imaging, limitations in spatial and temporalresolution have restricted its utility in cancer research. Theselimitations have also affected the sensitivity of clinical appli-cations of PET. To date, the major success of PET in oncol-ogy has been its ability to identify tumors with relativelyhigh levels of [18F]fluoro-deoxyglucose (18FDG) uptakecompared to normal tissues. However, an increasing numberof specific PET applications are emerging that require imag-ing capabilities beyond the current technology. There is agrowing demand from both the research and clinical arena toimprove PET scanner sensitivity and to identify and accu-rately localize lower levels of abnormal tracer uptake in in-creasingly smaller structures. Therefore, we are proposing toaddress these demands by designing and building a high per-formance PET scanner with integrated CT technology usingthe new scintillator lutetium oxy-orthosilicate (LSO). ThePET detectors are based on a novel large area panel designthat will extend axial coverage and achieve count rate per-formance significantly exceeding that of current PET scan-
ners. Four detector panels arranged in a hexagonal configura-


tion will allow space for a closer integration of the CT com-ponents than has previously been possible with both theinitial prototype and the commercial designs. A novel featureof this device is that the CT components will also use LSOas the detector material and cover a larger axial and transax-ial field-of-view than current CT scanners. Thus, by achiev-ing a closer integration of PET and CT, an extended axialfield-of-view and significantly improved imaging perfor-mance, this novel combined PET/CT scanner will open upnew areas for the imaging and treatment of cancer.

Thesaurus Terms: biomedical equipment development,computed axial tomography, neoplasm/cancer diagnosis,positron emission tomography computer program/software,digital imaging, image enhancement, noninvasive diagnosis,whole body imaging/scanning bioimaging/biomedical imag-ing, clinical research, human subject, patient oriented re-search

Institution: University Of Tennessee KnoxvilleKnoxville, TN 379961529


FUNCTIONAL AND MOLECULAR MRI OFMOUSE BRAIN TUMORS

Grant Number: 5R21CA099131-02PI Name: Turnbull, Daniel H.

Abstract: Description (provided by applicant): Primary braintumors are among the most aggressive and fatal human neo-plasms, often affecting children and younger adults. Theavailability of transgenic and gene targeting methods, andthe large number of spontaneous and induced mutant mousestrains, have led to the increased use of the mouse as a keyanimal model system to study cancer. In the past severalyears, the use of mouse genetics has led to significantprogress in understanding the genetic pathways and molecu-lar events involved in the formation and progression of bothmedulloblastoma and glioma, the most common pediatricand adult brain tumors, respectively. In order to realize thefull potential of these genetically engineered mouse models,it is imperative to develop in vivo microscopic imaging ap-proaches, allowing longitudinal analysis of tumor progressionand response to novel therapeutic agents. Angiogenesis isthought to be a critical prerequisite for tumor progression,and brain tumor malignancy is intimately related to angio-genesis and vascular density, especially in gliomas. Thebroad goals of this project are to develop both functional and
molecular magnetic resonance micro-imaging (mu MRI) ap-
proaches to detect and quantify angiogenesis in mouse braintumors. We have recently used in utero retrovirus injectionto induce medulloblastomas in the postnatal mouse cerebel-lum. We propose to use a similar retrovirus injection, a mea-sure of angiogenesis to induce gliomas, and will also investi-gate a transgenic mouse glioma model. We are developingcontrast-enhanced perfusion mu MRI techniques to measurecerebral blood volume (CBV) approach in normal mousebrain and brain tumors. A direct, in vivo molecular targetingapproach will also be developed to assess angiogenesis. Wewill generate transgenic mice that overexpress cell surfacereceptors in neovascular endothelial cells, and image thebrains of these mice after intravenous injection of a super-paramagnetic MRI contrast agent-tagged ligand. Brain tu-mors will be induced in these transgenic mice and imagedwith mu MRI to quantify vascular density in the developingbrain tumors. The functional and molecular mu MRI ap-proaches will be developed during an exploratory, feasibilityphase (R21) and later used in careful studies of tumor pro-gression and response to anti-angiogenic therapies in a de-velopment phase (R33). The new technologies developedunder this project are of critical importance for understand-ing angiogenesis and brain tumor progression, and will revo-lutionize tumor biology in genetically accurate mouse mod-els of cancer.

