Despite the panoply of therapeutic options currently available in oncology, their success is limited by the abnormal tumor vasculature that impairs drug and oxygen delivery. In addition, the efficacy of anti-cancer treatment is challenged by the severity of its side effects. Our recent evidence shows that reduced activity of the oxygen sensor PHD2 normalizes the tumor endothelium via a shift to a more quiescent, ‘phalanx’ endothelial cell fate, that allows vessels to readjust their shape, not numbers, and thus optimize perfusion and oxygen supply when the latter is insufficient (Mazzone et al., Cell, 2009). Based on these findings, we will further investigate the role of PHD2 as a target to increase the response of tumors to chemo- and radiotherapy. Moreover, given the involvement of oxygen sensors in tissue protection against oxidative stress, we will explore PHD2 as a novel target against iatrogenic damage of healthy organs. Altogether, this will offer new therapeutic opportunities to maximize the effect of chemo- and radiotherapeutic drugs and minimize their side effects, currently limiting their success and usage in the clinic.

Ischemia is a clinically relevant condition that affects hundreds of millions of people worldwide with formidable morbidity and mortality. Therapeutic angiogenesis is an attractive treatment for this pathology, but, despite initial promise in animal models, delivery of a recombinant angiogenic factor or angiogenic gene transfer has so far failed in clinical trials. Besides technical difficulties in establishing long-term, local delivery methods of the angiogenic factor, it remains challenging to build functional, perfused and mature new blood vessels. Our most recent report in Cell demonstrates that reduced activity of the oxygen sensor PHD2 in hypoxia induces endothelial normalization, via a shift to a more quiescent, phalanx-like endothelial cell fate, and thereby improves vessel perfusion and oxygenation. This project aims to understand whether directing endothelial cells towards a phalanx fate might represent a novel and so far untested therapeutic strategy to promote revascularization of ischemic tissues. Different from the conventional past therapeutic angiogenesis strategies, we will investigate whether shaping the endothelial layer of neovessels, not increasing their number, has beneficial effects in ischemia.

Since solid tumors require angiogenesis for their growth and metastasis, anti-angiogenic therapy has been extensively studied in both preclinical and clinical settings, however they are failing to produce enduring clinical responses in most patients. Various mechanisms contribute to the resistance and escape from anti-angiogenic therapy. Anti-angiogenic therapy prunes the tumor vasculature, thereby depriving tumor cells from oxygen. The resultant hypoxia is a strong stimulus for the expression of various cytokines, which evoke escape from anti-angiogenic therapy and promote tumor cell dissemination. Previous reports have shown that inhibition of Met, the receptor for hepatocyte growth factor (HGF), blocks both tumor vessel and tumor cell growth. Although the role of Met in cancer cells has been extensively elucidated, much less attention has been paid to the role of Met in endothelial cell specification. This project aims to understand whether the hypoxia-driven HGF/Met pathway is required to promote endothelial tip cells, that lead the way of the angiogenic sprout at the forefront. Such insights will deliver novel scientific knowledge for development of alternative therapeutic approaches that overcome resistance to conventional anti-angiogenic therapies.

Abnormal and hyperactive tumor endothelium compared to a tight, smooth and quiescent formation of phalanx cells