RB Function in Prostate Cancer Progression

RB 在前列腺癌进展中的功能

基本信息

批准号：
9196346
负责人：
KAREN E KNUDSEN
金额：
$ 43.13万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-14 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196346
关键词：
American Androgen Receptor Androgens Binding Bypass Cancer Etiology Cells Cessation of life Chromatin Clinical DNA damage checkpoint Data Diagnosis Disease Disease Progression E2F1 gene Employee Strikes Event Functional disorder Gene Amplification Gene Expression Genetic Genomics Genotoxic Stress Growth Human Hypersensitivity In Vitro Intervention Knowledge Lead Ligands Malignant Neoplasms Malignant neoplasm of prostate Mediating Modality Modeling Molecular Morbidity - disease rate Outcome Output Pathway interactions Patients Phase Phenotype Play Pre-Clinical Model Process Prostate Adenocarcinoma Prostatic Neoplasms Publishing Recurrent tumor Regulation Reporting Resistance Role Signal Transduction Therapeutic Therapeutic Intervention Tissues Treatment Failure Tumor Suppressor Proteins Up-Regulation Variant androgen deprivation therapy castration resistant prostate cancer chemotherapy follow-up human disease improved in vivo insight loss of function men neoplastic cell novel personalized medicine personalized therapeutic precision medicine prevent programs public health relevance therapeutic target therapy resistant tool transcription factor transcriptome tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostatic adenocarcinoma (PCa) is the most frequently diagnosed malignancy and 2nd leading cause of cancer death in American men. PCa is resistant to standard chemotherapy, but is exquisitely dependent on the activity of the androgen receptor (AR, a ligand-dependent transcription factor) for growth, survival, and progression. As such, AR is the first line therapeutic target for all patients with disseminated disease. AR- directed therapies entail the use of androgen deprivation therapy (ADT), which suppresses testicular androgen synthesis; these modalities prevent AR from binding chromatin and inducing gene expression, and are often used in combination with direct AR antagonists. While initially effective, recurrent tumors arise within 2-3 years wherein the AR has been inappropriately reactivated. This stage of disease, termed "castration-resistant prostate cancer" (CRPC) is the incurable phase, and underpins the significant morbidity associated with PCa. Thus, there is an urgent need to identify the diverse mechanisms utilized by tumors to reactivate AR, and to develop mechanisms of thwarting this process. Examination of human CRPC revealed that the major mechanism leading to therapy-resistance is upregulation of AR. Consonantly, preclinical modeling of even modest AR upregulation showed that this event alone is sufficient to drive progression to incurable CRPC. The mechanisms by which AR upregulation occurs during disease progression remained incompletely defined - while amplification of the AR locus accounts for a fraction of these observations, a significant proportion of CRPCs show upregulation of AR without gene amplification. Strikingly, our recently reported findings identify perturbation of the RB tumor suppressor as a major mechanism by which AR deregulation occurs and induces CRPC formation, independent of AR amplification. Our collective data have potentially dramatic clinical implications, and strongly support the hypothesis that perturbations of the RB/E2F1/AR axis play a major role in the transition to CRPC, and that RB status can be developed as a metric to direct personalized therapeutic intervention in prostate cancer. Three aims are proposed to challenge this hypothesis: Three aims are proposed will: 1) Define the molecular mechanisms and clinical consequence of RB dysfunction in CRPC; 2) Delineate the impact of RB loss on aberrant AR signaling; and 3) Examine targeting the RB/E2F1/AR axis to suppress PCa progression.

描述（由申请人提供）：前列腺癌 (PCa) 是美国男性中最常诊断的恶性肿瘤，也是癌症死亡的第二大原因。 PCa 对标准化疗具有抵抗力，但其生长、存活和进展高度依赖于雄激素受体（AR，一种配体依赖性转录因子）的活性。因此，AR 是所有播散性疾病患者的一线治疗靶点。 AR定向疗法需要使用雄激素剥夺疗法（ADT），抑制睾丸雄激素合成；这些方式可防止 AR 结合染色质并诱导基因表达，并且通常与直接 AR 拮抗剂联合使用。虽然最初有效，但 2-3 年内会出现复发性肿瘤，其中 AR 被不适当地重新激活。这一阶段的疾病被称为“去势抵抗性前列腺癌”(CRPC)，是不可治愈的阶段，是与 PCa 相关的显着发病率的基础。因此，迫切需要确定肿瘤重新激活 AR 的多种机制，并开发阻止这一过程的机制。对人类 CRPC 的检查表明，导致治疗抵抗的主要机制是 AR 的上调。一致地，即使是适度的 AR 上调的临床前模型也表明，仅这一事件就足以推动进展为无法治愈的 CRPC。 AR 上调在疾病进展过程中发生的机制仍未完全确定 - 虽然 AR 基因座的扩增占这些观察结果的一小部分，但很大一部分 CRPC 显示 AR 上调而没有基因扩增。引人注目的是，我们最近报道的研究结果表明，RB 肿瘤抑制因子的扰动是 AR 失调发生并诱导 CRPC 形成的主要机制，与 AR 扩增无关。我们的集体数据具有潜在的巨大临床意义，并强烈支持这样的假设：RB/E2F1/AR 轴的扰动在向 CRPC 的过渡中发挥着重要作用，并且 RB 状态可以作为一种指标来指导个性化治疗干预前列腺癌。提出三个目标来挑战这一假设：提出三个目标： 1) 定义 CRPC RB 功能障碍的分子机制和临床后果； 2) 描述RB丢失对异常AR信令的影响； 3) 检查靶向 RB/E2F1/AR 轴以抑制 PCa 进展。