Evaluation of mechanisms of action and utility of a new prostate cancer therapeutic, CT7001

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Prostate cancer, like many other tumour types, is "addicted" to transcription - prostate cancer cells require increased levels of transcription to grow. Uniquely it is also addicted to androgens (male steroid hormones), which signal via the androgen receptor. Both these addictions provide a therapeutic opportunity, which we propose to exploit simultaneously by inhibiting cyclin-dependent kinase 7 (CDK7). CDK7 is important both for transcription and for androgen receptor activity. We thus hypothesise that prostate cancer has additional vulnerabilities to this therapeutic approach, and inhibiting CDK7 in prostate cancer will act in a multifactorial way by inhibiting (i) RNA polII-mediated transcription generally, (ii) cell cycle, (iii) androgen receptor activity directly, by preventing its phosphorylation, (iv) androgen receptor activity indirectly activity, by preventing its interaction with Mediator complex. Specifically, we will be investigating the action in prostat cancer of a new CDK7 inhibitor drug, developed at Imperial and in clinical trials for prostate cancer in partnership with Carrick Therapeutics. We have previously shown that this can block androgen signalling and prostate tumour growth in vitro and in vivo We will determine precisely how CDK7 inhibition by our drug inhibits androgen receptor activity via its interaction with a critical cofactor protein recently shown to be important in prostate cancer progression. We will assess downstream effects on gene expression and cancer-associated processes. We will test whether CDK7 inhibition can improve the performance of already-established prostate cancer drugs when in combination, to prolong life expectancy and improve quality of life for men with advanced, therapy-resistant prostate cancer. Importantly, we may also identify markers to select which men would benefit from this treatment.