Checkpoint Signaling and Androgen Receptor Function in Prostate Cancer

前列腺癌中的检查点信号传导和雄激素受体功能

• 批准号: 9262061
• 负责人: Daniel G Gioeli
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262061
• 关键词: American; Androgen Antagonists; Androgen Receptor; Androgens; Automobile Driving; Biological Models; CDC2 Protein Kinase; CYP17A1 gene; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Castration; Cell Cycle; Cell Proliferation; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Complex; DNA; DNA Damage; Data; Disease; Disease Resistance; Effectiveness; Event; Generations; Genes; Genetic Transcription; Growth; In Vitro; Investigation; Link; Malignant neoplasm of prostate; Mediating; Mitosis; Modeling; Molecular; Mutation; Operative Surgical Procedures; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Prostatic Neoplasms; RNA interference screen; Radiation; Radiation therapy; Regulation; Repression; Resistance; Signal Pathway; Signal Transduction; Signaling Molecule; Specimen; Testing; Therapeutic; Tumor Suppressor Proteins; Work; Xenograft Model; abiraterone; androgen sensitive; cancer therapy; castration resistant prostate cancer; cell growth; checkpoint kinase 2; clinical application; clinically relevant; effective therapy; in vivo; in vivo Model; inhibitor/antagonist; insight; knock-down; loss of function mutation; men; novel; novel therapeutics; prostate cancer cell; public health relevance; radiation effect; receptor function; resistance mechanism; response; success; therapeutic target; therapy development; treatment response; tumor; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer deaths in North American men. For patients presenting with disseminated prostate cancer, the tumor is typically dependent on androgen for growth and is therefore responsive to therapies that take advantage of surgical and/or pharmacological depletion of circulating androgens. However, this type of therapeutic success is temporary. The disease almost invariably recurs, even in the face of low levels of circulating androgens, and progresses to a metastatic and lethal disease. The Androgen Receptor (AR) is essential for the growth and survival of castration-resistant prostate cancer (CRPC). The recent FDA approval of the CYP17 inhibitor abiraterone and the novel anti-androgen MDV3100 emphasize the clinical importance of targeting AR function in CRPC. Despite the justifiable excitement over these new therapies, the response to anti-androgens does not endure: the AR becomes reactivated with lethal consequences. It is essential to understand the mechanisms leading to AR reactivation, as they present targets for developing the combination therapies that will be required for effective deployment of next-gen anti-androgens. In this project, we propose studying a mechanism of resistance to anti-androgens that represents a prime opportunity for therapeutic co-targeting: AR regulation by signaling molecules. We recently discovered through a kinome wide RNA interference screen in prostate cancer cells that checkpoint kinase 2 (CHK2) knockdown significantly increased prostate cancer cell growth. This observation is clinically relevant since CHK2 inactivating mutations arise in over 10% of prostate cancer patients and CHK2 expression decreases as prostate cancer progresses to a castration- resistant disease. These data strongly suggest that CHK2 functions as a negative regulator or tumor suppressor in prostate cancer. We have determined that CHK2 knockdown increases AR transcriptional activity and that the growth increase resulting from CHK2 knockdown can be blocked with anti- androgens. This provides evidence that the CHK2 effect on prostate cancer cell growth functions, at least in part, through the AR. Moreover, we have discovered that CDK1, a downstream effector of CHK2 activity, can directly phosphorylate the AR on S308 in G2/M, and that androgen regulates a unique subset of genes in G2/M. This has significant clinical implications since CDK1 activity is elevated in CRPC. In this project we propose to determine the mechanism of CHK2 regulation of AR activity and CRPC cell growth. Specifically, we hypothesize that a reduction in CHK2 signaling increases AR activity and facilitates cell proliferation through AR S308 phosphorylation, thereby driving progression of prostate cancer to castration-resistance. Several CHK inhibitors and second-generation CDK1 inhibitors are now in clinical trials. Moreover, the CHK2 signaling pathway is activated in response to DNA damage such as that generated by radiation. Thus, delineating how CHK2 impinges on AR activity will provide important insights into how to more effectively combine radiation therapy with androgen blockade.

描述（由申请人提供）：前列腺癌是北美男性癌症死亡的第二大原因。对于表现为播散性前列腺癌的患者，肿瘤通常依赖于雄激素生长，因此对利用循环雄激素的手术和/或药物消耗的治疗有反应。然而，这种治疗成功是暂时的。这种疾病几乎总是复发，即使在循环雄激素水平低的情况下，也会进展为转移性和致命性疾病。雄激素受体（AR）对去势抵抗性前列腺癌（CRPC）的生长和存活至关重要。最近FDA批准的CYP 17抑制剂阿比特龙和新型抗雄激素MDV 3100强调了靶向CRPC中AR功能的临床重要性。尽管对这些新疗法的兴奋是合理的，但对抗雄激素的反应并不持久：AR被重新激活，具有致命的后果。了解导致AR再激活的机制至关重要，因为它们为开发有效部署下一代抗雄激素所需的联合疗法提供了目标。在这个项目中，我们建议研究抗雄激素的抗性机制，这代表了治疗共同靶向的主要机会：信号分子的AR调节。我们最近通过在前列腺癌细胞中的激酶组范围RNA干扰筛选发现，检查点激酶2（CHK 2）敲低显著增加了前列腺癌细胞的生长。该观察结果具有临床相关性，因为CHK 2失活突变出现在超过10%的前列腺癌患者中，并且CHK 2表达随着前列腺癌进展为去势抵抗性疾病而降低。这些数据有力地表明，CHK 2在前列腺癌中起负调节剂或肿瘤抑制剂的作用。我们已经确定CHK 2敲低增加AR转录活性，并且由CHK 2敲低引起的生长增加可以用抗雄激素阻断。这提供了CHK 2对前列腺癌细胞生长的作用至少部分地通过AR起作用的证据。此外，我们发现，CDK 1，CHK 2活性的下游效应子，可以直接磷酸化G2/M中S308上的AR，并且雄激素调节G2/M中独特的基因子集。这具有重要的临床意义，因为CDK 1活性在CRPC中升高。在这个项目中，我们建议确定CHK 2调节AR活性和CRPC细胞生长的机制。具体而言，我们假设CHK 2信号传导的减少增加AR活性并通过AR S308磷酸化促进细胞增殖，从而推动前列腺癌进展为去势抵抗。几种CHK抑制剂和第二代CDK 1抑制剂目前正在进行临床试验。此外，CHK 2信号通路响应于DNA损伤（例如由辐射产生的DNA损伤）而被激活。因此，描述CHK 2如何影响AR活性将为如何更有效地将联合收割机与雄激素阻断相结合提供重要的见解。