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Targeted Therapies for Cancer: Challenges and Opportunities

Targeted Therapies for Cancer: Challenges and Opportunities. Edward A. Sausville, M.D., Ph.D. Greenebaum Cancer Center University of Maryland. Self-sufficiency in growth signals. Insensitivity to anti-growth signals. Evading apoptosis. Sustained angiogenesis. Tissue invasion

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Targeted Therapies for Cancer: Challenges and Opportunities

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  1. Targeted Therapies for Cancer: Challenges and Opportunities Edward A. Sausville, M.D., Ph.D. Greenebaum Cancer Center University of Maryland

  2. Self-sufficiency in growth signals Insensitivity to anti-growth signals Evading apoptosis Sustained angiogenesis Tissue invasion & metastasis Limitless replicative potential SIX ESSENTIAL ALTERATIONSIN CELL PHYSIOLOGY IN MALIGNANCY Targets for classical drugs? Targets for novel drugs? Hanahan & Weinberg, Cell 100:57 (2000)

  3. Putative Markers Targets Ligands Assays Definitive Clinical Studies Clinical Trials (Proof of principle) • General Distribution • commerical • ? other Definitive Clinical Studies • General Distribution • commerical • ? other Diagnostic Path Interventional Path MOLECULAR TARGETS Correlational Studies Credentialing (Interventional) Lead Compound Lead Probe Drug Candidate ProbeCandidate

  4. WHAT IS A “TARGETED” THERAPY? • Drugs directed at the molecular or physiologic concomitants of malignancy • Implications: • -“Saturability” of dose – response • - “Biological Effective Dose” rather than • “Maximal Tolerated Dose” • -Patient Selection Possible by assaying • some aspect of the target • Biology of tumor inform the clinical development of its proper treatment!

  5. p16del KiRas p53 ER or AR WHAT MAKES A GOOD TARGET ? # of “genetic” lesions “Malignancy” of phenotype After W. Kaelin

  6. LINEAR VS CONCENTRIC TARGET ACTION Drug 1 Drug 2 Stimulus Drug A Target A Target B Receptor + + Drug B “Super State” A Drug C - + B Drug D Target C Target E + C Target D Drug 4 Drug E Output Drug 3

  7. FOUR CLASSES OF POTENTIAL DRUG TARGETS • Pathogenic • Ontogenic • Pharmacologic • Microenvironmental -relate to cause of tumor -relate to site of tumor origin -relate to distribution / metabolism of drug -relate to stroma

  8. ISSUES WITH “PATHOGENIC” TARGETS • How to define them? • When in the course of the disease best to • intervene? How does this reflect clinical “reality”? • What redundancy in target function exists? • “Upstream” vs. “Downstream” intervention best?

  9. MOLECULAR TARGET DEFINITION - HOW TO? • BIOLOGY • Cytogenetics yield breakpoints yields targets: e.g. bcr-abl • Transforming oncogenes: e.g., ras, raf etc. • BINDING PARTNERS • taxol : tubulin • actinomycin D : DNA • geldanamycins : hsp90 • CLASSICAL • Cytokinetics antimetabolites • CHEMICAL GENETICS

  10. STI 571: An oral in vivo bcr-abl kinase inhibitor (days) (hrs) (days) Antitumor activity in vivo Tyr phosphorylation in vivo le Coutre et al, JNCI 91:163, 1999

  11. EFFICACY AND SAFETY OF A SPECIFIC INHIBITOR OF THE BCR-ABLTYROSINE KINASE IN CHRONIC MYELOID LEUKEMIA Ph Chromosome + Cells White Cell Count 100 100 80 60 10 % in Metaphase (cells x 10-3 / mm3) 40 20 1 0 30 60 90 120 150 0 0 100 200 300 400 Duration of Treatment with STI571 (Days) Duration of Treatment with STI571 (Days) BRIAN J.DRUKER,M.D.,MOSHE TALPAZ,M.D.,DEBRA J.RESTA,R.N.,BIN PENG,PH.D., ELISABETH BUCHDUNGER,PH.D.,JOHN M.FORD,M.D.,NICHOLAS B.LYDON,PH.D.,HAGOP KANTARJIAN,M.D., RENAUD CAPDEVILLE,M.D.,SAYURI OHNO-JONES,B.S.,AND CHARLES L.SAWYERS,M.D. NEJM 344: 1031, 2001

