Recent Developments in Oncology

CASSIDY CANCER CENTERCompassion, Innovation, Trust

Recent Developments in Oncology

Robert H. Cassell, M.D., Ph.D.Medical Director, Cassidy Cancer Center

Clinical Assistant Professor, Dept. of Medicine,University of Florida College of Medicine


Recent Developments in Oncology

There have been many new and exciting developments in cancer

• New diagnostic modalities• New ways to predict the outcome and prognosis

of various cancers• New treatment advances

– New surgical techniques– New ways of delivering radiation therapy– New chemotherapy drugs– New supportive therapies


Recent Developments in Oncology – My Favorite

Use of new knowledge in science, including genetics and molecular biology, and the new fields of genomics and proteomics, to develop “rational” therapies to treat cancer


“CANCER” “CRAB”


How Do You Treat…

Crabgrass --

Cancer --

Cut It or Tear it Out

Surgery


How Do You Treat…

Crabgrass --

Cancer --

Cut It or Tear it Out

Surgery


How Do You Treat…

Crabgrass --

Cancer --

Burn It

Radiation Therapy


How Do You Treat…

Crabgrass --

Cancer --

Burn It

Radiation Therapy


How Do You Treat…

Crabgrass --

Cancer --

Poison It

Chemotherapy


How Do You Treat…

Crabgrass --

Cancer --

Poison It

Chemotherapy


What If…

• You could understand what makes crab grass crab grass, so that you could do something specific to kill only the crab grass

OR• You could change the crab grass, so it behaved

and looked like normal grass***********

I don't think we can do this with crab grass but we are starting to be able to do this sort of thing with cancer


Terminology

• The current buzzword in medicine is "personalized medicine."

• This means treating each patient as a separate individual based on their characteristics and the characteristics of their disease(s).

• In oncology, we generally use the term “targeted therapy” or, more precisely, “molecularly targeted therapy.”


What Makes Cancer Cells Cancerous?

• 1) Increased response to growth signals and production of their own growth signals

• 2) Insensitivity to anti-growth signals• 3) Evasion of apoptosis – failure to die at the

right time

Apoptosis(Programmed Cell Death)





right time• 4) Limitless replication potential – keep dividing

indefinitely• 5) Sustained angiogenesis (new blood vessels)

Angiogenesis(New Blood Vessel Growth)





right time• 4) Limitless replication potential – keep dividing

indefinitely• 5) Sustained angiogenesis (new blood vessels)• 6) Tissue invasion and metastasis



Other characteristics of cancer cells:• Stem cell or progenitor cell phenotype – they

start out looking like normal (or benign) cells but at a primitive stage of development

• Increased mutation rate• Evasion of, or resistance to, normal immune

responses

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100(1):57–70.


“Targeted” Cancer Treatment

How does it work? Attack targets which are specific for the cancer

cell and are critical for its survival or for its malignant behavior

Why is it better than chemotherapy?More specific for cancer cells –

chemotherapy hits rapidly growing cellsnot all cancer cells grow that rapidlysome normal cells grow rapidly

Possibly more effective

Cancer Targets

From National Cancer Institute, US National Institutes of Health.

Cancer Targets


Cancer Targets



Targets

• The targets currently being used are those that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.

• The focus is on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, how a cell responds to specific external stimuli, and even cell death.

• We use the term “signal transduction” to refer to the actions of these proteins.

TK TKATP ATP

Cell Cell ProliferatioProliferationn

AntiapoptAntiapoptosisosis

AngiogenesAngiogenesisis

Gene Transcription

Cell Cycle Progression

+

MetastaseMetastasess

SurvivSurvivalal

Tumor Cell StimulationTumor Cell Stimulation


Targeted Therapy

• The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone estrogen, which many breast cancers require for growth. When estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation.


Therapy Targeted at the Estrogen Receptor

• Selective estrogen receptor modulators (SERMs)– tamoxifen (Nolvadex)– toremifene (Fareston)

• Estrogen receptor inhibitor and destroyer– fulvestrant (Faslodex)

• Estrogen synthesis inhibitors – aromatase inhibitors (AIs)– anastrozole (Arimidex)– letrozole (Femara)– Exemestane (Aromasin)

TK TK TK

Strategies to Inhibit Signaling

-- -- --

tyrosine tyrosine kinase kinase

inhibitorinhibitorss

““-ibs”-ibs”

Anti- mAbsAnti- mAbs““-mab”-mab”

Anti-ligand Anti-ligand mAbsmAbs

““-mab”-mab”

ATP

Philadelphia Chromosome

Philadelphia Chromosome

(BCR-ABL Translocation)

BCR-ABL Translocation

RASBRAF

MEK

ERK

Oncogenes

CRAF

PI3K

AKT

mTor

PTEN

CDK4CDK2

p16

Cyclin D

c-met

RASBRAF

MEK

ERK

Targeted inhibitors in development

PI3K

AKT

mTor

PTEN

CDK4CDK2

p16

Cyclin D

PD0325901

AZD6244

Sorafenib

RAF-265

PLX4032

R115777

SCH66336

PD332991 CYC202

temsirolimus everolimus

AP23573

GSK690693VQD-002

BMS-387032

SF1126 XL147

XL880c-met

Signal Pathways in the Cancer CellSignal Pathways in the Cancer Cell


The “Nibs”

Small molecule tyrosine kinase inhibitors (or TKIs) – generic names end in “-nib”

