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PO-424 modulating hexokinase 2 (HK2) as a novel approach to target metabolic immuno-oncology
  1. V Behar,
  2. R Yosef,
  3. E Dor-On,
  4. N Amsalem,
  5. Y Horev,
  6. OM Becker
  1. Vidac Pharma, Discovery, Jerusalem, Israel

Abstract

Introduction Metabolic reprogramming is one of the hallmarks of cancer, to support their needs for massive growth and proliferation. One major metabolic reprogramming is from oxidative phosphorylation to aerobic glycolysis, a well-documented phenomenon known as the Warburg effect. A key enzyme in this process is hexokinase 2 (HK2), which catalyses the first step of glucose metabolism and is overexpressed in many cancer types. Unlike HK1, which is ubiquitously expressed in normal cells, HK2 is required for cancer initiation and transformation even though their catalytic activity is highly similar. HK2 in cancer cells is attached to the outer mitochondrial membrane via the VDAC1 channel. VDAC1/HK2 association blocks pro-apoptotic signals, is less sensitive to feedback inhibition by the HK product, glucose-6-phosphate, 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. Detachment of HK2 from VDAC1 in activated immune cells leads to a range of responses ranging from glycolysis inhibition, NLRP3-mediated inflammasome activation, and metabolic reprogramming to activate immune pathways.

Material and methods A novel small molecule VDAC/HK2 modulator, VDA-1102, is being developed as a bi-functional drug for the treatment of solid tumours – triggering apoptosis in cancer cells while simultaneously enhancing an immune-mediated anti-tumour response by regulating immune cell metabolism.

Results and discussions In vitro studies established that VDA-1102 selectively detaches HK2, but not HK1, from VDAC1 leading to cancer cell apoptosis, glycolysis inhibition, and prevention of cancer cell proliferation. In vivo efficacy studies demonstrated significant tumour growth delay and prolongation of survival in syngeneic solid tumour models. Analysis of tumor-associated macrophages in vivo indicated a treatment-induced change in these macrophage phenotype from M2 to M1.

Conclusion 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 stimulates an anti-tumour 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 tumours.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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