  12. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Myeloid (n=21) Lymphoid (n=14) 0 100 200 300 400 ACTIVITY OF A SPECIFIC INHIBITOR OF THE BCR-ABL TYROSINE KINASEIN THE BLAST CRISIS OF CHRONIC MYELOID LEUKEMIA AND ACUTELYMPHOBLASTIC LEUKEMIA WITH THE PHILADELPHIA CHROMOSOME BRIAN J.DRUKER,M.D.,CHARLES L.SAWYERS,M.D.,HAGOP KANTARJIAN,M.D.,DEBRA J.RESTA,R.N., SOFIA FERNANDES REESE,M.D.,JOHN M.FORD,M.D.,RENAUD CAPDEVILLE,M.D.,AND MOSHE TALPAZ,M.D. Time to Relapse in Patients with Myeloid or Lymphoid Blast Crisis Who Had a Response to STI571 Probability of Relapse Day • Yellow arrows indicate patients still enrolled in the study and in remission at the • time of the last follow-up • White arrows indicate the day on which patients were removed from the study NEJM 344: 1038, 2001

  13. Plasma Membrane C-OMe Ras SAM AAX Active FPP Methyl transferase CAAX Ras CAAX Protease   Inactive Cytoplasm Farnesyl Transferase FTIs RAS PROCESSING AND MEMBRANE ASSOCIATION IS CRITICAL FOR RAS TRANSFORMING ACTIVITY Cox et al in Signaling Networks and Cell Cycle Control (ed. Gutkind), 2000

  14. CHEMICAL STRUCTURES OF SMALL-MOLECULE INHIBITORS TARGETING THE RAS-MAP KINASE PATHWAY R115777 SCH66336 BAY-43-9006 CI-1040 Herrera & Sebolt-Leopold, Trends Mol Med 8:4 S27, 2002

  15. SCH 66336 / R115777: EARLY CLINICAL RESULTS • SCH 66336 Phase I: • - 20 pts; b.I.d. x 7d, q21d; MTD = 350 mg/dose • - DLT = fatigue • - 8 patients stable, treat out to 10 cycles. • - One response, out to 14 months • R115777 Phase Is: • -27 pts; b.I.d. x 5d; q 14 d; RP2D = 500mg/dose • -fatigue, transient renal, muscle • -b.I.d x 21d, q 28d • -DLTs fatigue, neutropenia, thrombocytopenia • - leukemia / MDS • - DLT neurotoxicity at 1200 mg/day; Response in 29% of 34

  16. [CANCER RESEARCH 55: 5302-5309, November 15, 1995] A Peptidomimetic Inhibitor of Farnesyl:protein Transferase Blocks the Anchorage-dependent and -Independent Growth of Human Tumor Cell Lines Laura Sepp-Lorenzino, Zhenping Ma, Elaine Rands, Nancy E Kohl, Jackson B Gibbs, Allen Oliff, and Neal Rosen Other Cell line FTI sensitivity Ras mutation Breast MCF7 MDA MB-468 MDA MB-453 T47-D BT 474 SkBr3 MDA MB-231 Colon Colo 205 HT-29 LoVo DiFi SW 620 SW 1417 DLD-1 LS 160 Pancreas PANC-1 AsPC-1 Capan-2 PSN-1 Prostate PC-3 DU 145 DuPro-1 LNCap S S S R R R S S S S S S R R R R R S S S R S S wt wt wt wt wt wt V12 wt wt Ki-D12 wt Ki-V12 wt Ki-D13 Ki-D12 Ki-D12 Ki-D12 Ki-V12 Ki- wt wt wt wt ER+ ER-/EGFR+++ ER-/erbB2+++ ER+ ER-/EGFR/erbB2+++ ER-/EGFR/erbB2+++ ER- p53-/APC-/lck/src/myb p53-/APC-/src p53-/APC-/src p53-/APC-/EGFR+++ p53-/APC-/src/myc p53-/APC-/ p53-/APC-/ p53-/APC-/src EGFR+++ EGFR+++ EGFR+++ AR-/IGF-autocrine AR-/TGF--autocrine AR- AR+ L-731,735

  17. WHY RAS IS LIKELY IRRELEVANT TO FTIs • Although Ras farnesylation is inhibited by FTIs, it • is not necessary or sufficient for anticancer effect of FTIs • FTIs inhibit growth in cells engineered to have • farnesyl-independent Ras • Other targets: rho, lamins • Susceptibility of cells does not correlate with ras status Prendergast, 1999

