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: 8691047
• 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/8691047
• 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; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Prostatic Neoplasms; RNA Interference; Radiation; Radiation therapy; Regulation; Repression; Resistance; Signal Pathway; Signal Transduction; Signaling Molecule; Specimen; Testing; Therapeutic; Tumor Suppressor Proteins; Work; Xenograft Model; abiraterone; cancer therapy; castration resistant prostate cancer; checkpoint kinase 2; clinical application; clinically relevant; effective therapy; in vivo; in vivo Model; inhibitor/antagonist; insight; loss of function mutation; men; novel; prostate cancer cell; public health relevance; receptor function; resistance mechanism; response; success; therapeutic target; therapy development; 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(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，肿瘤通常依赖雄激素生长，因此对利用手术和/或药物耗尽循环雄激素的治疗有效。然而，这种类型的治疗成功是暂时的。这种疾病几乎总是复发，即使在循环中雄激素水平较低的情况下也是如此，并进展为转移性和致命性疾病。雄激素受体(AR)对去势耐受前列腺癌(CRPC)的生长和生存至关重要。最近FDA批准了CYP17抑制剂阿比特龙和新型抗雄激素药物MDV3100，强调了靶向AR功能在CRPC中的临床重要性。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重新激活，带来致命的后果。了解导致AR重新激活的机制是至关重要的，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靶点。在这个项目中，我们建议研究一种抗雄激素抵抗的机制，这是治疗联合靶向的最佳机会：通过信号分子调节AR。我们最近在前列腺癌细胞中通过一个激动子宽的RNA干扰筛选发现，检查点激酶2(Chk2)的敲除显著促进了前列腺癌细胞的生长。这一观察结果具有临床意义，因为超过10%的前列腺癌患者会出现Chk2失活突变，并且随着前列腺癌进展为去势抵抗疾病，Chk2的表达减少。这些数据有力地表明，Chk2在前列腺癌中起负调控或肿瘤抑制作用。我们已经确定，Chk2基因敲除可以增加AR的转录活性，并且Chk2基因敲除导致的生长增加可以被抗雄激素阻断。这为Chk2对前列腺癌细胞生长的作用提供了证据，至少部分是通过AR实现的。此外，我们还发现，在G2/M细胞中，Chk2活性的下游效应因子CDK1可以直接磷酸化S308上的AR，雄激素调节G2/M中独特的基因亚集。这具有重要的临床意义，因为CDK1活性在CRPC中升高。在本项目中，我们打算确定Chk2调节AR活性和CRPC细胞生长的机制。具体地说，我们假设Chk2信号的减少增加了AR的活性，并通过AR S308的磷酸化促进了细胞的增殖，从而推动前列腺癌的进展到去势抵抗。几种CHK抑制剂和第二代CDK1抑制剂现在正在进行临床试验。此外，Chk2信号通路被激活，以响应DNA损伤，如辐射造成的损伤。因此，描绘Chk2对AR活性的影响将为如何更有效地结合放射治疗和雄激素阻断提供重要的见解。