Lung Cancer Research:From Prevention to Cure!

Ravi Salgia, M.D, Ph.D Ravi Salgia, M.D, Ph.D

Associate Professor of MedicineAssociate Professor of MedicineDirector, Thoracic Oncology Research ProgramDirector, Thoracic Oncology Research Program

Department of MedicineDepartment of MedicineSection of Hematology/OncologySection of Hematology/Oncology

University of Chicago Cancer Research CenterUniversity of Chicago Cancer Research Center

University of ChicagoUniversity of ChicagoPritzker School of MedicinePritzker School of Medicine

Introduction Lung cancer is one of the most common

cancer worldwide. There will be >170,000 diagnosed cases

of lung cancer in 2006. There will be >160,000 deaths from lung

cancer in 2006. About 75-80% of lung cancers are

associated with smoking However, over 50% have stopped

smoking. AND over 15-20% NEVERsmoked.

Lung Cancer: More ResearchNeeded Every three minutes someone is

diagnosed with lung cancer Men have a lifetime risk of 1 in 13 and

women 1 in 17 In 2003, the federal government spent

$14,045/breast cancer death,$10,761/prostate cancer death,$1,632/lung cancer death

Diagnosis of Lung Cancer

Signs and SymptomsCough (especially with blood), fevers, weight

loss, facial swelling, pain, etc. Scans

CXRAYCTPET

TestsBloodBronchoscopiesBiopsies

Next Generation Scanners CanSee a Pinhead-Size Spot

Prototypes capableof 1mm resolution

Scanning within abreath

Look deep insidethe lung

Kiessling et al, Nature Med online, 9/7/2004

Image Courtesy of Dianna Cody, MDAH

How Do You Study Lung Cancer?

Microscopy Cellular biology Genetics Proteomics

Lung Cancer—Anatomy

Silverberg, 3rd ed

Lung Cancer- Histology

SCLC

ADENOCARCINOMA SQUAMOUS CELL CARCINOMA

LARGE CELL CARCINOMA BAC

NSCLC

Normal Cells

Cancer Cells

EGFR

MET

ErbB-2

Tyrosine kinase domain

Tyrosine kinase domain

SEMA Tyrosine kinase domainJMPSI domain

Mutations in the EGFR, erbB-2 and MET Gene in Lung Cancer

L861QL858R

R776CdelL747-T751insS

delS752-I759

delL747-P753insS

L755Pins774(AYVM)

ins779(VGS)

delE746-A750

S1058P*R988C

G719C

*T1010I

*IVS 13-(52-53)insCT

del 141bp2942-3082

*E168DN375S

S323GL229F

Laser Microdissection-AssistedSequencing

Before During After

EGFR Expressing AdenocarcinomaNSCLC

EGFR

EGFR Mutations in LCM-Tumor Cells (Hilar LN)

Lumbar Puncture: CSF

CSF

NSCLC

Leukocyte

EGFR Mutations in LCM-Tumor Cells(CSF)

Tumor Tissue Microarray

University of Chicago TMA

Biological Targets for CancerTherapy

Tumor Cell

4. Proteasome, Heat Shock Proteins

1

2

345

6

1. Growth factors andgrowth-factor receptorsHER family, c-Met, VEGF/R, c-kit/SCFR

2. Signal-transduction pathwaysRas, raf, MAPK, MEK, ERK,protein kinase C, PI3K

3. Tumor-associatedantigens/markersGangliosides, CEA, MAGE,CD20, CD226. Extracellular matrix/

angiogenic pathwaysMMPs, VEGF, integrins

5. Cell-survival pathwaysCyclin-dependent kinases,mTOR, cGMP, COX-2, p53, Bcl-2

Therapy for Lung Cancer

Surgery Radiation Therapy Chemotherapy Novel Targeted Therapies

Breakthroughs inthe Treatment ofLung Cancer

Adjuvant Therapy for LungCancer Adjuvant therapy – treatment (e.g.

chemotherapy) after surgery to eradicatemicroscopic residual cancer and preventcancer recurrence

5 Large Studies have shown that AdjuvantChemotherapy can increase cure rate inlung cancer

Drugs Recently Approved for AdvancedNon-Small Cell Lung Cancer

Gefitinib (Iressa) – May 2003 (withdrawnJuly 2005)

Pemetrexed (ALIMTA) – February 2004

Erlotinib (Tarceva) – November 2004

Bevacizumab (Avastin) – October 2006

Pemetrexed

Chemotherapy approved for mesotheliomaand lung cancer

Given IV, usually with platinum Does not cause hair loss Vitamin B12 and folic acid need to be

taken with it.

Erlotinib

Oral EGFR tyrosine kinase inhibitors Have activity in non-small-cell lung cancer (~10-

15% of tumors will shrink; ~30-40% will bestable)

Tarceva improves survival in patients withmetastatic disease that have failed first-linechemotherapy

Occasional dramatic and durable tumorresponses are seen

Tarceva

Targets a receptorfound in lung cancer

Taken by mouth Less side effects (no

hair loss or nausea) Rash and diarrhea

seen

How Does Tarceva Work?

Tumor Shrinkage with Tarceva:

Normal and Tumor VasculatureTumor Blood VesselsNormal Blood Vessels

Reduced integrinexpression1

Less dependent on cellsurvival factors2

Maturation factors present(eg, Ang-1)1

.... ..... Less permeable3

.... .....

Supporting cellspresent2

Growth and survivalfactors (eg, VEGF, bFGF)

present2

........................

.... ..... .... .....

........................

.... .....

........................

........................

........................

Leaky3

Preferentialexpression ofαvβ3, αvβ5,and α5β1integrins1

Fewer supportingcells2

1. Griffioen and Molema. Pharmacol Rev. 2000;52:237.2. Blau and Banfi. Nat Med. 2001;7:532.3. Jain. Nat Med. 2001;7:987.

– monoclonal antibody - small molecule– binds VEGF (ligand) - inhibits VEGFR2

(receptor), c-Raf, etc.- intravenous QOW - oral twice daily-bleeding, arterial thrombi, - skin toxicities, alopecia,proteinuria diarrhea

BEVACIZUMAB SORAFENIB

Future for Lung Cancer—withEffective Research

In the future, we will have routine: Scans Blood tests Bronchoscopy/Sputum tests Family screens

In the future, we will have better: Prevention Diagnosis Ability Surgery Radiation Therapy Chemotherapy (Including Novel Therapies)

“If you wantto changethe world,be thatchange.”

--Mahatma Gandhi