1. 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.

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

3. 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

4. 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 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 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–
Raf
Raf
Sorafenib
Erlotinib
Sunitinib AG
Sorafenib
Sorafenib
mTOR = mammalian target of rapamycin

5. 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

6. 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

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

8. No real breakthrough yet in terms of survival !!

9. BRIDGING THE WORLD
Eau – Europa Uomo

10. I appreciate your attention
&
Vielen Dank!