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Targeting Multiple Pathways in the Treatment of Cancer : 

Targeting Multiple Pathways in the Treatment of Cancer Manuel Hidalgo, MD, PhD Associate Professor of OncologySidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland This program is supported by an educational donation from

About These Slides : 

DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials. Users are encouraged to include these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent. These slides may not be published or posted online or used for any other commercial purpose without written permission from Clinical Care Options. We are grateful to Manuel Hidalgo, MD, PhD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland, who aided in the content creation of these slides. About These Slides

Cancer Targets and Drugs : 

Cancer Targets and Drugs Better understanding of biology leads to strategic target discovery Effective discovery of targeted agents Demonstrated efficacy in clinical setting Major challenges remain Patient selection Strategic combinations Faster and cheaper development

Hallmarks of Malignancy : 

Hallmarks of Malignancy Independence from growthsignaling Development of angiogenic ability Invasionand metastasis No limit on proliferation Evasion ofapoptosis Insensitivity to growth inhibitorysignals Cancer cell Hanahan D, et al. Cell. 2000;100:57-70.

Cancer Is More Complex Than Ever Thought : 

Cancer Is More Complex Than Ever Thought Systematic analysis of genetic alterations in human breast and colorectal cancers (N = 22) 13,023 genes analyzed Average of 90 mutated genes per case Only a subset (average of 11 per case) thought to be relevant to neoplastic process Sjöblom T, et al. Science. 2006;314:268-274.

Different Models Emerge : 

1. Weinstein IB. Science. 2002;297:63-64. Different Models Emerge Tumors with real “oncogene addiction”[1] EGFR-mutated NSCLC, GIST, CML Tumors with a more complex genetic makeup Deciphering relative importance of one pathway vs others Importance of drug combinations

EGFR : 

EGFR

The Epidermal Growth Factor Pathway : 

The Epidermal Growth Factor Pathway Ciardiello F, et al. EGFR Antagonists in Cancer Treatment. N Engl J Med. 2008:358:1160-1174. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Structure of the EGFR: New Insights : 

Structure of the EGFR: New Insights Kumar A, et al. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol. 2008;26:1742-1751. Reprinted with permission of the American Society of Clinical Oncology

Available EGFR-Directed Therapeutics : 

Available EGFR-Directed Therapeutics Small-molecule TK inhibitors Gefitinib Erlotinib Monoclonal antibodies Cetuximab Panitumumab

EGFR-Directed Therapeutics: Clinical Indications : 

EGFR-Directed Therapeutics: Clinical Indications

Translational Research Questions : 

Translational Research Questions How do these drugs work? Signaling inhibition? Receptor internalization? Antibody-dependent cellular cytotoxicity? Patient prediction based on tumor or host factors? Drug combinations?

Which Target? : 

Shc PI3-K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 Which Target?

Which Target? : 

Shc PI3-K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 Which Target?

Slide 15: 

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.

Where’s the Target? : 

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center. Where’s the Target?

Predicting EGFR Treatment Outcome : 

Predicting EGFR Treatment Outcome Target based EGFR expression EGFR gene amplifications EGFR mutations Interactions with other signaling pathways Her3 c-Met Downstream signaling kRas PTEN PI3K/Akt Unknown Rash

Multitargeted TKIs : 

Multitargeted TKIs

Selected Targeted Agents With Potential as Breast Cancer Therapeutics : 

Selected Targeted Agents With Potential as Breast Cancer Therapeutics 5-AzacytidineDecitabineFazarabineDepsipeptide OxaliplatinGemcitabineIrofulven Paclitaxel DocetaxelDolastatin IxabepiloneBenzoylphenylurea Bortezomib CC49LMB-9Mab CO17-1A Survival Factors(eg, IGF1) Hormones(eg, Bombesin)(eg, Estrogen) TipifarnibBMS-214662 Growth Factors(eg, TGFa) ErlotinibSU6668SexaminibGefitinibTrastuzumabLapatinib ECM Cilengitide Cells Bryostatin-1 EverolimusTemsirolimus Bortezomib Cytokines(eg, ILs, IFNs) WNT Flavopiridol IL-4IL-12IFN UCN-01 Death Factors(eg, FasL) Oblimersen Ad-p53 17AAG Angiogenesis:SexaminibSU6668BevacizumabHuMV833CilengitideVitaxin 2CAIEndostatinAngiostatinThalidomideNeovastat2-Methoxy EstradiolSorafenibSunitinib VandetanibMotesanib diphosphate Matrix Metalloproteinases:Batimastat BB-94Marimastat BB-2516BMS-275291BAY 12-9566COL3

Multitargeted Agents: Trade-off Between Toxicity and Efficacy? : 

Increasing inhibition of each kinase: unknown effect Multitargeted Agents: Trade-off Between Toxicity and Efficacy?

