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

前列腺癌，像许多其他肿瘤类型一样，对转录“上瘾”-前列腺癌细胞需要增加转录水平才能生长。独特的是，它也对雄激素（雄性类固醇激素）上瘾，通过雄激素受体发出信号。这两种成瘾提供了一个治疗的机会，我们建议同时利用抑制细胞周期蛋白依赖性激酶7（CDK 7）。CDK 7对转录和雄激素受体活性都很重要。因此，我们假设前列腺癌对这种治疗方法具有额外的脆弱性，并且抑制前列腺癌中的CDK 7将通过抑制（i）RNA polII介导的转录，（ii）细胞周期，（iii）通过阻止其磷酸化直接抑制雄激素受体活性，（iv）通过阻止其与介体复合物的相互作用间接抑制雄激素受体活性，以多因素方式起作用。具体来说，我们将研究一种新的CDK 7抑制剂药物在前列腺癌中的作用，该药物是在帝国制药公司开发的，并与卡里克治疗公司合作进行前列腺癌的临床试验。我们之前已经表明，这可以在体外和体内阻断雄激素信号传导和前列腺肿瘤生长。我们将精确地确定我们的药物如何通过与最近显示在前列腺癌进展中重要的关键辅因子蛋白相互作用来抑制CDK 7抑制雄激素受体活性。我们将评估下游对基因表达和癌症相关过程的影响。我们将测试CDK 7抑制是否可以改善已经建立的前列腺癌药物联合使用时的性能，以延长预期寿命并改善晚期耐药前列腺癌患者的生活质量。重要的是，我们还可以确定标记，以选择哪些男性将从这种治疗中受益。

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.