Enhancing the Efficacy of Docetaxel in Prostate Cancer

增强多西紫杉醇治疗前列腺癌的疗效

基本信息

批准号：
10665071
负责人：
Steven P. Balk
金额：
$ 64.14万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-13 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665071
关键词：
Address Binding Biological Markers Biopsy Cancer Patient Castration Cell Line Cells Clinical Clinical Trials Computational Biology Data Development Drug Targeting Drug resistance Etiology Exhibits Failure Family Feedback Gene Amplification Genes Genetic Transcription Genomics Goals In Vitro Investigation Malignant neoplasm of prostate Mediating Messenger RNA Metastatic Prostate Cancer Microtubule Bundle Microtubule Stabilization Microtubule-Associated Proteins Microtubules Mitotic Modeling Molecular Morbidity - disease rate Neoplasm Circulating Cells Outcome Patient Selection Patients Pharmaceutical Preparations Plasma Cells Polymers Property Prospective Studies Proteins Public Domains Publishing Reporting Resistance Sampling Testing Therapeutic Time Translating Tubulin Up-Regulation Xenograft procedure androgen deprivation therapy biomarker identification castration resistant prostate cancer cell free DNA chemotherapy clinical biomarkers clinical care clinical predictors clinically significant digital docetaxel experience improved improved outcome in vivo in vivo Model knock-down member men mortality mouse model novel novel therapeutic intervention overexpression patient derived xenograft model polymerization pre-clinical precision medicine prevent protein expression resistance mechanism response targeted agent taxane therapeutic development therapy resistant transcription factor transcriptome sequencing transcriptomics tumor

项目摘要

Project Summary Taxanes are the first and only line of chemotherapy shown to prolong survival in men with metastatic castration- resistant prostate cancer (mCRPC) who have progressed after androgen deprivation therapy (ADT). Taxanes have not only demonstrated clinical benefits in mCRPC, but also in men with castration-sensitive metastatic prostate cancer (mCSPC) who received docetaxel given at the time of standard ADT. Despite these clinical benefits of taxane treatment, not all men respond equally and resistance to therapy leads to significant morbidity and mortality. Currently, the molecular determinants of clinical response and resistance (intrinsic and acquired) to taxane chemotherapy remain poorly understood, and new taxane combinations could greatly help patients with metastatic prostate cancer. We have recently reported that one mechanism for taxane resistance in patients and mouse models is failure of the drug to stabilize microtubules. The subsequent loss of microtubule bundling can be quantitated as loss of drug target engagement (DTE), and may be a biomarker for resistance in patients. Using mouse models we find that increased expression of FOXJ1, a master transcription factor regulating microtubule-related proteins, as well as a downstream microtubule associated protein TPPP3, are associated with taxane resistance. Moreover, we find that FOXJ1 gene amplification is associated with taxane treatment in patients. Recently we have also shown that FOXJ1 overexpression leads to docetaxel resistance in vivo and that docetaxel treatment leads to an increase in FOXJ1 RNA and protein expression. Aim 1 will focus on increased FOXJ1 and TPPP3 as mechanisms of resistance, and identification of potential vulnerabilities in these tumors. In Aim 2 we will explore precision medicine approaches for taxane resistance by examining circulating tumor cells and plasma cell free DNA in prostate cancer patients being treated with docetaxel to identify mechanisms of intrinsic or acquired resistance. A goal would be to develop clinical trials of agents targeting specific resistance mechanisms in these patients. Identification of new mechanisms of resistance to docetaxel could imminently translate to development of therapeutic combinations to prevent or delay resistance. Our ultimate goal is to develop new combinations to increase response and survival of patients with metastatic CRPC.

项目概要紫杉烷类药物是第一个也是唯一一个被证明可以延长转移性去势男性生存期的化疗药物。雄激素剥夺疗法（ADT）后病情进展的耐药性前列腺癌（mCRPC）。紫杉烷类不仅在 mCRPC 中表现出临床益处，而且在患有去势敏感转移性癌症的男性中也表现出临床益处在标准 ADT 时接受多西紫杉醇治疗的前列腺癌 (mCSPC)。尽管有这些临床紫杉烷治疗的好处，并非所有男性都有同样的反应，对治疗的抵抗会导致显着的发病率和死亡率。目前，临床反应和耐药性的分子决定因素（内在的和获得性的）对紫杉烷化疗的了解仍知之甚少，新的紫杉烷组合可以极大地帮助患者患有转移性前列腺癌。我们最近报道了患者紫杉烷耐药的一种机制小鼠模型则表明药物无法稳定微管。随后微管束的丧失可以量化为药物靶点结合丧失（DTE），并且可能是患者耐药性的生物标志物。使用小鼠模型，我们发现 FOXJ1（一种调节主转录因子）的表达增加微管相关蛋白以及下游微管相关蛋白 TPPP3 相关具有紫杉烷抗性。此外，我们发现 FOXJ1 基因扩增与紫杉烷治疗相关。患者。最近我们还发现 FOXJ1 过度表达会导致体内多西紫杉醇耐药性多西紫杉醇治疗导致 FOXJ1 RNA 和蛋白质表达增加。目标 1 将重点关注增加 FOXJ1 和 TPPP3 作为抵抗机制，并识别这些中的潜在漏洞肿瘤。在目标 2 中，我们将通过检查循环系统来探索紫杉烷耐药性的精准医学方法接受多西紫杉醇治疗的前列腺癌患者中的肿瘤细胞和浆细胞游离 DNA 内在或获得性抵抗的机制。目标是开发靶向药物的临床试验这些患者的特定耐药机制。多西他赛耐药新机制的鉴定可能会立即转化为治疗组合的开发，以预防或延缓耐药性。我们的最终目标是开发新的组合以提高转移性 CRPC 患者的反应和生存率。