Abstract 325: Evaluating the consequences of MCT1 inhibition in Burkitt lymphoma following treatment with AZD3965
Authors: Noble Richard A. , Bell Natalie , Blair Helen , Thomas Huw D. , Bomken Simon , Critchlow Susan E. , Wedge Stephen R. 
Published: July 2016

Many tumors display an altered metabolic phenotype with an increased reliance on glycolysis resulting in a greater production of the waste product, lactate [1]. Use of glycolysis, as opposed to oxidative phosphorylation, represents a less efficient means of ATP generation but provides a selective advantage to cancer cells in that it rapidly supplies intermediates to support anabolic pathways necessary for increased cellular proliferation. Lactate efflux, is facilitated by monocarboxylate transporters 1-4 and is essential to prevent feedback inhibition of major energy generating pathways. A sub-group of cancers express only MCT1 and are therefore exclusively reliant on this transporter to export lactate. Elevated MCT1 expression has previously been identified in Burkitt lymphoma (BL), a highly aggressive form of non-Hodgkin's lymphoma characterised by MYC translocations [2].

We have studied the effects of a potent, selective and orally available inhibitor of MCT1, AZD3965, in models of BL that predominantly express MCT1. MCT1 inhibition was associated with intracellular lactate accumulation in vitro and a significant growth inhibitory effect (AZD3965 72h GI50 &lt;10 nM). MCT1 inhibition was also associated with a number of changes in intracellular metabolites, including increases in TCA cycle and early glycolytic intermediates, indicating potential feedback mechanisms following lactate accumulation.

A measurable increase in lactate accumulation was also detectable in vivo following acute treatment with AZD3965 (100 mg/kg p.o.) using NOD/LtSz-scid IL-2Rγ -/- (NSG) mice bearing subcutaneous CA46 human xenografts. The efficacy of AZD3965 was subsequently investigated in vivo using a more clinically representative form of this BL xenograft model. Here, CA46 cells were engineered to express firefly luciferase (SLIEW lentivector) and then inoculated intravenously into NSG mice. Tumor engraftment was confirmed 6 days after inoculation by the detection of luciferase-based bioluminescence using the IVIS® Spectrum. Oral treatment with either AZD3965 (100mg/kg) or vehicle (both administered twice-daily Monday to Friday and once-daily at weekends) was then initiated for a period of 24 days. Bioluminescence was measured 3 days after the start of treatment and at weekly intervals to determine total tumor burden. Tumor growth relative to control xenografts was inhibited significantly by AZD3965 treatment (&gt;99% P&lt;0.005 Student's two-tailed t-test). In support of this efficacy, post-mortem macroscopic measurements revealed greatly reduced tumor cell engraftment of bone marrow and spleen in MCT1 inhibitor treated animals.

AZD3965 has potent growth inhibitory activity in both in vitro and in vivo models of Burkitt lymphoma that are reliant upon MCT1 for lactate transport.

[1] Science (1956) 123, 309-314

[2] Cancer Res (2014) 74, 908-920

Citation Format: Richard A. Noble, Natalie Bell, Helen Blair, Huw D. Thomas, Simon Bomken, Susan E. Critchlow, Stephen R. Wedge. Evaluating the consequences of MCT1 inhibition in Burkitt lymphoma following treatment with AZD3965. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 325.