Abstract 5992: Targeting glucose metabolism in cancer

Abstract

Abstract Positron emission tomographic studies with 2-18F-fluoro-2-deoxy-glucose (FDG-PET) consistently demonstrate that tumors take up significantly more glucose than adjacent normal tissues in vivo. Tumors rely on glucose metabolism to provide the energy and biosynthetic intermediates required to fuel their rapid growth and metastasis. Tumor glucose metabolism is stimulated in part by fructose-2,6-bisphosphate (F26BP), the product of the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4), which allosterically activates a key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). We have found that the PFKFB4 family member plays a significant role in regulating glucose metabolism in neoplastic cells. We determined that PFKFB4 is highly expressed in multiple cancer types and strongly induced by the transcription factor HIF-1α and that its suppression markedly reduced F26BP, glycolytic flux and the growth of xenograft tumors providing strong rationale for the development of anti-neoplastic agents selectively targeting PFKFB4. By the use of virtual screening, we discovered a first-in-class small molecule inhibitor of PFKFB4, termed 5MPN, that selectively inhibits PFKFB4 activity with a resultant decrease in F26BP, glycolysis and cancer cell growth in vitro and a marked suppression of growth in established tumors, importantly without systemic toxicity. During our studies, we unexpectedly observed that inhibition of a frequently co-expressed PFKFB family member, PFKFB3, increased PFKFB4 expression, indicating that PFKFB4 may compensate for decreased PFKFB3 expression. This observation is highly relevant given that a PFKFB3 inhibitor (PFK158) has recently been clinically evaluated in a Phase I trial and compensation by PFKFB4 may limit the efficacy of this and other PFKFB3 inhibitors. We examined the effects of simultaneous silencing of PFKFB4 and PFKFB3 on cell lines derived from multiple tumor types and found that co-knockdown led to a significant decrease in cell viability and glycolysis and a near-complete abrogation of anchorage independent growth in vitro. We also have now evaluated the effects of simultaneous inhibition of PFKFB4 and PFKFB3 on cancer cells using small molecule inhibitors of both enzymes and found that co-inhibition led to a significant decrease in F26BP production, a synergistic increase in cell death in vitro and marked suppression of xenograft tumor growth in vivo relative to either inhibitor alone. Taken together, our data indicate that targeting PFKFB4 may be a viable therapeutic option against cancer and strongly support the further exploration of co-targeting PFKFB4 and PFKFB3 as a potential therapeutic strategy for the successful treatment of cancer. Citation Format: Evan Meiman, Bryana Braxton, John Trent, Jason Chesney, Sucheta Telang. Targeting glucose metabolism in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5992.