Abstract 5487: Targeting glycolysis for the treatment of cancer

Abstract

Abstract Tumors exhibit markedly increased glucose uptake and glycolysis and this metabolic phenotype serves to satisfy their increased requirement for energy and biosynthetic intermediates. Tumor glucose metabolism is stimulated in part by fructose-2,6-bisphosphate (F26BP), which is the product of a family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) and allosterically activates a key glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). Previous studies have found the PFKFB3 family member to be a dominant source of F26BP in cancer cells due to a high kinase activity, expression in multiple tumor types and the inhibition of tumor growth by specific PFKFB3 inhibitors including a compound, PFK158, that is currently under evaluation in a phase I trial. Recent data, however, indicate that the PFKFB4 enzyme plays a significant role in regulating glucose metabolism in neoplastic cells. We have found that PFKFB4 is highly expressed in multiple cancers, strongly induced by HIF-1α, and that its suppression markedly reduced F26BP and glycolytic flux, increased apoptosis and inhibited growth of xenograft tumors in vivo, thus providing strong rationale for the development of antineoplastic agents selectively targeting PFKFB4. Using virtual screening, we have discovered a first-in-class small molecule inhibitor of PFKFB4, termed 5MPN, that selectively inhibits recombinant PFKFB4 activity with a resultant decrease in F26BP, glycolytic flux and cancer cell growth in vitro and markedly reduces the growth of established tumors without systemic toxicity. During our studies, we unexpectedly observed that PFKFB4 expression is increased by PFKFB3 inhibition, suggesting that PFKFB4 may compensate for decreased PFKFB3 expression and activity. We examined the effects of simultaneous silencing of PFKFB4 and PFKFB3 on cancer cell lines and found that co-knockdown led to a significant decrease in cell viability and glycolysis and to a near-complete abrogation of anchorage-independent growth in vitro. We additionally examined the effect of simultaneous inhibition of PFKFB4 and PFKFB3 using 5MPN and several PFKFB3 inhibitors in vitro and found a synergistic increase in cell death. Taken together, our data indicate that targeting PFKFB4 may be a viable therapeutic option against cancer and strongly support the further development of PFKFB4 small-molecule inhibitors as well as the co-targeting of PFKFB4 and PFKFB3 as potential strategies for the treatment of cancer. Citation Format: Jason Chesney, Aubrey Mojesky, Yoannis Imbert-Fernandez, John Trent, Sucheta Telang. Targeting glycolysis for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5487.