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Opening Remarks: The Rational Approach to Cancer Drug Development

Opening Remarks: The Rational Approach to Cancer Drug Development. Edward A. Sausville National Cancer Institute, USA. Treatment A. % Alive. Treatment B or no R. x. Time. R. x. Untreated. R. Cytostatic. x. Tumor Size. Time. Cancer Drugs: How Do We Know We Have a Winner?.

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Opening Remarks: The Rational Approach to Cancer Drug Development

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  1. Opening Remarks: The Rational Approach to Cancer Drug Development Edward A. Sausville National Cancer Institute, USA

  2. Treatment A % Alive Treatment B or no R x Time R x Untreated R Cytostatic x Tumor Size Time Cancer Drugs:How Do We Know We Have a Winner? - PHASE III CLINICAL TRIAL = WINNER - PHASE II = POTENTIAL WINNER ; Time? - PRECLINICAL MODEL (e.g., mouse or rat) Cytotoxic

  3. 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 Hanahan & Weinberg, Cell 100:57 (2000) Targets for classical drugs? Targets for novel drugs?

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

  5. TARGET-DEPENDENT IN VIVO MODEL IND DIRECTED TOX/FORM PHASE I: DOSE/SCHEDULE: HUMAN PHARM/TOX; ? AFFECT TARGET PHASE II: ACTIVITY = ? AFFECT TARGET PHASE III: SURVIVAL/TIME TO PROGRESSION “Rational” Drug Discovery MOLECULAR TARGET SCREEN PHARMACOLOGY (to affect target) Biochemical Engineered cell Animal (yeast/worm/fish) CHEMISTRY

  6. STI571:An Oral In Vivo Bcr-abl Kinase Inhibitor (days) (hrs) (days) Tyr phosphorylation in vivo Antitumor activity in vivo le Coutre et al, JNCI 91:163, 1999

  7. Efficacy and Safety of a Specific Inhibitor of the Bcr-abl Tyrosine Kinase in Chronic Myeloid Leukemia 100 100 80 60 10 40 20 1 0 30 60 90 120 150 0 0 100 200 300 400 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. Ph Chromosome + Cells White Cell Count % in Metaphase (cells x 10-3 / mm3) Duration of Treatment with STI571 (Days) NEJM 344: 1031, 2001

  8. 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 Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic 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 • Orange 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

  9. 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

  10. -Mutation, overexpression etc. of target -Drug handling(efflux/influx) -Cell response to damage -Switch pathway dependence Complications in Definition/ Pursuit of Cancer Targets • One histology: actually many diseases • “Plasticity” of targets in natural history • of a particular patient’s tumor • Resistance mechanisms

  11. GC B-like Activated B-like P=0.01 GC B-like Low clinical risk Activated B-like High clinical risk GC B-like DLBCL Activated B-like DLBCL P=0.05 P=0.002 All patients Distinct Types of Diffuse Large B-cell Lymphoma Identified by Gene Expression Profiling Probability Overall survival (yrs) All patients Low clinical risk pts Probability Overall survival (yrs) Alizadeh et al, Nature 403: 503, 2000

  12. Control 2 mg/ml tetracycline in drinking water Modulation of Tumor Angiogenesis by Conditional Expression of Fibroblast Growth Factor-2 Affects Early but not Established Tumors Raffaella Giavazzi, Roberta Giuliani, Daniela Coltrini, Maria Rosa Bani, Cristina Ferri, Barbara Sennino, Maria Pia Molinari Tosatti, Antonella Stoppacciaro, and Marco Presta LATE FGF OFF EARLY FGF OFF FGF2-B9 Tet-FGF2 15H blood vessels/400x field Tumor Weight (mg) Days after transplantation Cancer Res 61: 309, 2001

  13. EGFR p170 +C225 A431P R1R5 HER-2 p185 -actin p42 Tumor size (% of day 0) A431P R1 R5 TGF- 0 5 10 50 0 5 10 50 0 5 10 50 pEGFR 1400 -actin p42 220 1200 Days 180 1000 A431P R1 R2 R3 R4 R5 140 800 100 600 VEGF (pg/ml/105 cells) 60 400 20 200 8 16 24 32 40 48 -20 0 A431P R1 R3 R4 R5 R6 Control (Basal level in 1% FBS) C225 (50 g/ml) Acquired Resistance to the Antitumor Effect of Epidermal Growth Factor Receptor-blocking Antibodies in Vivo: A Role for Altered Tumor Angiogenesis Alicia Viloria-Petit, Tania Crombet, Serge Jothy, Daniel Hicklin, Peter Bohlen, Jean Marc Schlaeppi, Janusz Rak, and Robert S. Kerbel Cancer Res 61: 5090, 2001

