1 / 75

New Cancer Therapies Based on Thyrosine Kinase Inhibitors Axel Ullrich

New Cancer Therapies Based on Thyrosine Kinase Inhibitors Axel Ullrich Max-Planck-Institute of Biochemistry Martinsried, Germany November 7, 2008. Targeted Cancer Therapy „The Dream of the Magic Bullet“ Side Effect-Free Cure of Cancer. Paul Ehrlich 1854 - 1915. Father of Chemotherapy

abra-mcpherson
Download Presentation

New Cancer Therapies Based on Thyrosine Kinase Inhibitors Axel Ullrich

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. New Cancer Therapies Based on Thyrosine Kinase Inhibitors Axel Ullrich Max-Planck-Institute of Biochemistry Martinsried, Germany November 7, 2008

  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” Ehrlich in his office

  4. Signalling Pathways

  5. 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

  6. EGFR / v-erbB EGF-R v-erbB-H v-erbB-ES4 F/S699 T/K718 H/R811 Q/L840 S/I932 Δ1034 Δ 1042-1062 Y/N1091 F/S699 I/V705

  7. neu v-fms M/V 11 R/Q 91 S/L 301 S/A 374 Y/H 461 P/Q 505 T/A 587 P/L 680 G/D 711 V/E RTK-derived Oncogene Products v-erbB-H v-erbB-ES4 v-kit F/S699 T/K718 H/R811 Q/L840 S/I932 Δ1034 Δ1042-1062 Y/N1091 F/S699 I/V705 ΔAY G/D Δ 34 aa Δ 71 aa Δ 40 aa Δ 40aa

  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. “The Herceptin Story”Oncogene Homology-Based Target Discovery Genentech: R. Hudziak M. Shepard B. Fendley L.Coussens P. Carter Herceptin Development Team Clinical Collaborator: D. Slamon, UCLA

  10. 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 Approval In Europe 2000 Phase III 1995 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 HERCEPTIN History

  11. HERCEPTIN • 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 - other MABs - etc

  12. The EGFR Family Signalling Network TGFa(1) EGF(1) Epiregulin(1,4) Beta-cellulin(1) HB-EGF(1,4) Amphi-regulin(1) NRG1(3,4) NRG2(4) NRG3(4) NRG4(4) LPAThrombinET, etc. Ligands Cytokines a b a b Inputlayer Receptordimers 2 4 1 4 2 2 2 3 4 1 4 1 4 3 2 1 3 3 3 1 SRC JAK CBL SHC CRK p21-GDP PLC GRB7 P13K VAV GRB2 SHP2 Adaptors& enzymes NCK GAP SOS RAC p21-GTP Hiddenlayers RAF PAK AKT Cascades ABL MEK JNKK PKC BAD S6K MAPK JNK Transcriptionfactors JUN SP1 MYC FOS ELK EGR1 STAT Outputlayer Growth Migration Apoptosis Adhesion Differentiation Yarden and Sliwkowski (2001) Nature Rev. Mol. Cell Biol, 2,127-137.

  13. Mechanism-Based Target Identification HER3 • Wallasch et al. and Ullrich EMBO J. 1995HRG-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3 • Holbro et al. and Hynes PNAS 2003The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation • Htun van der Horst et al. and Ullrich IJC 2005Anti-HER3 MAbs inhibit HER3-mediated signaling in breast cancer cell lines resistant to anti-HER2 antibodies

  14. HER3 is a Determinant for Poor Prognosis in Melanomaand a Target for Therapeutic Intervention Markus Reschke Daniela Mihic-Probst Edward Htun van der Horst Pjotr Knyazev Peter J. Wild Markus Hutterer Stefanie Meyer Reinhard Dummer Holger Moch Martin Treder (U3 Pharma) AMGEN

  15. MELANOMA HER3 protein expression in primary melanoma and metastases 40x 40x 20x 40x 40x

  16. Multivariate Analysis HER3 p=0.044 (Hazard ratio: 2,636) Metastases p=0.000 (Hazard ratio: 22,251) Other variables sex age tumor thickness (p=0.065) HER3 Expression Confers Poor Prognosis for Melanoma Patients Kaplan-Meier Curve HER3 low HER3 high Cumulative Survival p = 0.014 Overall Survival

  17. IgG1 (25 mpk per mouse) Anti-HER3 mAb (25 mpk per mouse) pHER3 -Actin Treatment with Human Anti-HER3 mAb Significantly Reduces pHER3 Levels in BxPC3 Tumor Xenografts U3Pharma/AMGEN