Generally oralSide effects vary, depending on which enzymes

they inhibit (what their target is)Eight are FDA-approved, numerous others are in

developmentSeveral are effective against cancers resistant to

most previous therapies

FDA-Approved TKIs

Generic Name Brand Name Cancer

Imatinib Gleevec CML, GIST, others

Dasatinib Sprycel CML, ALL

Nilotinib Tasigna CML

Gefitinib Iressa Lung

Erlotinib Tarceva Lung, Pancreas

Lapatinib Tykerb Breast

Sorafenib Nexavar Kidney, Liver

Sunitinib Sutent Kidney


Monoclonal Antibodies

Another type of targeted therapy – they are large molecules produced through genetic engineering

They usually have to be given IVSide effects can include reactions to non-human

proteinsThey can cause cell damage in several ways, most

often by attacking cell-surface receptors

VEGF PDGF HGF

NRPsEph

TGFβ bFGF Ang

Endothelial cell & Pericyte

BRAF

MEK

ERK

RASPI3K

AKT

mTor

Tumor


Trastuzumab

• Monoclonal antibody against epidermal growth factor receptor 2 (EGFR2, HER-2)

• Very effective against breast cancers in which HER-2 is “over-expressed” (more than usual amount per cell) (about 20% of all breast cancers)

• Often used in combination with chemotherapy


Cetuximab

• Monoclonal antibody against epidermal growth factor receptor 1 (EGFR1)

• Effective in colon cancer and head and neck cancer; possibly useful in lung cancer

• Used with chemotherapy and with radiation therapy


Bevacizumab

• Monoclonal antibody against vascular endothelial growth factor (VEGF), which stimulates angiogenesis (growth of new blood vessels into tumor)

• Deprives tumors of the blood supply they need for growth and invasion

• Effective against cancers of colon, lung, breast, kidney, and brain



FDA-Approved “Naked” (Non-Conjugated) MoAbs

Generic Name Brand Name Target Cancer(s)

Alemtuzumab Campath CD52 CLL

Bevacizumab Avastin VEGF Multiple

Cetuximab Erbitux EGFR1 Colon, H&N

Panitumumab Vectibix EGFR1 Colon

Rituximab Rituxan CD20 Lymphomas

Trastuzumab Herceptin HER-2 Breast



• Conjugated antibodies currently approved– Radio-conjugated antibodies

• Tositumomab (Bexxar)• Ibritumomab (Zevalin)• Both used against refractory lymphomas

– Toxin-conjugated antibody• Gemtuzumab ozogamicin (Mylotarg)• Used against AML


Monoclonal Antibodies In Development

• Epratuzumab • Matuzumab• Nimotuzumab• Zalutumumab• Pertuzumab• Mapatumumab• Lexatumumab• Volociximab• Pemtumomab• Labetuzumab

• ch806• CP-751,871• IMC-A12• VEGF-Trap• IMC-18F1• IMC-1121B• IMC-3G3• Vitaxin• CNTO 95


Types of MoAbs

Structure % Human Example Comments

Mouse 0 Tositumomab, Ibritumomab

Radio-conjugates

Chimeric 65 Cetuximab, Rituximab

Humanized 95 Trastuzumab

Human 100 Panitumumab Transgenic mice


Nomenclature of MoAbs

• Last syllable is always –mab• Next to last syllable

-u- human (100%) : Panitumumab -zu- humanized (95%) : Trastuzumab -xi- chimeric (65%) : Rituximab -o- mouse, -a- rat, -e- hamster, -i- primate : Tositumomab

• Previous syllable– -tu(m)- for tumor in general [-ma(r)- breast, -pr(o)- prostate, -

co(l)- colon, etc.]– -ci(r)- for circulatory : Bevacizumab


New Directions

• Combination of different targeted therapies (multiple TKIs, TKI with MoAb; occasionally multiple MoAbs)

• Combination with standard chemotherapy or with radiotherapy

• Targeted agents to “clean up” after surgery• Use with other novel agents


Other Novel Types of Cancer Therapies Now in Use

• Proteasome inhibitors (Bortezomib)• mTOR inhibitors (Temsirolimus, Everolimus)• DNA demethylating agents (Azacytidine,

Decitabine)• Histone deacetylase inhibitors (Vorinostat)• Translocation targeters (retinoic acid)• Antiangiogenic agents (Thalidomide,

Lenalidomide)


Other Novel Types of Cancer Therapies in Development

• Integrin inhibitors (Volociximab)• “Death” receptor stimulants• Telomerase inhibitors• Apoptosis promoters• DNA repair inhibitors (PARP inhibitors, etc.)• Heat shock protein targeters• Antagonists of specific gene mutations• Antisense agents


Biotherapeutic Agents

• Interferons• Interleukins• Cancer Vaccines• Immunomodulatory agents• Colony stimulating factors• Monoclonal antibodies• Gene therapy


Take Home Points

• Molecularly targeted therapy is a new way of approaching cancer treatment

• It is based on recent scientific advances in molecular biology, chemistry, and genetics

• It involves the rational selection of drugs which target specific processes in cancer cells that make them different from normal cells

• A number of targeted therapies are currently available and many others are in development

• Targeted therapies are frequently effective but are not perfect: There are side effects to the treatments, and there may be development of resistance

• Targeted therapies are increasingly being used in combination with other targeted therapies or with other treatment modalities

• We definitely will be hearing much more about targeted therapies for cancer in the future


Thank You for your Attention

Cassidy Cancer CenterWinter Haven Hospital

200 Ave. F, NEWinter Haven, FL 33881-4131

863-292-4670www.winterhavenhospital.com/facilities/CCC

Date post:	10-Feb-2016
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Recent Developments in Oncology

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