Pre-Clinical Targeting Of The Metabolic Phenotype Of Lymphoma By Azd3965, A Selective Inhibitor Of Monocarboxylate Transporter 1 (Mct1)

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction - The metabolic phenotype of tumours (relative to most normal tissues) is shifted from oxidative phosphorylation to aerobic (Warburg Effect) or anaerobic glycolysis. This enables tumours to meet their energetic and biosynthetic demands even under conditions of low nutrient and O2. The end-product of glycolysis is lactate, a metabolic dead end, which if allowed to accumulate in the tumour cell may cause feedback inhibition of glycolysis and intra-cellular acidification resulting in inhibition of cell growth or survival. Experimental data - We have studied the effects of a potent, selective and orally available inhibitor of MCT1 in lymphoma cell lines and in vivo models. AZD3965 is a small molecule inhibitor of MCT1 with a binding affinity of 1.6 nM, is 6 fold selective over MCT2 and does not inhibit MCT4 at 10 μM. Both lactate transport and cell growth are potently inhibited by AZD3965 in lymphoma cell lines that preferentially express MCT1. Lactate transport inhibition in some cell lines also induces a cytotoxic effect. In vitro combination studies show that lactate transport inhibition can enhance the induction of cell death by doxorubicin. Blocking lactate transport in vitro also leads to a rapid inhibition of glucose uptake in the Raji Burkitt's lymphoma cell line. In vivo, AZD3965 is well tolerated and induces a dose and time dependent accumulation of lactate in the tumours, suppresses tumour growth and in the Raji model potentiates the effects of Rituxan, doxorubicin and bendamustine. Conclusions - Here we demonstrate that selective inhibition of lactate transport by the MCT1 inhibitor AZD3965 offers an novel mechanism for targeting the metabolic phenotype in tumours that preferentially express MCT1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3224. doi:1538-7445.AM2012-3224