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Giampaolo Tortora Fisiopatologia dellAngiogenesi oltre il VEGF Cattedra di Oncologia Medica e U.O.C. di Oncologia Medica Policlinico G.B. Rossi Azienda.

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Presentation on theme: "Giampaolo Tortora Fisiopatologia dellAngiogenesi oltre il VEGF Cattedra di Oncologia Medica e U.O.C. di Oncologia Medica Policlinico G.B. Rossi Azienda."— Presentation transcript:

1 Giampaolo Tortora Fisiopatologia dellAngiogenesi oltre il VEGF Cattedra di Oncologia Medica e U.O.C. di Oncologia Medica Policlinico G.B. Rossi Azienda Ospedaliera Universitaria Integrata Verona

2 Development of Anti-angiogenic drugs in BC st Phase 1/2 study of Bev in MBC initiated; modest single agent activity st Phase 1 study of Bev initiated st negative Phase 3 Bev trial reported in MBC st positive open-label Phase 3 Bev trial in MBC reported (E2100) 2003 Bev OS in mCRC leading to FDA approval in Phase 1/2 trials of sorafenib & sunitinib reported with modest single agent activity in MBC; RCTs with chemoRx initiated TKIs sorafenib & sunitinib FDA- approved in RCC Bev granted accelerated FDA- approval with 1 st line paclitaxel in MBC

3 The cardiovascular system The lymphatic immuno vascular system The two vascular systems

4 LAngiogenesi è un fenomeno complesso e multifattoriale Alla neo-angiogenesi partecipano molti tipi cellulari diversi che acquisiscono la capacità di produrre fattori angiogenici e/o di originare o trasformarsi in cellule endoteliali o simil-endoteliali. I fattori proangiogenici sono molto numerosi : VEGFsVEGFs PlGFPlGF bFGFsbFGFs HGFHGF EGFsEGFs IL-8IL-8 PDGFPDGF IGF-I TGF - TNF - GM-CSF Angiopoietins Angiogenin

5 Binding del VEGF ai recettori VEGFR-1/Flt-1 VEGFR-2/KDR VEGFR-3/Flt-4 LINFANGIOGENESI ANGIOGENESI

6 Binding of different isoforms of VEGF to VEGF-R Hicklin and Ellis, JCO 2005

7 VEGFR signalling pathways

8 PKC, PI3K and Akt are involved in angiogenesis Adapted from Graff J, et al. Cancer Res. 2005;65: Proliferation Angiogenesis

9 VEGF and breast cancer VEGF expression and MVD is increased in breast cancer Increased VEGF levels in breast cancer correlates with poor clinical outcome Anti-VEGF treatment inhibits breast cancer growth Brown, et al. Hum Pathol 1995; Borgstrom, et al. Anticancer Res 1999; Linderholm, et al. JCO 2000

10 HYPOXIA AND ANGIOGENESIS IN BREAST CANCER [Affymetrix array-C Sitiriou] Hypoxia related to down regulation of ER Selection of more aggressive phenotype Radiation resistance Independent of all other factors in prognosis Low oxygen tension is associated with increased metastasis and decreased survival of patients

11 VEGF (ng/cell) MCF-7 Neo MCF-7 HER-2/neu Concentration of VEGF in Conditioned Media of MCF-7 Neo and MCF-7 HER-2/neu Cells HER2-negative HER2-positive HER2-overexpressing breast cancer cells exhibit increased angiogenesis compared with control cells Slamon D.

12 VEGF Polymorphism in breast cancer

13 E2100, Schneider, B. P. et al. J Clin Oncol; 26: ; 2008 In E2100 Bev Arm, Improved Survival by Genotype VEGF-2578 VEGF-1154 VEGF-2578 AA VEGF-1154 AA N=363 tumor tissue AA Genotype at VEGF-2578 and Confers OS Advantage

14 VEGFs and VEGFRs

15 Blocking antibodies to VEGFR-3 and TKI as inhibitors

16 Blocking growth factor binding is inefficient at high ligand concentrations Tvorogov et al., Cancer Cell 2010

17 Helena Schmidt, K. Alitalo

18 VEGF IS DIFFERENTIALLY EXPRESSED IN THE VARIOUS GROWTH PHASES Modificato sulla base di : Sund M et al., GASTROENTEROLOGY 2005;129:2076–2091 ; Relf M et al., Cancer Res 1997;57:963–969; Arteaga et al.. Breast cancer Colon cancer ?

