Abstract CT206: PFK-158, first-in-man and first-in-class inhibitor of PFKFB3/ glycolysis: A phase I, dose escalation, multi-center study in patients with advanced solid malignancies
Authors: Redman Rebecca , Pohlmann Paula , Kurman Michael , Tapolsky Gilles H. , Chesney Jason 
Published: August 2015

Abstract
Metabolic alterations in cancer have been recognized as important novel targets, especially glycolysis. Over-expression of HIF-1α, activation of Ras, AKT or PI3K, loss of p53 or PTEN are associated with the development of human cancers and converge on glycolysis by activating PFKFB3, a bifunctional enzyme. This enzyme interconverts fructose-6-phosphate (F6P) to fructose-2,6-bisphosphate (F2,6BP) and F2,6BP is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and control point in the glycolytic pathway. PFKFB3 is of particular interest since it controls the intracellular concentration of F2,6BP, is required for tumorigenic growth and it has been found to be activated in human cancer cell lines and tumors, to be increased by hypoxic exposure via HIF-1α and by several oncogenes and mutations.
PFK-158 is a potent and selective inhibitor of PFKFB3 that is currently being investigated in a phase I study in patients with advanced solid malignancies. PFK-158 is: (i) is a nanomolar inhibitor of recombinant PFKFB3; (ii) inhibits PFKFB3 activity and glycolysis in cancer cells; (ii) is well tolerated in vivo; and (iv) is very effective in multiple preclinical mouse models of human-derived tumors and syngeneic murine models. IND-enabling safety and toxicity studies demonstrated that PFK158 is well tolerated in rats and dogs and supported the initiation of a phase I trial that is now underway.
The primary objective of the study is to describe the dose limiting toxicity and to determine either the maximum tolerated dose or biological effective dose of PFK-158 in a “3+3” cohort-based dose escalation design that follows a modified Fibonacci scheme. The pharmacokinetic profile of PFK-158 will also be determined. Multiple secondary endpoints have been incorporated to assess the effects of PFK-158 on peripheral blood mononuclear cell (F6P; F2,6BP; 14C-2-dexoyglucose uptake) and on glucose uptake using FDG-PET imaging. This trial, opened at two US sites, is currently enrolling Cohort 3 (96 mg/m2). Prior cohorts (24 and 48 mg/m2) have been completed without dose-limiting toxicities or drug-related significant adverse events. Of the patients enrolled to date, a patient of Cohort 1 was on study for 6 cycles during which his overall hepatic metastatic tumor burden decreased.
In addition, numerous publications demonstrated that over-expression of HIF-1α, activation of Ras, AKT or PI3K, loss of p53 or PTEN converge on glycolysis by activating PFKFB3. Results of preclinical studies show that combination of PFK-158 with targeted agents, which indirectly activate glycolysis, leads to clear therapeutic benefits.
In conclusion, PFK158 is the first-in-man and first-in-class PFKFB3 inhibitor to be examined in a phase I trial and may have significant clinical utility either as a monotherapy or when combined with targeted agents.
Citation Format: Rebecca Redman, Paula Pohlmann, Michael Kurman, Gilles H. Tapolsky, Jason Chesney. PFK-158, first-in-man and first-in-class inhibitor of PFKFB3/ glycolysis: A phase I, dose escalation, multi-center study in patients with advanced solid malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT206. doi:10.1158/1538-7445.AM2015-CT206