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Introduction to the Basics of Signal Transduction

Introduction to the Basics of Signal Transduction

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Introduction to the Basics of Signal Transduction

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  1. Introduction to the Basics of Signal Transduction Mauricio Lema Medellín, Colombia

  2. … Porque algunos en la audiencia no hablan español. Y ellos también fueron invitados.

  3. Signal Transduction • Introduction / Definition • Components of ST • Selected pathways • Some newer drug targets • Cross-Talk • Concluding remarks

  4. Growth factors Nutrients & O2 Hormones Cell-Cell inter.

  5. Signal Transduction Signal transduction describes the process through which extracellular signaling molecules bind specific receptors on target cells, which consequently activate selected intracellular biochemical pathways

  6. Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors

  7. Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors

  8. Kinases Post-translational modifications are key to signal transduction • Phospholylation of Ser / Thr / Tyr may TURN ON / OFF a specific protein • The balance of P / de-P will establish a response

  9. Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors

  10. Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors

  11. Signal Transduction Pathways • “Growth Factor” pathways • Rb • c-myc • TGFB • Hypoxia pathway • mTOR • IGR • MET • VEGF • EGFR

  12. Anti VEGF

  13. PI3K inhibitors RAF inhibitors Temsirolimus / Everolimus

  14. PI3K inhibitors Raf Inhibitors

  15. mTOR inhibitors

  16. Shc Grb2 PI3-K Sos-1 Ras AKT Raf MEKK-1 MEK mTOR MKK-7 ERK JNK Angiogenesis Metastasis Apoptosis Resistance Proliferation Signaling EGFR

  17. VEGF ANGIOGENESIS PLC PLC PI3-K PI3-K FAK FAK Ras Ras P P P P PKC PKC IP3 IP3 AKT AKT Paxillin Paxillin MAPK MAPK Migration Migration Survival Survival Proliferation Proliferation ANGIOGENESIS VEGF Binding & Activation of VEGFR Endothelial-Cell activation

  18. Let’s put it simple… Signal – Receptor interaction

  19. Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC

  20. Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC Some “further” P is exchanged ERK mTOR Rb

  21. Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC Some “further” P is exchanged ERK mTOR Rb EFFECTOR TF – DNA interaction

  22. Signal Transduction • Introduction / Definition • Components of ST • Selected pathways • Some newer drug targets • Cross-Talk • Concluding remarks

  23. Cyclin Dependent Kinases Inhibitor • SCH 727965 (J. Nemunaitis, P.ASCO 2009, Abstract 3535) • 0/43 Responses

  24. Raf Kinase Inhibitor • XL-281 (GK Schwartz, P.ASCO 2009, Abstract 3513) • 1/30 PR • 12/30 SD HSP • Alvespimycin (SC Pacvev, P. ASCO 2009, 3534) • 2/25 PR • OGX-427 (SJ Hotter, P. ASCO 2009, 3506) • 5/34 SD

  25. Akt inhibitor • MK-2206 (AW Tolcher, P.ASCO 2009, Abstract 3503) • 6/19 SD

  26. PI3K inhibitors • XL-147 (G. Shapiro, P.ASCO 2009, Abstract 3500) • 6/39 SD • GDC-0941 (AJ Wagner, P.ASCO 2009, Abstract 3501) • 3/19 SD • XL-765 (P. LoRusso, P.ASCO 2009, Abstract 3502) • 5/34 SD • Enzastaurin (MA Carducci, P.ASCO 2009, Abstract 3517) • 9/43 PR (Con Bevacizumab)

  27. IGF1R/Aurora/SRC inhibitor • XL 228 (DC. Smith, P.ASCO 2009, Abstract 3512) • 1/30 PR • 9/30 SD