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

新型前列腺癌治疗剂 CT7001 的作用机制和效用评估

• 批准号: 2598405
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2598405
• 关键词: Evaluation; mechanisms; action; utility; new

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.

与许多其他肿瘤类型一样，前列腺癌对转录“上瘾”——前列腺癌细胞需要增加转录水平才能生长。独特的是，它还对雄激素（男性类固醇激素）上瘾，雄激素通过雄激素受体发出信号。这两种成瘾都提供了治疗机会，我们建议通过抑制细胞周期蛋白依赖性激酶 7 (CDK7) 同时利用这一机会。 CDK7 对于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CDK7将以多因素方式发挥作用，通过抑制（i）RNA polII介导的转录，（ii）细胞周期，（iii）通过防止其磷酸化直​​接抑制雄激素受体活性，（iv）通过防止其与介体相互作用来间接抑制雄激素受体活性。 复杂的。具体来说，我们将研究一种新的 CDK7 抑制剂药物在前列腺癌中的作用，该药物是帝国理工学院开发的，并与 Carrick Therapeutics 合作进行前列腺癌临床试验。我们之前已经证明，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。我们将精确确定我们的药物抑制 CDK7 如何通过其与最近被证明在前列腺癌进展中很重要的关键辅因子蛋白的相互作用来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 CDK7 抑制是否可以提高现有前列腺癌药物联合用药的性能，从而延长患有晚期、治疗耐药性前列腺癌的男性的预期寿命并提高其生活质量。重要的是，我们还可以确定标记来选择哪些男性将从这种治疗中受益。