  18. ? p21 ? • Anoikis • Cell cycle inhibition • Phenotypic reversion • Loss of anchorage independence RhoB-F FTI RhoB RhoB-GG THEN HOW DO FTIs WORK? Nuclear lamins: Block Cell Cycle? Prendergast, 1999

  19. ISSUES WITH “ONTOGENIC” TARGETS • Target reflect tissue of origin • or • Target “acquired” during the course of a tumor’s • ontogeny • In both cases, the target has nothing to do with the genetic • lesions causing the tumor, but may facilitate cancer • cell survival • Examples: Cell surface antigens in Lymphoma; Hypoxia • -induced genes in most solid tumors • How good a target = f(accessibility/restriction) of target

  20. ISSUES WITH “PHARMACOLOGICAL” TARGETS • Target reflect unique / restricted handling of drug • in tumor vs. normal tissue • Target may facilitate: • -drug uptake (e.g. folate trasnporter) • -drug efflux (e.g., pgp, mrp, bcrp, etc. • -drug activation(e.g., nucleoside kinases) • -drug metabolism(e.g., diaphorase, cytochrome p450 et al.) • -drug retention (e.g., polyglutamoylation) • In all these cases, the target has nothing to do with the genetic • lesions causing the tumor, but may facilitate cancer • drug function or efficacycell survival • How good a target = Susceptibility of drug to modulation

  21. ISSUES WITH “STROMAL” TARGETS • The stroma is a complicated place: • -matrix a mix of normal basement membrane components; • unique tumor – induced alterations; products of dead • and dying cells; secreted growth factors from tumor cells; • cytokines / chemokines from tumor / accessory cells • -accessory cells: macrophages, tumor-infiltrating lymphocytes, • antigen presenting cells • -blood vessel components: mature/immature endothelial cells, • pericytes, ?specialized tumor cells forming vascular spaces • Influence of hemodynamic / micro-physiological influences • These targets not determined by genetic alterations in tumor • cell but reflect interaction these changes with host

  22. HOW TO CAPITALIZE ON DIFFERENCES “TARGETED AGENTS AND CONVENTIONAL CYTOTOXICS IN THEIR DEVELOPMENT? • Cytotoxics designed / screened to disrupt proliferation per se --- “Targeted agents” designed / screened to regulate a process • Targeted agents by definition should allow patient selection / definition • Target expression definition prior to clincal study: better therapeutic index?

  23. ISSUES CONFRONTING THE DEVELOPMENT OF ANY “TARGETED” AGENT We need from pre-clinical studies to know the following relationships to Have an efficient and predictable drug development campaign: AUC or “LD” Causing host death AUC or ED50 with “Off-target” host effect |---WINDOW----------| THERAPEUTIC Δ3 Δ2 Δ4 Δ1 AUC or ED50 Causing anti-tumor effect AUC or ED50 Causing effect on target in tumor compartment AUC or ED50 Causing effect on target in surrogate compartment

  24. 105 104 103 102 101 100 PS-293 PS-273 PS-341 0.1 1 10 100 1000 10000 CORRELATION BETWEEN 20S PROTEASOMEINHIBITORY POTENCY & GROWTH INHIBITIONFOR 13 DIPEPTIDE BORONIC ACIDS Correlation r2=0.92 Mean GI50 (nM) Ki (nM) Adams et al, Cancer Res 59:2615, 1999

  25. 700 600 500 400 300 200 100 0 Vehicle (n=15) PS-341 0.3 mg/kg (n=15) Treatment PS-341 1.0 mg/kg (n=10) 0 1 2 3 4 5 6 EFFECT OF PS-341ON PC-3 TUMOR GROWTH IN MICE Tumor Volume (% Vehicle) Week Adams et al, Cancer Res 59:2615, 1999

  26. 120 100 80 60 40 20 0 120 100 80 60 40 20 0 Vehicle 0.3 0.6 Vehicle 0.1 0.3 1.0 3.0 PS-341 (mg/kg) PS-341 (mg/kg) EFFECT OF PS-341ON 20S PROTEASOME ACTIVITY Mouse WBC PC-3 20S Activity (% Vehicle) 20S Activity (% Vehicle) Adams et al, Cancer Res 59:2615, 1999

  27. 120 MDACC MSKCC Mayo 100 NYU Wisconsin UNC 80 DFCI Cortes 60 40 20 0 0.1 1 10 EX VIVO PROTEASOME ACTIVITY:1 HOUR POST TREATMENT % 20S Activity 1.96 mg/m2 PS-341 (Log dose, mg/m2)

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