Reduction of Tyrosine Kinase Activity by Multitargeted TKIs : 

*Murine-based protein used.1. Mendel DB, et al. Clin Cancer Res. 2003;9:327-337. 2. Herbst, et al. EORTC-NCI-AACR 2004. 3. Wilhelm SM, et al. Cancer Res. 2004:64;7099-7109. 4. Wood JM, et al. Cancer Res. 2000;60:2178-2189. 5. Chow L, et al. J Clin Oncol. 2007;25:884-896. 6. Podar K, et al. Proc Natl Acad Sci U S A. 2006;103:19478-19483. 7. Hess-Stumpp H, et al. ChemBioChem. 2005;6:550-557. 8. Kim D, et al. J Clin Endocrinol Metab. 2006;91:4070-4076. 9. Carlomagno F, et al. J Natl Cancer Inst. 2006;98:326-334. 10. Carlomagno F, et al. Cancer Res. 2002;62:7284-7290. Reduction of Tyrosine Kinase Activity by Multitargeted TKIs

Multitargeted TKI Toxicities : 

Multitargeted TKI Toxicities Hypertension Fatigue Increased clotting events Bleeding (epistaxis, pulmonary hemorrhage, tumor associated) Headache Neurologic events Increased LFTs Pain at tumor sites Proteinuria Hypothyroidism? And . . . Skin rash Myelosuppression Nausea/vomiting Diarrhea Others

Multitargeted Kinase Inhibitors : 

Multitargeted Kinase Inhibitors Are these just “combination studies” using 1 pill? Can/should they be combined with other agents still? Cytotoxics? Other biologics? Are they not “broad” enough? Long-term tolerability? Can another in the class be used when one fails? Why are we not curing all cancers with them?

Tumor/Bone Microenvironment : 

Tumor/Bone Microenvironment

Directly Targeting the Cancer Cell: Disadvantages : 

Directly Targeting the Cancer Cell: Disadvantages Major heterogeneity across and between histologies[1] Biologically/genetically unstable target Acquired genetic instability Increases with progression/stage/pretreatment Limits efficacy of treatment Homeostatic response/selection of resistant clones (acquired and de novo resistance) 1. Sjoblom T, et al. Science. 2006;314:268-274.

What Is the Tumor Microenvironment? : 

What Is the Tumor Microenvironment? Normal cells and molecules surrounding a tumor cell Fibroblasts Cells that make up the blood vessels Infiltrating immune cells from the bloodstream Extracellular matrix Growth factors (chemokines and cytokines) Oxygenation and pH American Association for Cancer Research. Available at: http://www.aacr.org. Accessed May 26, 2008.

Importance of Tumor Microenvironment : 

Importance of Tumor Microenvironment Tumor cells emerge and exist in a microenvironment Interactions between these components are critical Lack of understanding about tumor microenvironment limits many existing cancer models Lack of tumor microenvironment: major limitation of many cancer models Important targets in the microenvironment: angiogenesis, bone, etc More genetically stable component Less likely to develop drug resistance

Attraction of Targeting the Microenvironment : 

Attraction of Targeting the Microenvironment Genetically stable substrate Less amenable to mutation/acquired resistance Common final pathways possible Less heterogeneity of target Relatively predictable response of tissues to cancer Addresses poorly understood and most lethal hallmark of malignancy: metastasis Plethora of potential novel targets

VEGF: A Key Mediator of Angiogenesis : 

Dvorak HF. J Clin Oncol. 2002;20:4368-4380. Ebos JM, et al. Mol Cancer Res. 2002;1:89-95. Ferrara N, et al. Nat Med. 2003;9:669-676. Increased VEGF levels VEGF: A Key Mediator of Angiogenesis

The VEGF Family and Its Receptors : 

The VEGF Family and Its Receptors Neufeld G, et al. FASEB J. 1999;13:9-22. VEGFR-3 (Flt-4) VEGFR-2 (Flk-1/KDR) VEGFR-1 (Flt-1) Angiogenesis Lymphangiogenesis PIGF VEGF-A VEGF-B VEGF-C VEGF-D

Summary of Anti-VEGF MOAs Based on Preclinical Models : 

Summary of Anti-VEGF MOAs Based on Preclinical Models May regress existing microvasculature May normalize surviving mature vasculature May inhibit vessel regrowth and neovascularization

Conclusions : 

Conclusions Cancer is a very complex disease Gains in molecular understanding are revealing therapeutic targets EGFR: example of a single-gene, broad, useful target However, most tumors will require a combination of agents targeting several key pathways The tumor comprises the cancer cells plus a dynamic and rich stroma Stromal targets are also important

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