Abstract 1725: A bi-functional mechanism of action: Activating the NLRP3 inflammasome and triggering apoptosis in cancer via a HK2-VDAC modulator
Authors: Behar Vered , Hamo Reut Yosef , Dor-On Eyal , Becker Oren M. 
Published: August 2018

Abstract
Introduction: Cancer cells undergo metabolic reprogramming to enable the efficient conversion of glucose needed for massive cell growth and proliferation, a well-documented phenomenon known as the Warburg effect. A key enzyme in this process is hexokinase 2 (HK2), which catalyzes the first step of glucose metabolism. Unlike HK1, which is ubiquitously expressed in normal cells, high levels of HK2 are found in cancer where it is required for cancer initiation and transformation. HK2 in cancer cells is attached to the outer mitochondrial membrane via the VDAC1 channel. VDAC1/HK2 association blocks pro-apoptotic signals as well as allows a continuous flux of mitochondrial ATP to HK, leading to apoptosis prevention and a high rate of glycolysis.
Temporal high HK2 expression, and binding to VDAC, is also found in a variety of activated immune cells to support their changing metabolic needs. It has been recently published that detachment of HK2 from VDAC is one of the first events leading to the NLRP3-inflammasome activation, resulting in IL-1β and IL-18 secretion from macrophages (Cell 166:624 (2016)).
Methods: A novel small molecule VDAC/HK2 modulator, VDA-1102, is being developed as a bi-functional drug for the treatment of solid tumors – triggering apoptosis in cancer cells while simultaneously activating the NLRP3-inflammasome in macrophages to induce an anti-tumoral immune response.
Results: In vitro studies established that VDA-1102 selectively detaches HK2, but not HK1, from VDAC leading to cancer cell apoptosis, glycolysis inhibition, and prevention of cancer cell proliferation. VDA-1102 treatment of mouse primary bone marrow-derived macrophages and of human macrophage cell line, THP-1 cells, established a dose-dependent NLRP3-inflammasome activation and cytokine secretion. In vivo efficacy studies demonstrated significant tumor growth delay in syngeneic solid tumor models.
Analysis of tumor-associated macrophages indicated a treatment-induced change in these macrophage phenotype from M2 to M1. This change was associated with a notable increase in spleen size, an increase ratio of naïve T cell in the spleen, and a significant increase in CD8+ and CD4+ tumor-infiltrating T cells.
Conclusions: This data supports the notion that VDA-1102 is a bi-functional drug that targets both cancer and the innate immune system. In cancer cells it induces apoptosis, whereas in macrophages it activates the NLRP3-inflammasome machinery and stimulates an anti-tumor immune response. Our findings support further development of VDA-1102 to evaluate its potential as an anti-cancer therapy, either as a monotherapy or in combination with checkpoint inhibitors in high HK2-expressing solid tumors.
Citation Format: Vered Behar, Reut Yosef Hamo, Eyal Dor-On, Oren M. Becker. A bi-functional mechanism of action: Activating the NLRP3 inflammasome and triggering apoptosis in cancer via a HK2-VDAC modulator [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 1725.