Mechanistic Basis of Resistance to Chemohormonal Treatment in Prostate Cancer

前列腺癌化学激素治疗耐药的机制基础

• 批准号: 10219799
• 负责人: Zachary Rockow Chalmers
• 金额: $ 5.1万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219799
• 关键词: Address; Androgen Antagonists; Biological Assay; Biopsy; Cancer Etiology; Cancer Patient; Caring; Cells; Cessation of life; Chemoresistance; Clinical; Clinical Skills; Core Facility; Cytotoxic agent; Data; Development; Diagnosis; Disease; Equipment; Face; Facility Accesses; Fellowship; Funding; Generations; Genetic Transcription; Goals; Homeodomain Proteins; Human; Image; In Vitro; Indolent; Institution; Knowledge; LNCaP; Label; Laboratories; Luciferases; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Mentorship; Mesenchymal; Metastatic Prostate Cancer; Molecular; Mus; Outcome; Pathogenesis; Pathogenicity; Patients; Phenotype; Physicians; Prognosis; Prostate Cancer therapy; Regional Disease; Research Personnel; Resistance; Role; SCID Mice; Scientist; Testing; Tissues; Training; United States; Universities; Work; androgen deprivation therapy; anticancer research; chemotherapy; clinically relevant; docetaxel; effective therapy; epithelial to mesenchymal transition; experimental study; genetic signature; improved; in vitro Model; in vivo; insight; male; men; migration; mortality; mouse model; overexpression; programs; prostate cancer cell; prostate cancer model; therapy design; therapy resistant; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor initiation

PROJECT SUMMARY In 2019, prostate cancer will be diagnosed in an estimated 174,650 men, and account for 31,620 deaths, second only to lung cancer in terms of mortality for men. While local and regional disease typically carries an excellent prognosis, prostate cancer is a heterogeneous and diverse disease that includes both indolent and aggressive phenotypes. Androgen deprivation therapy (ADT) was the first successful treatment for men with advanced metastatic prostate cancer more than 50 years ago, and it remains a cornerstone of treatment today, but not all men will respond to ADT. The use of chemotherapy in combination with ADT significantly improved upon ADT alone in terms of overall survival. Unfortunately, despite these advances, a significant portion of men are resistance to combination chemohormonal therapy. The long-term goal of this proposal is to enable more effective treatments for men with prostate cancer. This application proposes to address this goal by investigating the mechanistic basis for chemohormonal resistance in prostate cancer using in vitro cellular studies, in vivo murine models, and retrospective patient data. Our laboratory has identified Paired-Related Homeobox Protein 2 (PRRX2) as contributing to ADT resistance in vitro. Interestingly, PRRX2 is known to promote an epithelial to mesenchymal transition (EMT), which is associated with chemoresistance in prostate cancer. However, the role of PRRX2-driven EMT has not been investigated in the context of chemohormonal resistance. Therefore, my central hypothesis is that a PRRX2- driven increase in EMT causes chemohormonal treatment resistance in prostate cancer. To test my hypothesis, with Aim 1 I will determine the contribution of PRRX2 to EMT and chemohormonal resistance using in vitro models of prostate cancer. In Aim 2, I will use in vivo mouse models determine the sufficiency of PRRX2-driven EMT for chemohormonal resistance. Finally, in Aim 3, I will evaluate the clinical relevance of my results by developing a gene signature of PRRX2-driven EMTness, and determining its association to clinical features of prostate cancer using patient data. Together, these aims will fill a fundamental gap in the understanding of prostate cancer pathogenesis, and allow for more effective treatments to be developed. I will carry out these experiments under the mentorship of my sponsor, Dr. Sarki Abdulkadir, with his extensive expertise in prostate cancer research. Dr. Abdulkadir will provide all of the necessary equipment and facilities, and access to the core facilities of Northwestern University. The training plan set out by Dr. Abdulkadir will train me as an independent researcher, while also maintaining my clinical skills to prepare me exceptionally well for the next steps of my training as a physician scientist.

项目摘要 2019年，估计将有174，650名男性被诊断出患有前列腺癌，并导致31，620人死亡， 男性死亡率仅次于肺癌。虽然当地和区域性疾病通常携带 前列腺癌是一种异质性和多样性的疾病，包括惰性和非惰性。 攻击性表型雄激素剥夺疗法（ADT）是第一个成功治疗男性 晚期转移性前列腺癌，50多年前，它仍然是今天治疗的基石， 但并非所有男性都会对ADT做出反应。化疗联合ADT的使用显著改善了 在总生存期方面，不幸的是，尽管取得了这些进展， 男性对激素联合化疗有抵抗力。该提案的长期目标是使 更有效的治疗方法。本申请提出通过以下方式来实现这一目标： 使用体外细胞培养技术研究前列腺癌中化学激素抵抗的机制基础 研究、体内鼠模型和回顾性患者数据。 我们的实验室已经确定配对相关同源异型盒蛋白2（PRRX 2）有助于ADT耐药 体外有趣的是，已知PRRX 2促进上皮向间充质转化（EMT），这是一种免疫调节。 与前列腺癌的化疗耐药性有关。然而，PRRX 2驱动的EMT的作用尚未得到证实。 在化学激素抗性的背景下进行研究。因此，我的中心假设是PRRX 2- EMT的驱动增加导致前列腺癌的化学激素治疗抗性。测试我 假设，目标1我将确定PRRX 2的EMT和化疗激素耐药的贡献 使用前列腺癌的体外模型。在目标2中，我将使用体内小鼠模型来确定 PRRX 2驱动的EMT用于化学激素抗性。最后，在目标3中，我将评估 通过开发PRRX 2驱动EMT的基因签名，并确定其与 前列腺癌的临床特征。总之，这些目标将填补一个根本性的空白， 前列腺癌的发病机制的理解，并允许更有效的治疗被开发。我会 我在我的赞助商Sarki Abdulkadir博士的指导下进行这些实验，他有着广泛的 前列腺癌的治疗方法阿卜杜勒卡迪尔博士将提供所有必要的设备和设施， 以及西北大学的核心设施阿卜杜勒卡迪尔博士制定的培训计划将培训 我作为一个独立的研究人员，同时也保持我的临床技能，让我做好准备， 我作为一名医生科学家的下一步训练。