  14. Molecular Target Definition - How To? • BIOLOGY: • “ RETROFIT” ACTIVE MOLECULES: • “CLASSICAL”: • CHEMICAL GENETICS: * Cytogenetics Breakpoints Molecules (bcr-abl) * “Positive” selection from tumor DNA Active oncogenes (signal transduction) * Tumor gene expression profiling (CGAP) * Binding partners (geldanamycin, rapamycin, fumagillin) * Computational algorithm (molecule target) * Cell metabolism / Cell cycle effects * Suggest single targets Inefficient * Libraries of molecules and precisely defined organisms - COMPARE - Cluster analysis

  15. Cancer Genome Anatomy Project www.ncbi.nlm.nih.gov/CGAP/ Genes over/under expressed in cancer = The “Signature” of a Cancer Type is its unique pattern of gene expression

  16. Cancer Biology to Define Targets:Cancer Genome Anatomy ProjectPROCESS • Tumor material (archival) • “Laser capture microdissection” of tumor cells • from defined sections • Creation of tumor-derived cDNA libraries • Sequence to establish uniqueness • Deposit in public domain

  17. Gene Expression: The Cell’s Fingerprint Normal Cell Cancer Cell Establishing for a cell the repertoire of genes expressed, together with the amount of gene products produced for each, yields a powerful "fingerprint." Comparing the fingerprints of a normal cell versus a cancer cell will highlight genes that by their suspicious absence or presence (such as Gene H ) deserve further scientific scrutiny to determine whether such suspects play a role in cancer, or can be exploited in a test for early detection. Source: www.ncbi.nlm.nih.gov/CGAP/

  18. benzoquinone ansa ring carbamate NSC R Geldanamycin 17-AAG 122750 330507 OMe NHCH2CH=CH2 Geldanamycin Structure

  19. Three-Dimensional View of Geldanamycin Binding Pocket in Amino Terminus of Hsp90 Stebbins et al, Cell 89:239, 1997

  20. G0 degradation erbB2 EGFR lck, met, etc X-mRNA X raf ER folding X X hsp 90 nucleus Hsp 90 EIF2 kinase pAKT Immature X Mature X * Cyclin D hsp 90 ER PR etc telomerase nucleus * hsp 90 * hsp 90 Hsp 90 A. C. B.

  21. +HGF/ SF + GA +HGF/ SF + GA analog +HGF/ SF Ctrl uPAR uPAR uPA-PAI uPA uPA p170Met p140Met Met Ansamycins Potently Inhibit HGF/MET Action Webb et al, Cancer Res 60: 342, 2000

  22. -relate to cause of tumor -relate to site of tumor origin or neoplastic vs. normal physiology -relate to distribution/metabolism of drug -relate to stroma/tumor microcirculation: can the drug get there? Classes of Potential Drug/Imaging Targets • Pathogenic • Ontogenic • Pharmacologic • Microenvironmental

  23. What “Validates”/“Credentials” a Target? • Differential expression (tumor vs. normal)? • Mutation (tumor vs. normal)? • Model systems: • Epidemiology: incidence/prevalence/survival • “Achilles Heel”: death dealing in tumor vs. normal -Nature of target: turn off an “on” vs. adding an “off” *Cells? *Animals? (tumor/normal/stroma) -Inducibility of phenotype -Knock in/knock out/dominant negative

  24. Drug Discovery/Early Clinical TrialsPlans for Change GUIDING PRINCIPLES: • Cancer biology has defined molecules responsible • Successful drugs of the future will be directed at • The optimal drug development process allows test of • Imaging tools: greater insight into Rx level and use for cancer occurrence and progression these molecular targets a molecular hypothesis as well as assessment of pharmacology, toxicity, and anti-proliferative effect

  25. Questions and Discussion Thank you!

  26. Our next speaker is: Dr. Susan Holbeck Information Technology Branch Developmental Therapeutics Program

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