(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: 9281694
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281694
• 关键词: Acetates; Address; Affect; Agonist; Androgen Antagonists; Androgen Receptor; Animal Model; Binding; Bioinformatics; Biometry; Blood specimen; Cancer Biology; Cancer Patient; Castration; Cell Nucleus; ChIP-seq; Clinical; Data; Disease; Dose; Drug resistance; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Evolution; Family; 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; Physicians; Plasma; Prediction of Response to Therapy; 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; androgen deprivation therapy; cancer cell; castration resistant prostate cancer; cell free DNA; chemotherapeutic agent; chemotherapy; design; differential expression; experience; filamin; genetic makeup; improved; inhibitor/antagonist; member; men; mouse model; novel; phase II trial; phase III trial; predicting response; pressure; prevent; profiles in patients; programs; promoter; public health relevance; resistance mechanism; response; standard of care; targeted treatment; transcriptome; 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（由申请人提供）：本申请是对 RFA-CA-12-021：NCI 挑衅性问题 D 组 (R01) 的研究答案的回应，并解决 PQD1：使用不同类型和剂量的靶向治疗所施加的选择压力如何改变耐药性的演变？该应用的总体目标是研究雄激素剥夺疗法（ADT）（复发性前列腺癌（CaP）的标准治疗方法）的变化引起的后续治疗耐药机制的差异。我们假设不同遗传背景的男性接受不同类型的 ADT 会导致肿瘤对额外治疗的反应不同，并可能直接影响生存。该应用代表了具有癌症生物学、遗传学、生物统计学、生物信息学和临床经验的研究人员的团队努力，因此提供了检验这一假设的独特机会。我们的初步数据表明，这些差异可能是由于 AR 辅助调节因子 Filamin A (FlnA) 的差异表达而产生的，FlnA 影响 AR 调节的转录程序，并导致某些基因的差异表达，例如新的 AR 靶点 Nrdp1，但不会导致其他基因的差异表达，例如众所周知的 AR 靶点 PSA。使用经过各种形式的 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进行研究，结合 ChIP-Seq 来识别 AR 靶点，并结合 RNA-Seq 来研究总体分子谱、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 的分子特征是否受到治疗的影响，以及由此产生的分子成分是否决定这些肿瘤对额外治疗的反应（例如化疗后使用 AR 拮抗剂与未接受化疗的 AR 拮抗剂）。此外，我们将确定包括 FlnA 在内的 AR 协同调节因子如何影响 AR 转录程序，以及为什么某些基因受该程序影响，而其他基因则不受此影响。最后，我们将研究差异分子谱，特别是新型 AR 转录靶点 Nrdp1 及其下游效应子 ErbB3 的表达，是否可用于预测患者对 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（而非 PSA 水平）与疾病的侵袭性相关。预期总体影响：该提案将利用新确定的 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 患者分配一种治疗与另一种治疗。预测 AR 拮抗剂与化疗药物的反应，以及用于最大化患者反应的事件顺序，将显着提高这组患者的生存率。这项研究的结果如果在人类患者中得到验证，有可能转化为 III 期试验，以确定患者反应的分子预测因子是否可以区分哪些患者可以从立即 AR 抑制剂中受益，哪些患者应该接受化疗。

项目成果

Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer.

• DOI: 10.1038/s41388-022-02382-y
• 发表时间: 2022-07
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Dutta, Samikshan;Polavaram, Navatha Shree;Islam, Ridwan;Bhattacharya, Sreyashi;Bodas, Sanika;Mayr, Thomas;Roy, Sohini;Albala, Sophie Alvarez Y.;Toma, Marieta, I;Darehshouri, Anza;Borkowetz, Angelika;Conrad, Stefanie;Fuessel, Susanne;Wirth, Manfred;Baretton, Gustavo B.;Hofbauer, Lorenz C.;Ghosh, Paramita;Pienta, Kenneth J.;Klinkebiel, David L.;Batra, Surinder K.;Muders, Michael H.;Datta, Kaustubh
• 通讯作者: Datta, Kaustubh