Abstract

Despite recent advances, ovarian cancer remains an inadequately treated disease with only 40% of patients surviving more than 5 years with advanced disease. Rather than developing new drugs to treat this disease, an alternative is to repurpose existing drugs that are normally used to treat diseases other than cancer. A large body of preclinical research has suggested that statins, drugs normally used to treat elevated cholesterol, should be effective anti-cancer agents. However, this has not been borne out in numerous clinical trials. In the first part of this seminar, I will argue that this is because the clinical trials have not been designed with due regard to preclinical data and that the failure of statins as anti-cancer therapeutics in patients to date reflects, at least in part, a lack of diligent clinical trial design. Importantly, the data that will be presented will point to how statins might be used effectively to treat cancer, including cancers such as pancreatic cancer that are dependent on K-Ras.

In the second part of the seminar, I will present the results of a screen to identify genes which contribute to the resistance to the chemotherapeutic agents to treat ovarian cancer. One hit from this screen unexpectedly is involved in regulating branched-chain amino acid (BCAA) metabolism, a biological process not previously implicated in drug resistance. Inhibition of branched-chain keto-acid dehydrogenase kinase (BCKDK) stimulates BCAA metabolism and sensitizes both ovarian and breast cancer cells to paclitaxel. The reduced BCAA levels inhibit the mTORC1-Aurora signalling axis which regulates microtubule function during cell division. Considering that paclitaxel also impairs microtubule function, this suggests a mechanistic basis for the synergy between BCKDK inhibitors and paclitaxel. Considering that some cancers are dependant on BCAA metabolism, these data suggest that improved inhibitors of BCKDK may be useful as either single agents or in combination with chemotherapy to treat cancer.