Scientists from the Cancer Research UK Manchester Institute, based at The University of Manchester, and part of the Manchester Cancer Research Centre, have tested a new drug with the potential to treat small cell lung cancer, the most aggressive form of lung cancer.
The study, a collaborative effort with AstraZeneca, aimed to identify which patients were most likely to respond to AZD3965, a monocarboxylate transporter 1 (MCT1) inhibitor that kills tumor cells relying on glycolysis via lactate transport modulation.
Drugs that take advantage of the change in energy production in tumors have an enormous potential, since cancer cells rely heavily on glycolysis, a biological process that uses less oxygen and produces lactate as a by-product. Monocarboxylate transporters (MCTs) are involved in the transport of lactate out of cells, and drugs that target these molecules have been shown to stop tumor growth.
“Small cell lung cancer has a dismal prognosis and we have seen little improvement in treatment for many years. More targeted therapies are needed to help those patients whose tumors become resistant to chemotherapy. This new drug – AZD3965 – is currently in clinical trials, but it has not yet been tested in small cell lung cancer” said lead researcher Professor Caroline Dive.
The team determined the sensitivity of AZD3965 in vitro for seven small cell lung cancer (SCLC) cell lines in normal (normoxic) or low (hypoxic) oxygen conditions finding that AZD3965 sensitivity varied but was highest in hypoxia and cells lacking an alternate lactate transporter, MCT4, are not sensitive to the drug.
Additionally, the team created an in vivo tumor xenograft mouse model, and found that AZD3965 reduced tumor growth and increased intratumor lactate.
The expression and clinical significance of MCT1 and MCT4 were further investigated in a tissue microarray from tumor samples of 78 patients with SCLC, revealing that high MCT1 expression was associated with worse patient prognosis.
“We propose that this drug will be most useful in this subset of patients who have elevated MCT1 levels and need more effective treatments. Our laboratory results are promising and certainly provide encouragement to test this treatment clinically in patients with small cell lung cancer,” said Professor Dive.
Susan Galbraith, head of the oncology innovative medicines unit at AstraZeneca, added “lung cancer is still the leading cancer killer, and we are working on a number of potential treatment options that could provide patients with a better chance of beating the disease. Targeting tumor cell metabolism represents a novel and exciting approach, and we are delighted to be working with The University of Manchester and Cancer Research UK to investigate the utility of AZD 3965 as a potential novel cancer treatment.”
This study, published in the journal Clinical Cancer Research, provides a rationale for clinical testing in this disease and possible predictive biomarkers for trial use.
