(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（应用程序提供）：此应用程序是对RFA-CA-12-021的响应：对NCI挑衅性问题组D（R01）的研究答案（R01）并解决了PQD1：通过使用不同类型和靶向疗法施加的选择性压力如何改变耐药性的演变？该应用的总体目的是调查由雄激素剥夺治疗（ADT）引起的对随后治疗的抗药性机制的差异，雄激素剥夺治疗（ADT）是复发性前列腺癌（CAP）的护理标准治疗。我们假设在不同遗传背景的男性中，不同类型的ADT导致对其他治疗的反应各不相同，并且可能直接影响生存。该应用程序代表了一个团队的努力，涉及研究癌症生物学，遗传学，生物统计学，生物信息学和临床经验的研究人员，因此为检验这一假设提供了独特的机会。我们的初步数据表明，这些差异可能是由于AR共同调节剂Filemin a（FLNA）的差异表达而产生的，该表达会影响由AR调节的转录程序，并导致某些基因的差异表达，例如新颖的AR靶NRDP1，但不是其他基因，但不是其他基因，例如其他知名的AR靶标PSA。使用用各种形式的ADT处理的患者衍生的异种移植物（PDX），我们建议通过快速高吞吐量平行测序进行研究，并与CHIP-SEQ结合使用，以识别AR靶标和RNA-Seq，以查看整体分子曲线，以这些差异的差异和分子机制，并且这些差异通过这些差异。我们将确定PDX的分子谱是否受到处理的影响以及所得的分子构造是否决定了这些肿瘤对其他治疗的反应（例如，AR拮抗剂，AR拮抗剂与化学纳维AR拮抗剂）。此外，我们将确定AR共同调节因子如何影响AR的转录程序，以及为什么某些基因受该程序影响而其他基因而不是其他基因。最后，我们将研究差异分子谱，特别是新型AR转录靶标NRDP1及其下游效应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，在CRPC患者的血清中，NRDP1或其靶向ERBB3的水平与疾病的侵略性相关。预期的总体影响：该提案将利用新确定的AR靶基因（NRDP1）来解决CRPC当前管理中的一个重大问题，在该管理中，医生通常必须盲目分配一种治疗方法，而另一种治疗则针对CRPC患者。预测对AR拮抗剂与化学治疗剂的反应以及用于最大化患者反应的事件的序列将显着提高这组患者的生存。如果在人类患者中进行验证，这项研究的结果有可能被转化为III期试验，以确定患者反应的分子预测因子是否可以区分那些将受益于直接AR抑制剂的患者和应该接受化学疗法的患者。

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