BERKELEY, CA (UroToday.com) - Current treatment options for advanced renal cancer include the VEGF-targeted therapeutics and mTOR inhibitors. While targeted therapies have substantially improved progression-free survival for kidney cancer patients, acquired resistance results in disappointingly low survival rates. Up-regulation of alternative angiogenic pathways and increased tumor hypoxia resulting from VEGF inhibition are two possible mechanisms by which renal cancers evade anti-angiogenic therapy. Combining VEGF-targeted therapeutics with hypoxia-inducible factor (HIF) inhibitors may be one strategy to overcome hypoxia-mediated resistance. Some of the best characterized HIF-inhibitors belong to the topoisomerase I family of chemotherapeutic drugs (camptothecin, topotecan, irinotecan) and results of on-going clinical trials of Avastin combined with a camptothecin-based nanoparticle (CRLX101) are awaited.
In sporadic clear cell renal cell carcinoma, loss of function of the von Hippel-Lindau (VHL) tumor suppressor protein not only activates the HIF pathway, but also renders kidney cancer resistant to p53-dependent apoptosis. Second generation mTOR therapeutics – mTORC1/2 kinase inhibitors that target both mTOR complexes – may overcome the limitations of currently available mTORC1 drugs in their ability to inhibit both HIF-α subunits (HIF-1α and HIF-2α), thereby providing increased clinical benefit. Despite this, our observation that mTOR was also required for p53-mediated apoptosis in this tumor type may limit the potential use of mTOR inhibitors in combination with chemotherapeutics for renal cancer.
Our work has highlighted some key issues when tackling decisions concerning combination strategies for clear cell renal cell carcinoma as well as the need for patient stratification. It will be important to select the most effective HIF-inhibitor for combination therapy with anti-VEGF targeted drugs: the ability of some HIF-inhibitors to activate alternative undesirable pathways should be considered. It would also be interesting to know whether patients with intact VHL – which accounts for approximately 10% of sporadic clear cell renal cancers – gain additional benefit from CRLX101, given that this group of patients is more likely to have functional p53.
Veronica A. Carroll, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Division of Biomedical Sciences, St George's University of London, Cranmer Terrace, London, United Kingdom