PHD2 IN METASTASIS

DISSECTING THE ROLE OF HIF-PROLYL-HYDROXYLASE 2 (PHD2) IN BREAST CANCER METASTASIS – IDENTIFYING NOVEL THERAPEUTIC TARGETS

Coordinatore	VIB    more  Organization address address: Rijvisschestraat 120 city: ZWIJNAARDE - GENT postcode: 9052 contact info Titolo: Mr. Nome: Rik Cognome: Audenaert Email: send email Telefono: 3292446611 Fax: 3292446610
Nazionalità Coordinatore	Belgium [BE]
Totale costo	177˙000 €
EC contributo	177˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2012-IEF
Funding Scheme	MC-IEF
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-07-01   -   2016-10-13

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	VIB  Organization address address: Rijvisschestraat 120 city: ZWIJNAARDE - GENT postcode: 9052 contact info Titolo: Mr. Nome: Rik Cognome: Audenaert Email: send email Telefono: 3292446611 Fax: 3292446610	BE (ZWIJNAARDE - GENT)	coordinator	177˙000.00

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 Obiettivo del progetto (Objective)

'Breast cancer (BC) is the most frequently diagnosed cancer in women, affecting one in eight women. Despite improved treatment strategies, BC recurrence after initial therapy is still responsible for nearly 500,000 deaths worldwide each year. This is related to the fact that BC cells metastasize very early in the disease course, and often remain unnoticed at the time of diagnosis. Novel therapeutic approaches that block metastasis offer thus great promise. Hypoxia is a key characteristic of solid tumors including breast cancer. Hypoxia inducible factor (HIF) is the main transcription factor involved in the cellular hypoxic response. The oxygen sensor enzymes, HIF-prolyl hydroxylases (PHD1-3) prevent HIF activity under normoxic conditions. Initial results indicate that haplodeficiency of the oxygen sensor HIF-prolyl hydroxylase 2 (PHD2) in tumor and stromal cells reduced metastasis by 80% in a clinically relevant spontaneously arising PyMT BC mouse model. We propose to dissect the molecular mechanisms of how PHD2-blockade inhibits tumor cell dissemination and breast cancer metastasis. Using a multi-disciplinary approach of state-of-the-art conditional and cell type-specific mouse genetics, transplantation assays, in combination with cell biological and molecular analysis in vitro we will determine the effect of PHD2 haplodeficiency on tumor cells as well as on cancer-associated fibroblasts (CAFs). Preliminary data indicate that these stromal cells have reduced invasive properties in the background of PHD2 halpodeficiency compared to wildtype CAFs. Besides promising to yield novel fundamental insights in the role of PHD2 in metastasis, this proposal will also test the clinically relevant question if a induction of global PHD2-silencing at various stages after onset of tumor growth can halt metastatic progression. Such “genetic treatment” experiments will yield valuable insights for the design of future pharmacological PHD2-blockade treatment of BC patients.'