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HERCEPTIN and SUTENT: From mono-specific to multi-targeted cancer therapies

Learn about the development and efficacy of HERCEPTIN and SUTENT, two cancer therapies that have revolutionized the treatment of cancer by targeting multiple areas of the disease. Explore the history, mechanisms, and clinical applications of these groundbreaking drugs.

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HERCEPTIN and SUTENT: From mono-specific to multi-targeted cancer therapies

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  1. „HERCEPTIN and SUTENT (Sunitinib): From mono-specific to multi-targeted cancer therapies“ Axel Ullrich Max-Planck-Institute of Biochemistry Martinsried, Germany

  2. Targeted Cancer Therapy „The dream of the Magic Bullet“ Side Effect-Free Cure of Cancer

  3. Paul Ehrlich 1854 - 1915 • Father of Chemotherapy • Salvarsan for Treatment of Syphilis • Nobel Prize 1908 • “Magic Bullet Concept”

  4. Aneuploidy Imune Defense Evasion Angiogenesis Immortalization (Anti-Apoptosis) Altered Energy Metabolism Deregulated Proliferation Invasivity Motility Hallmarks of Cancer Target Areas for Therapeutic Interventions

  5. Signalling Pathways

  6. Human Epidermal Growth Factor Receptor (EGFR) Size: 170.000 Da Length: 1186 aa 131.000 MW mRNA: 5.8 / 10.5 kb Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, and Waterfield MD (1984). Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307. 521-527 Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J, Downward J, Bye J, Whittle N, Waterfield MD, and Seeburg PH (1984). Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309. 418-425

  7. EGFR / v-erbB EGF-R v-erbB-H v-erbB-ES4 F/S699 T/K718 H/R811 Q/L840 S/I932 Δ1034 Δ1042-1062 Y/N1091 F/S699 I/V705

  8. Human EGF Receptor-Related Receptor HER2 / neu / c-erbB2 Size: 185.000 Da Length: 1234 aa 136.000 MW mRNA: 4.8 kb King CR, Kraus MH, and Aaronson SA. (1985) Amplification of a Novel v-erbB-related Gene in a Human Mammary Carcinoma. Science 229, 974-976 Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, Levinson A, and Ullrich A. (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal localization with neu oncogene. Science 230, 1132-1139 Schechter AL, Hung MC, Vaidyanathan L, Weinberg RA, Yang-Feng TL, Francke U, Ullrich A, and Coussens L (1985). The neu gene: An erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 229. 976-978

  9. From Science to Blockbuster Genentech Inc. “The Herceptin Story” Genentech: R. Hudziak M. Shepard B. Fendley P. Carter Herceptin Development Team Collaborator: D. Slamon, UCLA

  10. HERCEPTIN History Slamon et al. Science HER2 gene amplification in Breast Cancer and correlation with disease progression 1987 Cloning of EGFR cDNA Relation to V-erbB 1984 Phase I Rhu MAb 1992 Phase III 1995 Approval In Europe 2000 1985 HER2 Sequence published Coussens et al. 1989 Hudziak et al. MCB Anti-tumor effect Of MAb 4D5 and 2C4 1993 Phase II 1998 FDA Approval 2002 MAb 2C4 In Development

  11. Efficacy of Monotherapy in HER2/neu +++ Patients Low (15%) Reminder: Cancer is NOT a Monogenic Disease Moving Disease Target due to Genetic Plasticity of Tumor Cells Combination Therapy HERCEPTIN + - Anthracyclines - Taxotere - Platinum Salts - etc HERCEPTIN

  12. MPI for Biochemistry Munich From Science to Multi-Targeted Cancer Drug“Flk-1/VEGFR2 as Target in Anti-Angiogenesis Therapy” MPI Biochemistry, Martinsried, Germany Birgit Millauer Werner Risau SUGEN Laura Shawver Jerry McMahon Annie Fong Development Team Collaborators Alex Levitzki, Hebrew University, Jerusalem Gyorgy Keri, Vichem, Budapest Pharmacia Drug Development Team Pfizer Clinical Development Team SUGEN San Francisco

  13. RTK Subclasses EGFR HER2/ neu HER2 HER4 I-R IGF-1R IRR PDGFRα PDGFRβ CSF-1R KIT FLK2/FLT3 VEGFR1 VEGFR2 VEGFR3 FGFR-1 FGFR-2 FGFR-3 FGFR-4 CCK4 TRKA TRKB TRKC MET RON EPHA1- EPHA8 EPHB1- EPHB7 AXL MER TYRO3 TIE TEK RYK DDR-1 DDR-2 RET ROS LTK ALK ROR1 ROR2 MUSK MDK4 AATYK AATYK2 AATYK3

  14. Terman et al. Biochem Biophys Res Commun 1992 Quinn et al. Proc Natl Acad Sci USA 1993 Millauer et al. Cell 1993

  15. Gene Therapy with Dominant-Negative VEGF-R Retrovirus

  16. Receptor for VEGF Specifically Expressed in Endothelial Cells Essential for Tumor Angiogenesis DEVELOPMENT OF SELECTIVE FLK-1 KINASE SMALL MOLECULE INHIBITORS Flk-1/VEGFR2: Validation as Anti-Angiogenesis Drug Development Target

