Targeting hypoxia in tumor: a new promising therapeutic strategy

The fundamental importance of adequate oxygenation for energy production has been recognized for centuries, but how cells and tissues are able to sense and adapt to changes in oxygen availability remained elusive until the late twentieth century. In the last 30 years, three physician-scientists, William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza, focused their studies on the molecular mechanisms of oxygen detection in human and animal cells and the signaling pathways and biological processes by which they respond to low oxygen level, referred to as hypoxia. Their work provided a series of closely overlapping and sometimes competitive contributions that ended with the Nobel Prize in Medicine 2019. In 1995, Semenza identified the Hypoxia Inducible Factor-1 (HIF-1) as a basic-helix-loop-helix-PAS α/β heterodimeric transcription factor regulated by cellular oxygen tension [1]. Afterward, the three scientists independently identified different molecular mechanisms through which cells regulate HIF-1 activity and the downstream induced genes, among which, erythropoietin (EPO) [1] and angiogenic factors [2], modulating about 5% of the human genome (Fig. 1a) and affecting many different diseases, as evidenced by the increased number of papers published on this topic in the last 25 years (Fig. 1b). HIF-1-dependent induction of hypoxia-responsive genes has been shown in hypoxic regions of tumor xenografts, suggesting a connection between HIF and cancer. Ratcliffe and Kaelin demonstrated the relevance of the von Hippel–Lindau (VHL) tumor suppressor protein for HIF-1α degradation through oxygen-regulated prolyl hydroxylation [3, 4], and Semenza identified the factor inhibiting HIF-1 (FIH-1) as a novel protein interacting with HIF-1α and VHL gene to mediate repression of HIF-1 transcriptional activity [5]. Prolyl hydroxylation at specific sites of HIF-1α is the crucial oxygen-dependent post-translational modification required for its recognition and degradation by the VHL ubiquitin proteasome pathway. This process is blocked under hypoxic conditions because oxygen-requiring HIF hydroxylases no longer act, and HIF-1α can be stabilized and assembled with the HIF-1β dimerization partner, binding to the hypoxia response elements (HRE) of hypoxia-regulated genes and transactivating their expression [4] (Fig. 1a). Furthermore, regulation of HIF-1 activity has been shown to depend also on hypoxia-independent genetic alteration [3‐5]. Starting from these studies, a plethora of regulators of HIF-1 transcriptional activity and HIF target genes affecting cellular responses to oxygen availability and, in particular, to hypoxic conditions, have been identified by researchers from all over the world [6, 7]. In 2010 the three scientists shared the Canada Gairdner International Award and in 2016 they received the Albert Lasker Award for Basic Medical Research for their work on oxygen sensing.

HIF-1 plays important roles in critical aspects of cancer biology, including angiogenesis, regulation of glucose and energy metabolism, epithelial-to-mesenchymal transition, invasion, metastasis, and stem cell maintenance (Fig. 1a), thus allowing tumor cells to proliferate and survive under hypoxic conditions. These discoveries provided proof-of-principle that inhibition of HIF-1 activity may represent a novel strategy for the therapy not only of cancer but also for other diseases characterized by impaired oxygenation, such as anemia, coronary artery disease, obstructive pulmonary diseases, chronic ischemic cardiomyopathy, inflammatory synovitis, atherosclerosis, systemic sclerosis, etc. [8, 9].

Over the last two decades, to bridge basic science to the clinical situation, dozens of putative small molecule HIF inhibitors that directly or indirectly downregulate HIF-1α have been identified and are currently tested in clinical trials for various forms of cancer [10]. Several HIF prolyl hydroxylase inhibitors, that prevent VHL from binding to HIF-1α, have also been developed and are now in late-stage clinical trials in disease in which HIF signaling is beneficial, e.g. to augment endogenous EPO production for the treatment of renal-based anemia. Such drugs are also being investigated for the treatment of circulatory diseases and for the protection against ischemic injury and inflammatory diseases, other than as anticancer molecules.