ET-1 acting via ETAR promotes: The Endothelin Axis: Oncogenic Mechanisms ET-1 ETAR Ras PLC Plasma membrane G-protein Ins P3 Raf DAG PKC ET-1 acting via ETAR promotes: Ca2+ release MAPK Cell growth Inhibition of apoptosis Angiogenesis Osteoblastic remodeling Nociceptive pain response Via the ETA receptor, ET-1 implicated in prostate cancer ET-1 induces cell proliferation Functions as a mitogen Exhibits synergistic action with other growth factors ET-1 inhibits apoptosis ET-1 modulates peripheral nociception ET-1 induces osteoblastic remodeling ET-1 facilitates angiogenesis ET-1 increases cell proliferation1 Stimulation of ETA with ET-1 induces a signal transduction pathway Induces transcription of the proto-oncogenes Increases cell growth and proliferation Activates kinases involved in cell survival and proliferation Protein Kinase C (PKC) Epidermal Growth Factor (EGF) Insulin-like Growth Factor-1 (IGF-1) Mitogen-activated protein kinase (MAPK) Produces Rapid induction of early-response genes c-FOS, c-JUN, c-MYC Nucleus Modified from Bagnato A, Catt KJ. Trends Endocr Metab. 1998;9(9):378–383.

Mechanism of action Endothelin receptor antagonist Cancer cell NEP ETA receptor ETB receptor ET-1 Cancer cell NEP Neutral endopeptidase 24.11 NEP

Tumour angiogenesis promotes tumor growth and metastasis The creation of new vessels and lymphatic tissue by tumors allows them to enlarge and to metastasize Inhibition of tumour angiogenesis has the potential to inhibit tumor growth and spread

Anti-angiogenic Agents = HIF mTOR Bevacizumab CCI 779 VEGF PDGF VEGFR PDGFR EGFR RCC: therapeutic targets Increased understanding of the VHL–HIF pathway and the consequences of VHL gene mutation has led to the identification of a number of therapeutic targets in RCC1 simultaneously targeting the VEGF and PDGF pathways provides a potentially synergistic approach to inhibiting RCC-associated angiogenesis targeting TGF-α/epidermal growth factor receptor (EGFR) and downstream signalling molecules, such as Raf, provides an approach to inhibiting RCC tumour proliferation. A number of targeted therapies are under evaluation in phase II or III trials in patients with advanced RCC bevacizumab inhibits the binding of VEGF to its receptor, VEGFR2 erlotinib targets the epidermal growth factor pathway by blocking EGFR3 sunitinib, sorafenib and AG-013736 inhibit both VEGFR and PDGFR, providing a potentially synergistic approach to inhibiting RCC-associated angiogenesis4–6 in addition, sorafenib inhibits Raf kinase, an important downstream signalling molecule involved in both proliferative and angiogenic pathways4 CCI-779, a water-soluble ester of the mTOR (mammalian target of rapamycin) inhibitor sirolimus, is a novel inhibitor of the mTOR kinase.7 Kaelin WG. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002;2:673–82. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 2005;23:1028–43. Pollack VA, Savage DM, Baker DA, et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 1999;291:739–48. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099–109. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327–37. Inai T, Mancuso M, Hashizume H, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 2004;165:35–52. Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett 2005;10:479–98. . Raf Raf Sorafenib Erlotinib Sunitinib AG-013736 Sorafenib Sorafenib mTOR = mammalian target of rapamycin

Stem Cell Targeted Therapy True PCa stem-cell phenotype not yet identified, however, several stem-cell targets overexpressed in PCa hedgehog signaling pathway, human telomerase, and CD133

New concepts needed for new challenges Think differently 20th century ‘Seek and destroy’ 21st century ‘Target and control’ Andrew von Eschenbach Director of the National Cancer Institute

The HRPC - Team Urologist Medical oncologist Pain specialist Neurosurgeon Radiation oncologist Support group Psychologist

No real breakthrough yet in terms of survival !!

BRIDGING THE WORLD Eau – Europa Uomo

I appreciate your attention & Vielen Dank!