19 Theoretical pathways by which VEGF-targeted therapies can increase tumor aggressiveness in preclinical models ©2009 by American Association for Cancer Research Ellis L M, Hicklin D J Clin Cancer Res 2009;15: Potential mechanisms of resistance to VEGF inhibitors

20 Angiogenic signaling network: A gene regulatory network constructed from inversely regulated proangiogenic genes. Abdollahi A, Transcriptional network governing the angiogenic switch in human pancreatic cancer. PNAS 104: , 2007

21 Metabolic stress during tumor development Jones R. and Thompson C, Genes & Development 2009 tumors experiencing metabolic stress

22 mTOR integra i segnali di nutrienti e fattori di crescita mTOR Glucosio ATP Aminoacidi TSC2 TSC1 AMPK Glucosio ATP Segnale di crescita PI3K Akt LAT GLUT 1 mTOR è un sensore per la disponibilità di amminoacidi, rifornimenti metabolici ed energia I depositi di nutrienti e di energia sono essenziali per la sintesi proteica, la crescita cellulare e la sopravvivenza. L attivazione di mTOR può aumentare lespressione dei trasportatori dei nutrienti, Aumentando laccesso cellulare ai rifornimenti metabolici, mTOR può sostenere la crescita cellulare Sintesi proteica Angiogenesi Bioenergia Proliferazione cellulare

23 Interazione vasi- tumore Folkman J et al., Nature Reviews Cancer, 2007

24 Viable CEPS in non tumor-bearing BALBC mice after chemotherapy Patients who received chemotherapy exhibited significant increases in circulating VEGF-A, G-CSF and SDFα levels. The SDF-1α plasma levels were significantly induced in taxane-treated patients. ( Furstenberger, G et al )

25 Circulating Bone Marrow–Derived cell populations that stimulate or amplify tumor angiogenesis. Kerbel R, New England Journal Medicine,358: , F4/80, a pan macrophage cell-surface markerM; CXCR4, CXC chemokine receptor 4, RBCCs, recruited bone marrow–derived circulating cells, VE-cad vascular endothelial-cell cadherin (an adhesion molecule) The various hematopoietic (CD45+) cell types have a perivascular location with respect to the tumor neovasculature, whereas the CD45 endothelial progenitor cells can become incorporated into the lumen of a growing blood vessel and differentiate into mature endothelial cells. In recent preclinical studies, neutrophils have also been shown to contribute to the induction of tumor angiogenesis. potential to differentiate to endothelial cells and contribute to tumor vasculature

26 Switching in angiogenesis: the two-faces of microenvironment Noonan DM, Cancer Metastasis Rev.2007

27 Macrophages, angiogenesis and cancer Lee et al. J. Cancer Mol. 2(4): , 2006 TAM produce HIF-1-2 Attract monocyte that differentiate into TAM

28 Circulating Bone Marrow–Derived cell populations that stimulate or amplify tumor angiogenesis. Kerbel R, New England Journal Medicine,358: , F4/80, a pan macrophage cell-surface markerM; CXCR4, CXC chemokine receptor 4, RBCCs, recruited bone marrow–derived circulating cells, VE-cad vascular endothelial-cell cadherin (an adhesion molecule) The various hematopoietic (CD45+) cell types have a perivascular location with respect to the tumor neovasculature, whereas the CD45 endothelial progenitor cells can become incorporated into the lumen of a growing blood vessel and differentiate into mature endothelial cells. In recent preclinical studies, neutrophils have also been shown to contribute to the induction of tumor angiogenesis. potential to differentiate to endothelial cells and contribute to tumor vasculature

29 They find that cells derived from the bone marrow (green) precede tumour cells (red) to the lung, the site of metastasis. The bone marrow cells create a proposed pre- metastatic niche, and the tumour cells join them to form a metastasis (yellow; in fluorescence microscopy, green overlaid with red produces a yellow colour). The experiments of Lyden and the concept of premetastatic niche Kaplan, R. N. et al. Nature 438, 820–827 (2005). Steeg P. Nature 438, Editorial (2005). BM cells arrive to sites of future metastasis prior to tumor cells

30 Arrival of VEGFR1+ BM and VEGFR2 + Endothelial Cells Courtesy of David Lyden

31 Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis Lobos JBL… Kerbel, Cancer Cell 15, 232–239, March 2009 Accelerated experimental metastasis and decreased survival after short-term sunitinib treatment before and after Intravenous Tumor Inoculation 231/LM2-4LUC+ No treatment Rx before implantation Rx after implantation

32 Change in the paradigm of antiangiogenic therapy NO to treatments that reduce the number of vessels, cause hypoxia and consequent angiogenic factors (VEGF) production, thus favouring tumour regrowth. YES to treatments that normalize vessels without affecting their number and the oxygenation. Jain R, Science 2005; 307: 58 Endothelial cells sense O2 and have reduced oxygen consume.

33 Frequency Among GFP+ Cells CD11b+ Gr1+ CD11b+Gr Anti-VEGFControl TIB6B16F1EL4LLCTIB6B16F1EL4LLC * * * ++ + * * * LegendPrimed Mice B16F1 Cell Line B16F1 EL4 LLC None LLC EL4 BMMNCs CD11b+Gr1+ CD11b-Gr1- + * * * Mean Tumor Volume (mm 3 ) 3500 Reduced responsiveness to anti-VEGF-A therapy following co-injection of CD11b+Gr1+ (but not CD11b-Gr1-) cells from VEGF-independent tumors Shojaei et al. Nature Biotechnol., 8:911-20, 2007 Refractoriness to anti-VEGF-A is not mediated by the VEGFR-1 specific ligands VEGF-B or PlGF

34 Anti-Bv8 antibodies suppress tumor angiogenesis and growth Anti-VEGFAnti-Bv8 Control HM7 tumor Shojaei et al., Nature 450: , 2007 Additive effects of anti-VEGF and anti-Bv8 in treating established tumors

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