(PQD-1) Selective pressure of antiandrogens on castration resistant prostate canc

(PQD-1) 抗雄激素对去势抵抗性前列腺癌的选择性压力

• 批准号: 8687395
• 负责人: PARAMITA M. GHOSH
• 金额: $ 25.81万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687395
• 关键词: Acetates; Address; Affect; Agonist; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Binding; Bioinformatics; Biometry; Blood specimen; Cancer Biology; Cancer Patient; Caring; Castration; Cell Nucleus; Cells; ChIP-seq; Clinical; DNA; Data; Disease; Dose; Drug resistance; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Evolution; Family; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Transcription; Hormones; Human; Institution; Laboratories; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Molecular; Molecular Profiling; Mus; Nature; Nuclear; Orchiectomy; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phase III Clinical Trials; Physicians; Plasma; Prostate; Prostate-Specific Antigen; Publications; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent tumor; Relapse; Reporting; Research; Research Personnel; Resistance; Scheme; Serum; Specificity; Testing; Translating; Variant; Work; Xenograft Model; Xenograft procedure; abiraterone; castration resistant prostate cancer; chemotherapeutic agent; chemotherapy; deprivation; design; experience; filamin; improved; inhibitor/antagonist; member; men; mouse model; novel; pressure; prevent; programs; promoter; prostate cancer cell; public health relevance; resistance mechanism; response; transcriptome sequencing; tumor; tumor growth; tumor progression; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): This application is in response to RFA-CA-12-021: Research Answers to NCI's Provocative Questions-Group D (R01) and addresses PQD1: How does the selective pressure imposed by the use of different types and doses of targeted therapies modify the evolution of drug resistance? The overall objective of this application is to investigate differences in mechanisms of resistance to subsequent therapy caused by variations in androgen deprivation therapy (ADT), the standard-of-care treatment for recurrent prostate cancer (CaP). We hypothesize that different types of ADT in men of different genetic background result in tumors of varied response to additional therapy and may directly affect survival. This application represents a team effort involving investigators with cancer biology, genetics, biostatistics, bioinformatics and clinical experience and therefore provides a unique opportunity to test this hypothesis. Our preliminary data indicate that these differences may arise due to differential expression of the AR co-regulator Filamin A (FlnA) which affects the transcriptional program regulated by the AR and result in differential expression of certain genes, such as the novel AR target Nrdp1, but not that of others, such as the well-known AR target PSA. Using patient derived xenografts (PDX) treated with various forms of ADT, we propose to investigate by rapid high throughput parallel sequencing, in conjunction with ChIP-Seq to identify AR targets and RNA-Seq to look at overall molecular profiles, the targets that are differentially regulated and the molecular mechanisms by which these differences arise. We will determine whether the molecular profile of the PDX is affected by the treatment and whether the resulting molecular constituency determines the response of these tumors to additional treatment (e.g. chemotherapy followed by AR antagonists vs chemo-na¿ve AR antagonists). Additionally, we will determine how AR co-regulators including FlnA affect AR transcriptional programs and why certain genes are affected by this program while others are not. Finally, we will investigate whether the differential molecular profile, in particular, the expression of the novel AR transcriptional target Nrdp1 and its downstream effector ErbB3, may be used to predict response of patients to AR inhibitors. We intend to demonstrate that levels of the Nrdp1 or its target ErbB3, but not PSA levels, in the serum of CRPC patients correlate to the aggressiveness of the disease. Expected overall impact: This proposal will utilize a newly identified AR target gene (Nrdp1) to address a significant problem in current management of CRPC where physicians often have to blindly assign one treatment vs. another for patients with CRPC. Prediction of response to AR antagonists' vs chemotherapeutic agents, and the sequence of events to be used to maximize patient response, will significantly improve survival in this group of patients. The results of this study, if validated in human patients, has the potential of being translated to a Phase III trial to determine whether molecular predictors of patient response may differentiate between patients who would benefit from immediate AR inhibitors and those who should get chemotherapy.

描述(申请人提供)：本申请是对RFA-CA-12-021的回应：研究回答了NCI的挑衅性问题-D组(R01)，并解决了PQD1：使用不同类型和剂量的靶向治疗施加的选择压力如何改变耐药性的演变？这项应用的总体目标是调查雄激素剥夺疗法(ADT)的差异导致对后续治疗的抵抗机制的差异，ADT是复发性前列腺癌(CAP)的治疗标准。我们假设，不同遗传背景的男性不同类型的ADT会导致肿瘤对额外治疗的不同反应，并可能直接影响生存。这项申请代表了一个团队的努力，涉及癌症生物学、遗传学、生物统计学、生物信息学和临床经验的研究人员，因此提供了一个独特的机会来检验这一假设。我们的初步数据表明，这些差异可能是由于AR协同调节因子丝氨酸A(Flna)的差异表达，它影响了AR调控的转录程序，并导致某些基因的差异表达，如新的AR靶标Nrdp1，而不是其他基因的差异表达，如众所周知的AR靶标PSA。使用不同形式的ADT处理的患者来源的异种移植物(PDX)，我们建议通过快速高通量并行测序，结合CHIP-SEQ来识别AR靶点和RNA-SEQ来查看整体分子图谱、差异调节的靶点以及产生这些差异的分子机制。我们将确定PDX的分子图谱是否受到治疗的影响，以及由此产生的分子组成是否决定了这些肿瘤对额外治疗的反应(例如，化疗后使用AR拮抗剂与化疗后使用AR拮抗剂)。此外，我们将确定包括FLNA在内的AR共同调节因子如何影响AR转录程序，以及为什么某些基因受到该程序的影响，而其他基因则不受影响。最后，我们将研究差异分子图谱，特别是新的AR转录靶点Nrdp1及其下游效应因子ErbB3的表达，是否可以用来预测患者对AR抑制剂的反应。我们打算证明CRPC患者血清中Nrdp1或其靶标ErbB3的水平，而不是PSA水平，与疾病的侵袭性相关。预期的总体影响：这项建议将利用新发现的AR靶基因(Nrdp1)来解决当前CRPC管理中的一个重大问题，即医生经常不得不盲目地为CRPC患者分配一种治疗方案与另一种疗法。预测AR拮抗剂对化疗药物的反应，以及用于最大化患者反应的事件序列，将显著提高这类患者的存活率。这项研究的结果如果在人类患者中得到验证，有可能被转化为第三阶段试验，以确定患者反应的分子预测指标是否可以区分哪些患者将受益于立即服用AR抑制剂的患者，哪些患者应该接受化疗。