Molecular investigation of drug synergy in cancer

点击翻译按钮获取中文摘要

A major challenge for cancer treatment rationales is predicting the actual clinical response to anti-cancer drugs for each individual patient. As well as predicting if a patient will be resistance or sensitive to a particular drug, the ability to predict which combinations of drugs may work synergistically for a particular patient is also critical i.e. the personalised medicine approach. To this end we created an expert system bioinformatic pathway that emulates the decision-making ability of a human expert, utilising drug IC-50 values for 139 drugs across 689 cell lines with gene mutation, gene regulation and copy number data, covering a multitude of cancers. This system has been validated by the "re-discovery" of many known associations between molecular signatures and drug sensitivity (paper submitted, 2016). It was also able to "re-discover" known drug combinations that work in synergy (e.g. BRAF and MEK inhibitors for melanoma); taken together this proves the success of the novel bioinformatics approach we have designed. This project would verify novel predictions of sensitivity and synergy as well as elucidating the mechanisms of synergetic relationships. The objective of this project is to investigate validity and elucidate mechanisms of predicted synergistic drug combinations. Sensitivity predictions and predictions of synergism, between drug combinations of particular interest, will be in validated in existing cancer cell lines, using a panel of cell lines for which genomic and transcriptomic profiling is available for but were not originally used in bioinformatics predictions. Validated synergism will be further investigated and the mechanism behind the synergy elucidated. Our bioinformatic pipeline above identifies gene mutations, expression values or copy numbers that are potentially crucial in predicting the synergy between drugs (e.g. common mutations which lead to sensitivity of these drugs). These predictive markers will be used to identify target molecules for investigations into synergistic mechanisms. The mechanism will then be probed by over expression, silencing, or pharmacological modulation of targets of interest. The mechanism of cell death/senescence and the cells molecular response will also be probed using various appropriate assays, immunoblotting, qPCR, etc.Strong drug combination candidates will be taken forward for investigation in primary cancer cell cultures and if time allows to in vivo models.If successful our project will validate a novel strategy for identifying clinically useful drug combinations as well as validating specific drug combinations with clinical potential.