  18. hIgG1 , 25 mg/kg 2X/wk 900 Anti-HER3 mAb C , 25 mg/kg 2X/wk 800 Anti-HER3 mAb A, 25 mg/kg 2X/wk 700 600 Anti-HER3 mAb B, 25 mg/kg 2X/wk 500 Gemcitabine, 80mg/kg weekly 400 300 200 100 0 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Treatment with Human Anti-HER3 mAbs Results in Inhibition of BxPC-3 Pancreatic Carcinoma Xenografts p<0.0001 vs. hIgG1 Control RMANOVA Analysis Time (days) Blinded Study n=10 per group U3Pharma/AMGEN

  19. Conclusion: HER3- Specific MAbs • Have an HER2-independent Inhibitory Effect in Melanoma and Pancreatic Cancer Cell Models • May Be Valuable Therapeutic Agents Alone as Well as in Combination with Herceptin, Lapatinib and other Drugs

  20. MPI for Biochemistry Munich From PCR-Based Discovery of a Novel RTK to a 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 György Kéri, Vichem, Budapest Pharmacia Inc. Pfizer Inc. SUGEN San Francisco

  21. 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 RTK Subclasses

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

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

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

  25. SU5 416 Response in AIDS Kaposi’s Sarcoma Protocol 5416.003, Patient #003, R-P Before treatment with SU541 After treatment with SU5416

  26. Patient 018/JZH: SU5416 ResponseFacial Lesions

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

  28. 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

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

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

  31. From Mono- to Multi-Targeted Kinase Inhibitors

  32. 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

  33. 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

  34. SU 11248/SUTENT January 26, 2006 FDA approves SUTENT for Treatment of Gleevec-Resistant GIST and RCC July 19,2006 EMEA Approval for Europe

  35. SUTENT History Flk-1 shown to be VEGF-R (Millauer et al., Quinn et al.) Dominant negative VEGFR-2 inhibits tumor angiogenesis and-growth 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

  36. P P P P Y Y Y Y Migration Receptor-Tyrosine-KinasesDrivers of Cancer Progression Activated Receptor Ligand Binding Receptor- Tyrosine-Kinase Cell Membrane Tyrosine Kinase Domain Signal Transduction Proliferation Survival Tumor Growth and Metastasis Formation

  37. Activated Receptors P P P P P P P P Y Y Y Y Sunitinib Sunitinib Y Y Y Y Multi-Targeting = Blocking Multiple Tyrosine Kinases Simultaneously Ligand Binding Receptor Tyrosine Kinase    Proliferation Survival Migration Tumor Growth and Metastasis Formation

  38. Sunitinib

  39. Sunitinib   Tumor Angiogenesis   

  40. SUTENT/Sunitinib going forward…. • Comprehensive Kinase Interaction Profile • Cell Line-Characteristic Biological Responses • Identification of Therapeutically Relevant Kinase Targets (Clinical Response Prediction Signature) • Identification of Kinase Targets Responsible for Side Effects (Fatigue, Cardiotoxicity etc.) • Resistance Formation

  41. P Receptor Tyrosine Kinase P P P P P P P DOK SHC GRB-2 BMS354825(Bristol-MS) Imatinib (Novartis) RAS-GAP SU11248 (Pfizer) SOS SRC PI3K Zarnestra (JNJ) CT2584 (CTI) RAS-GTP RAS-GDP RAF-1 P P P P P P AKT mTOR ? STAT1+3 BAY43-9006 (Bayer) MEK1/2 P SAPK RAD001(Novartis) SKI 606(Wyeth) BAD BCLXL 14-3-3 BAD MYC MAPK 14-3-3 BCLXL Nucleus Mitochondria Molecular Targets in Cancer

  42. Future of Individualized Cancer Therapy Diagnostic Data Traditional Pathological Parameter Tumor Gene Expression Analysis Oncogene Mutation Profile Tumor Markers Germline SNP Profile

  43. Future of Individualized Cancer Therapy Multi-Targeted Kinase Inhibitors (Gleevec, SUTENT, Nexavar….) Traditional Chemotherapy (Taxol, Anthracyclines…..) Target Specific Monoclonal Antibodies (Herceptin, HER3 Ab…..) Combinatorial Treatment Hormonal therapy Radiotherapy

  44. AcknowledgementsSUTENT Response Prediction Project Michaela Bairlein Henrik Daub (MPI for Biochemistry) Cooperations: György Kéri (Vichem, Hungary) Singapore OncoGenome Project (Singapore) Matthias Mann (Dept. Proteomics, MPI for Biochemistry)

More Related