Thesaurus Terms: angiogenesis, brain imaging/visualiza-tion/scanning, brain neoplasm, diagnosis design/evaluation,magnetic resonance imaging, neoplasm/cancer diagnosis, tu-mor progression Retroviridae, brain circulation, disease/dis-order model, glioma, longitudinal animal study, medulloblas-toma, neoplasm/cancer blood supply, receptor expression,transferrin receptor, viral carcinogenesis bioimaging/biomedi-cal imaging, genetically modified animal, laboratory mouse

Institution: New York University School OfMedicine

550 1st AveNew York, NY 10016

Fiscal Year: 2004Department: RadiologyProject Start: 01-May-2003Project End: 30-Apr-2006ICD: National Cancer InstituteIRG: ZCA1

ASTATINE 211 & RADIOIODINE LABELEDOCTREOTIDE CONJUGATES

Grant Number: 5R01CA091927-04PI Name: Zalutsky, Michael R.

Abstract: Description (Provided by Applicant): Somatostatinreceptors, particularly the somatostatin receptor subtype 2
(sst2), are found on many tumor types. Ii this proposal, we
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shall focus on the development of radiohalogenated oct-reotide conjugates and related peptides as radiodiagnosticsand therapeutics for medulloblastoma. Recent studies havedemonstrated that the concentratior of sst2 on human medul-loblastoma is extremely high, even higher than on neuroen-docrine tumors. Medulloblastoma is the most frequent centralnervous system tumor in children with dismal outcome.There is no effective treatment for this disease, making thedevelopment of more specific and selective diagnostics anctherapeutics for medulloblastoma of high clinical signifi-cance. Finally, medulloblastoma appears to be an idea clini-cal setting for exploiting the radiobiological advantages ofa-particles such as those emitted by 211At Ou hypothesis isthat octreotide conjugates and labeling methods for thesepeptides which maximize the trapping of the radiohalogenwithin the tumor cell will enhance tumor retention and tu-mor-to-normal organ ratios, thereby improving their clinicalpotential as diagnostic and therapeutic agents. Our specificaims are: 1) To synthesizL he2’ ’At-labeled octreotide ana-logues [N-(3-[211 At]astatobenzoyl)-D-phe1]octreotide and5[211 ’At]astato-nicotinoylD-phe1]octreotide and comparetheir properties to the corresponding iodo analogues; 2) Tolabel glycate octreotide and octreotate conjugates with radio-iodine nuclides and 211At; peptide conjugates of glucose,maltose and maltotriose will be investigated; 3) To adapttwo strategies originally developed for labeling intemalizini
antibodies - D-amino acid linkers and acylation agents bear-
e182

ing polar substituents - for labeling octreotide analogue with211At and radioiodine nuclides; 4) To evaluate the potentialutility of promising 211 octreotide conjugates in comparisonwith their radioiodinated analogues as diagnostic and thera-peutic radiopharmaceuticals. The proposed in vitro studiesinclude characterization of binding, internalization and catab-olism; the proposed in vivo studies include evaluation oftissue distribution, dosimetry, catabolism as well as therapeu-tic efficacy.

Thesaurus Terms: chemical conjugate, halogen, medullo-blastoma, neoplasm/cancer radionuclide therapy, nonhumantherapy evaluation, octreotide diagnosis design/evaluation,drug metabolism, drug receptor, glucose, iodine, maltose,neoplasm/cancer radionuclide diagnosis, pharmacokinetics,radionuclide, radiopharmacology, radiotracer, receptor bind-ing, triose athymic mouse, autoradiography, chemical synthe-sis, laboratory rat

Institution: Duke UniversityDurham, NC 27710

IRG: ZRG1

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Pet imaging of breast cancer via sigma-2 receptors

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