权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10615052
负责人：
Zachary Rockow Chalmers
金额：
$ 5.27万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10615052
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 Fellowship Funding Generations Genetic Transcription Goals Homeodomain Proteins Hormonal Human In Vitro Indolent Institution Invaded Knowledge LNCaP Label Laboratories Localized Disease Luciferases Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Mentorship Mesenchymal Metastatic Prostate Cancer Molecular Mus Neoplasm Metastasis Organogenesis Outcome Pathogenesis Pathogenicity Patients Phenotype Physicians Prognosis Progressive Disease Proliferating Prostate Cancer therapy Regional Disease Research Personnel Resistance Role SCID Mice Scientist Testing Tissues Training Tumor Escape United States Universities Work androgen deprivation therapy anticancer research bioluminescence imaging chemotherapy clinically relevant docetaxel effective therapy empowerment enzalutamide epithelial to mesenchymal transition experimental study genetic signature hormone therapy 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

项目摘要

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.

项目概要 2019 年，估计将有 174,650 名男性被诊断出前列腺癌，并导致 31,620 人死亡，就男性死亡率而言，仅次于肺癌。虽然地方和区域疾病通常会携带预后极好，前列腺癌是一种异质性和多样化的疾病，包括惰性和惰性攻击性表型。雄激素剥夺疗法（ADT）是第一个成功治疗男性 50 多年前，它仍然是晚期转移性前列腺癌的治疗基石，但并非所有男性都会对 ADT 产生反应。化疗联合ADT显着改善就总生存率而言，仅使用 ADT 即可。不幸的是，尽管取得了这些进步，但很大一部分男性对联合化学激素疗法有抵抗力。该提案的长期目标是使对患有前列腺癌的男性进行更有效的治疗。该应用程序建议通过以下方式实现这一目标使用体外细胞研究前列腺癌化学激素抵抗的机制基础研究、体内小鼠模型和回顾性患者数据。我们的实验室已确定配对相关同源盒蛋白 2 (PRRX2) 有助于 ADT 耐药体外。有趣的是，PRRX2 已知可促进上皮间质转化 (EMT)，即与前列腺癌的化疗耐药相关。然而，PRRX2 驱动的 EMT 的作用尚未得到证实。在化学激素抵抗的背景下进行研究。因此，我的中心假设是 PRRX2- EMT 的驱动增加会导致前列腺癌对化学激素治疗产生耐药性。为了测试我的假设，目标 1 我将确定 PRRX2 对 EMT 和化学激素抵抗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 PRRX2 驱动的 EMT 用于化学激素耐药。最后，在目标 3 中，我将评估以下内容的临床相关性：我的结果是通过开发 PRRX2 驱动的 EMT 性的基因特征，并确定其与使用患者数据了解前列腺癌的临床特征。这些目标共同将填补一个根本性的空白了解前列腺癌的发病机制，并有助于开发更有效的治疗方法。我会在我的资助者 Sarki Abdulkadir 博士的指导下进行这些实验，他广泛的前列腺癌研究方面的专业知识。阿卜杜勒卡迪尔博士将提供所有必要的设备和设施，并可使用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名独立研究员，同时也保持我的临床技能，为我做好准备我作为一名医师科学家接受培训的下一步。