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Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients’ tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed in vivo: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks in vitro resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death in vitro and reduced CA46 disease burden in vivo. These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.

PURPOSE: To evaluate the pharmacokinetics (PK) of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in mice after IV and oral administration and to develop mechanistic PK models to assess the potential enterohepatic circulation (EHC) and target-mediated drug disposition (TMDD) of AZD3965. METHODS: Female BALB/c mice were administered AZD3965 by IV injection (10, 50 and 100 mg/kg) or oral gavage (100 mg/kg). Plasma samples were analyzed using LC/MS/MS, and PK parameters determined by compartmental and non-compartmental analyses. RESULTS: AZD3965 exhibited a large volume of distribution and rapid oral absorption, with a high oral bioavailability. Prominent reentry peaks were observed after both oral and IV administration, suggesting potential EHC of AZD3965 or of a potential glucuronide conjugate. The dose-dependent studies indicated greater than proportional increases in exposure, an increase in the terminal half-life, and decrease in clearance and volume of distribution with increasing IV doses, indicating nonlinear pharmacokinetics and potential TMDD of AZD3965. Mechanistic compartmental models were developed to characterize the complex pharmacokinetics of AZD3965. CONCLUSIONS: The current study represents the first comprehensive report of the pharmacokinetics of AZD3965 in mice, indicating the potential contribution of EHC and TMDD in the disposition of AZD3965.

Purpose: The monocarboxylate transporter 1 (MCT1) inhibitor, AZD3965, is undergoing phase I evaluation in the United Kingdom. AZD3965 is proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. We investigated the therapeutic potential of AZD3965 in small cell lung cancer (SCLC) seeking rationale for clinical testing in this disease and putative predictive biomarkers for trial use. Experimental Design: AZD3965 sensitivity was determined for seven SCLC cell lines, in normoxia and hypoxia, and for a tumor xenograft model. Proof of mechanism was sought via changes in intracellular/tumor lactate. Expression of MCT1 and related transporter MCT4 was assessed by Western blot analysis. Drug resistance was investigated via MCT4 siRNAi and overexpression. The expression and clinical significance of MCT1 and MCT4 were explored in a tissue microarray (TMA) from 78 patients with SCLC. Results: AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intratumor lactate. In the TMA, high MCT1 expression was associated with worse prognosis (P = 0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumors. Conclusions: This study provides a rationale to test AZD3965 in patients with SCLC. Our results suggest that patients with tumors expressing MCT1 and lacking in MCT4 are most likely to respond. Clin Cancer Res; 20(4); 926–37. ©2013 AACR.

Increased glycolytic rates in cancer cells generate high levels of lactate that are exported by the monocarboxylate transporters (MCTs) 1-4. AZD3965 is an orally bioavailable inhibitor of MCT-1 that was originally developed by AstraZeneca (Macclesfield, England, UK) for use in transplant rejection / autoimmune disease. It has increased selectivity for MCT1 over MCT2 and does not inhibit MCT4. A Cancer Research UK phase I study of AZD3965 in solid tumours is ongoing (NCT01791595). Small cell lung cancer (SCLC) is a highly proliferative tumour proposed to be reliant on glycolysis. We therefore conducted preclinical evaluation of AZD3965 in SCLC cell lines and xenografts with the aims to determine its therapeutic potential and putative predictive biomarkers for application in clinical trials. A cohort of tumour biopsies from SCLC patient s was also assessed for expression and clinical significance of MCT1, MCT4 and the hypoxia marker, CAIX. In seven SCLC cell lines sensitivity to AZD3965 varied and was highest in hypoxic culture conditions. Resistance was associated with high expression of MCT4. Treatment of the COR-L103 SCLC xenograft model with AZD3965 resulted in growth inhibition and increased levels of intratumour lactate. A tissue microarray (TMA) was constructed for 78 patients, immunostained with anti-MCT1, MCT4 and CAIX antibodies and scored by two independent observers. Clinical outcome data was available for 47 patients. Patients were stratified into MCT1 high/low, MCT4 high/low or CAIX high/low based on the median immunoscore from the complete TMA dataset. There were no significant associations with known clinical prognostic factors such as lactate dehydrogenase. Higher MCT1 expression was significantly associated with worse survival in univariate analysis (p = 0.014). A pattern of high MCT1 and hypoxia marker CAIX expression with low MCT4 expression was observed in 21% of SCLC cases. The preclinical results provide a rationale to evaluate AZD3965 in patients with SCLC, in particular those with presence of hypoxia, high MCT1 and low MCT4 expression. (Polanski et al. 2013 Clin Cancer Res; 20(4) 926-937)