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WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

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Potential drug for the treatment of Small Cell Lung Cancer

11 June 2014
The journal Clinical Cancer Research has recently published work undertaken by the Clinical and Experimental Pharmacology (CEP) group on the potential use of an experimental drug, AZD3965, in the treatment of Small Cell Lung Cancer (SCLC).  SCLC is the most aggressive form of lung cancer which often develops resistance to current therapies.  As SCLC is a fast growing cancer and as such is thought to use a sugar dependent mechanism of energy generation called glycolysis, which may allow it to be targeted with the latest family of targeted therapies.
 

AZD3965 is a drug which specifically blocks monocarboxylate transporter 1 (MCT1), a protein involved in the transport of lactate (a by-product of glycolysis).  By blocking MCT1, it is hoped that lactate would accumulate within the cells leading to the cellular contents, becoming acidic and toxic to the cancer cells.  To investigate this theory, the CEP group tested AZD3965 in several models of SCLC and showed a good response when SCLC was found to have low levels of oxygen (i.e. was hypoxic) and did not express a different transporter (MCT4) – a situation which was found in 21% of patient samples.  To confirm these findings, MCT4 levels were increased in SCLC cell lines which resulted in increased resistance to AZD3965, whereas decreasing the levels of MCT4 resulted in increased sensitivity in previously resistant cell lines.  During the study, it was also demonstrated that AZD3965 did not induce cancer cell death via either the apoptotic or the autophagic pathways but most likely acted to induce necrosis.

It is hoped that this and future studies will allow AZD3965 to be trialled in a subset of SCLC patients who have significant levels of MCT1 expressed in the hypoxic tumour regions and low levels of MCT4 expression, a subset which has been demonstrated to exist.