  17. Chemical Structure of SU5416 - An Inhibitor of VEGF Receptor Kinase SU5416 3-[2, 4-dimethylpyrrol-5-yl methylidenyl]-2-indolinone

  18. SU5 416 Response in AIDS Kaposi’s Sarcoma Protocol 5416.003, Patient #003, R-P Before treatment with SU5416 After treatment with SU5416

  19. Patient 018/JZH: SU5416 ResponseFacial Lesions

  20. SU5416 • Highly Selective • Efficacious in Mouse Models • Anti - Metastatic • Sub – Optimal Pharmacological Properties • Efficacious in Phase I Kaposi-Sarcoma Trial • Colon Cancer Trial Terminated

  21. Biochemical Effects of SU6668 a VEGFR-2, PDGFR, & FGFR RTK Inhibitor SU6668 SU5416 PDGFRb EGFR FGFR-1 Flk-1 Ki Ki Ki Km (ATP) Km (ATP) IC50 Km (ATP) SU5416 SU6668 0.32 0.008 0.16 2.1 6.2 6.2 0.43 0.43 19.5 1.2 >100 >100 2.6 2.6 Mean Ki and Km values are shown (mM) • Both compounds exhibit competitive (with respect to ATP) inhibition • Both compounds also inhibit ligand-dependent phosphorylation of c-Kit

  22. An Oral Multi-Targeted Receptor Tyrosine Kinase Inhibitor with Anti-Tumor and Anti-Angiogenic Activity SU11248

  23. SU11248 A Multitargeted Kinase Inhibitor * Proliferation driven by mutant receptor

  24. Baseline Week 4 SU11248 Exhibits Cytoreductive Activity in Diverse Tumors of Patients in Phase I Clinical Trials Patient with metastatic renal cell carcinoma • Phase I trials ongoing at multiple international sites • Patients heavily pre-treated, with progressive disease at entry • Confirmed partial responses observed • SU11248 is well tolerated • most common toxicities seen in patients are fatigue, GI, and hematologic toxicity Eric Raymond et al., 2002 NCI/EORTC/AACR

  25. SU 11248/SUTENT August 2005: Pfizer Submits a New Drug Application (NDA) to the FDA for the Use of SUTENT in the Treatment of Gleevec-Resistant GIST January 26, 2006: FDA approves SUTENT for treatment of Gleevec-resistant GIST and RCC July 19,2006 EMEA Approval for Europe

  26. Sunitinib in metastatic RCC Before Treatment After 4 weeks of Sunitinib Lung lesion response in RCC; Courtesy of Dr. Ronald Bukowski, Cleveland Clinic Foundation Sunitinib is new first-line therapy in metastatic Clear Cell Renal Cell Carcinoma (RCC) Adverse side effects are tolerable

  27. Open multicentric phase II study with 64 patients Patients had been treated with chemotherapy that included at least an anthracycline or a taxane In average, patients had received 3.5 different chemotherapies 85% of patients had received adjuvant chemotherapy Primary endpoint: Response (RECIST) Secondary endpoints: 1-year – survival, duration of response, tolerance Sunitinib in Breast Cancer Patients Miller et al., ASCO 2005, Oral Presentation May 16

  28. Sunitinib has significant efficacy when used as a monotherapy in patients with breast cancer Partial response in 14% of patients (who had been treated before with various chemotherapeutic agents) Moderate Side Effects Miller et al., ASCO 2005, Oral Presentation May 16 Results

  29. From Mono- to Multi-Targeted Kinase Inhibitors

  30. SUTENT History Flk-1 shown to be VEGF-R (Millauer et al., Quinn et al.) Dominant negative VEGFR-2 Inhibits tumor angiogenesis and-grwoth in vivo (Millauer et al.) SU5416 inhibits tumor growth In vivo (Fong et al.) SU11248 orally active multi-targeted drug (O‘Farrell et al.) SUTENT approval by FDA and EMEA (Pfizer) 1993 1994 1999 2003 2006

  31. P P P P P P P P DOK SHC GRB-2 RAS-GAP SOS PI3K RAF-1 P P P P P P AKT mTOR MEK1/2 P BAD BCLXL 14-3-3 MYC 14-3-3 Receptor Tyrosine Kinase Molecular Targets in Cancer BMS354825(Bristol-MS) Imatinib (Novartis) SU11248 (Pfizer) SRC Zarnestra (JNJ) CT2584 (CTI) RAS-GTP RAS-GDP ? STAT1+3 BAY43-9006 (Bayer) SAPK RAD001(Novartis) CCI779 (Wyeth) Rapamune (Wyeth) BAD MAPK BCLXL Mitochondria Nucleus

  32. MPI for Biochemistry Munich CMM Singapore A*STAR Genentech Inc. Biopolis

  33. Significantly Expand Cancer Mutation Database Start with Cancer Kinome Analysis Identify New Drugable Cancer Targets Screening of Compound Librarys – Drug Discovery and Optimization Singapore OncoGenome Project (SOG)

  34. Future of Individualized Cancer Therapy Diagnosis Traditional Pathological Criteria - Tumor Gene Expression Analysis – Germline SNP Pattern - Tumor Markers Multi-Targeted Kinase Inhibitors (MTKIs) (Gleevec, SU11248) Traditional Chemotherapy (Taxol, Anthracyclines) Target Specific Monoclonal Antibodies (Herceptin) Treatment Hormonal therapy Radiotherapy

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