Oxygen-independent regulation of HIF-1α levels

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2 Oxygen-independent regulation of HIF-1α levels Growth factors THIOREDOXIN (TRX) OXIDATIVE STRESS PKC PI3K Akt mtor PTEN HIF1α p70s6k Target gene mrnas SP1 HIF-1α mrna

3 Intratumor hypoxia Genetic alterations Increas in HIF-1α levels and HIF-1 activity Metabolic adaptation Invasion & metastasis Angiogenesis Aapoptosis resistance Microfotografie da: Aebersold, D. M. et al. Cancer Res. 61, (2001).

4 HIF-1 as a drug target RESVERATROL 103D5R TRX INHIBITORS HIF-1α mrna HIF1α HSP90 GELDANAMYCIN 17AAG EZN2968 (LNA) TOPOTECAN 26S CHAETOMINE 2-METHOXYESTRADIOL RESVERATROL; YC-1 p300 HIF1α HIF1β HRE Geni bersaglio mrna ENZIMA PRODRUG ACTIVE DRUG

6 ANGIOGENESIS IS ESSENTIAL TO TUMOR DEVELOPMENT Growth factors Tumor Pathologic angiogenesis Blood vessels

7 ANGIOGENESIS IS ESSENTIAL TO TUMOR DEVELOPMENT Normal vasculature Abnormal tumor vasculature

14 INTEGRINE Eterodimeri transmembrana 18 subunità e 8 subunità > 24 integrine i

21 INIBITORI DELLE INTEGRINE E i b i Etaracizumab: anti- v 3 Cilengitide

23 Nature Reviews Cancer 4, (2004);

25 HIF-1 activation can result in autocrine circuits IGF-2, TGF-α PKC PI3K Akt mtor HIF1α Survival signals p70s6k Target gene mrnas Synthesis SP1 HIF-1α mrna

29 VEGF IS THE MAJOR PRO-ANGIOGENIC FACTOR Effects of VEGF on tumor vasculature

30 VEGF IS THE MAJOR PRO-ANGIOGENIC FACTOR Si Stimulates the growth of new vessels and contributes to tumor progression Contributes t to vascular abnormalities that t may restrict t tumor access to chemotherapeutics Promotes survival of existing vessels

31 Expression of proangiogenic factors during a tumor s life cycle VEGF VEGF bfgf VEGF TGF -1 bfgf TGF -1 PIGF VEGF bfgf TGF -1 PIGF PD- ECGF VEGF bfgf TGF -1 PIGF PD-ECGF Pleiotrophin a VEGF EXPRESSION IS CONTINUOUS

32 1 VEGF-B Ligands VEGF-E VEGF-A 2 VEGF-A PlGF VEGF-C/D ANGIOGENESIS 3 VEGFR-1 Recettori Chinasi VEGFR-3 VEGFR-2 The VEGF system

33 GENETIC STABILITY OF ANTITUMOR TARGETS Autocrine growth factors (e.g. PDGF).Paracrine growth factorse.g. VEGF) Tumor Tumor Blood vessel TUMOR PROLIFERATION principally mediated by autocrine signal transduction pathways Receptors on tumor cells are subject to mutationi Tumor cell instability does not allow continuous inhibition of autocrine signal transduction pathways Blood vessel ANGIOGENESIS direct paracrine signal transduction pathway VEGF is genetically stable Relative ligand and receptor stability allows continuous inhibition of the VEGF system

34 STRATEGIES TO INHIBIT THE VEGF SYSTEM VEGF 1 Anti- ligand antibodies VEGFR-1 (flt-1) VEGFR-2 (KDE/flk-1) Endothelial cell VEGFR-3 (fls-4) 2 Low molecular weight TKIs

35 EFFECT OF CONTINUOUS VEGF INHIBITION Regression of the existing microvasculature Normalization of mature surviving vessels Inibition of vascular regrowth and neovascularization 1 2 3

36 CESSATION OF anti VEGF TREATMENT IS FOLLOWED BY CESSATION OF anti-vegf TREATMENT IS FOLLOWED BY RAPID VASCULAR REGROWTH

37 1 VEGF Tumor bfgf TGF -1 PIGF 2 Blood vessel Progression through non-mutational pathways

47 = VEGF-trap

48 CHARACTERISTICS OF VEGF-trap VEGF-trap is a fusion protein, made from key domains from VEGFR1 and VEGFR2 and from the Fc fragment of human IgG1 It only include human aminoacid sequences High affinity block of all VEGF-A isoforms as well as the placental growth factor (PlGF) Smaller size than monoclonal antibodies (MW ~ ) Long eliminaton half-life in man (20 giorni)

49 Angiogenesis inhibitors approved in the U.S. (and other 28 Countries) Date approved Drug Place Disease December 2003 Thalidomide Australia Multiple myeloma February 2004 Avastin U.S. (FDA) Colorectal cancer November 2004 Tarceva U.S. (FDA) Lung cancer December 2004 Avastin Switzerland Colorectal cancer December 2004 Macugen U.S. (FDA) Macular degeneration January 2005 Avastin European Union (25 countries) September 2005 Endostatin (Endostar) China (SFDA) Colorectal cancer Lung cancer

50 ADVANTAGES OF ANTI-ANGIOGENIC THERAPIES facile accessibilità del bersaglio selettività ità minore probabilità di sviluppo di fenotipi resistenti REALITY OR MYTHS?

53 Agenti diretti

59 VASCULAR TARGETING AGENTS

65 colchicine combretastatin A-4-P Flavone acetic acid (FAA). DMXAA (5,6-dimethylxanthenone-4-acetic acid).

Cancer as a disease of development; Developmental therapies: Anti- Angiogenesis; Stem cells and tissue regeneration.

Cancer as a disease of development; Developmental therapies: Anti- Angiogenesis; Stem cells and tissue regeneration Mitesh Shrestha What is Cancer? Unrestricted cell growth: tumor cell population 1x10^9