Hypoxic stress signalling as a target for cancer drug development
Garth Powis
MD Anderson Cancer Center, Houston, USA
Solid tumors exist in a stressed environment. As even the smallest tumors grow they rapidly outstrip new blood vessel formation leading to poor perfusion and hypoxia. Genes induced by hypoxia allow the cancer cell to adapt to the hostile hypoxic environment by switching to anaerobic metabolism, decreasing overall protein synthesis, causing resistance to cell death, producing factors that increase the formation of new blood vessels from the existing vasculature (angiogenesis), and increased metastasis. Tumor cells also frequently develop constitutive upregulation of genes that regulate the hypoxic stress response. These constitutive and adaptive changes make tumors aggressive, resistant to radiation and chemotherapy, and lead to a poor patient prognosis. The hypoxic stress response is a normal physiological process employed in the early stages of embryogenesis but with a limited role in well perfused normal adult tissues. Although the changes result in aggressive, drug-resistant tumors they also provide an Achilles heel for selectively attacking the tumor, because without them the cancer cells will die. The most studied mechanism mediating the cancer cell’s response to hypoxia is an increase in the levels of the hypoxia inducible factor-1α (HIF-1α). The increase in HIF-1α is caused by a combination of decreased degradation by the ubiquitin/proteasome degradation pathway, and maintained or even increased synthesis during hypoxia at a time when the synthesis of nearly all other proteins is inhibited as an energy saving measure by the cell. HIF-1α combines with HIF-1β to form the HIF-1 transcription factor that moves to the nucleus and binds to a conserved HIF binding sequence (HBS) within the hypoxia-responsive element (HRE) in the promoter or enhancer regions of target genes to control the expression of more than 90 target genes that play critical roles in the acute and chronic adaptation to low oxygen. HIF-1α is expressed ubiquitously while a related protein HIF-2α displays more tissue-specific expression. HIF-2α regulates the expression of some of the same genes regulated by HIF-1α but also some specific genes. Recent studies suggest that HIF-1α and HIF-2α may play complementary roles in the survival of normal stem cells and tumor progenitor cells which are often in regions of hypoxia. Increased HIF-1 activity increases tumor growth, vascularisation and energy metabolism, whereas loss of HIF-1 activity dramatically suppresses these responses. It has been found that HIF- 1α over-expression is a marker of aggressive clinical disease associated with poor patient prognosis and treatment failure in a number of cancers. HIF-1α is, thus, an attractive target for cancer drug development. Two first-in-class agents, PX-12 and PX-478, that, act by different mechanisms to decrease tumor HIF-1α levels have been developed and are now in clinical trial.
