Enhancing the Efficacy of Docetaxel in Prostate Cancer

增强多西紫杉醇治疗前列腺癌的疗效

• 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
• 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

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.

项目摘要 紫杉烷类是第一种也是唯一一种能延长转移性去势患者生存期的化疗药物- 雄激素剥夺治疗（ADT）后进展的耐药前列腺癌（mCRPC）。紫杉烷 不仅在mCRPC中证明了临床获益，而且在去势敏感性转移性前列腺癌男性中也证明了临床获益。 在标准ADT时接受多西他赛给药的前列腺癌（mCSPC）患者。尽管这些临床 紫杉烷治疗的好处，不是所有的人都一样，对治疗的抵抗导致显着的发病率 and mortality.目前，临床反应和耐药性的分子决定因素（内在和获得性） 对紫杉烷类化学疗法的认识仍然很少，新的紫杉烷类化合物可以极大地帮助患者 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， 和小鼠模型的区别是药物不能稳定微管。随后的微管集束的丧失 可以量化为药物靶点接合（DTE）的丧失，并且可能是患者耐药的生物标志物。 使用小鼠模型，我们发现FOXJ 1的表达增加，FOXJ 1是一种主要的转录因子， 微管相关蛋白，以及下游微管相关蛋白TPPP 3， 对紫杉烷有抗药性此外，我们发现FOXJ 1基因扩增与紫杉烷治疗相关， 患者最近，我们还发现FOXJ 1过表达导致体内多西他赛耐药， 多西他赛治疗导致FOXJ 1 RNA和蛋白表达增加。目标1将侧重于 增加FOXJ 1和TPPP 3作为抗性机制，并确定这些机制中的潜在脆弱性 肿瘤的在目标2中，我们将通过检查循环中的紫杉烷耐药性， 用多西他赛治疗的前列腺癌患者中的肿瘤细胞和浆细胞游离DNA， 内在或获得性抗性的机制。一个目标是开发针对药物的临床试验 这些患者的具体耐药机制。多西他赛耐药新机制的鉴定 可以立即转化为治疗组合的发展，以防止或延迟耐药性。我们 最终目标是开发新的组合，以增加转移性CRPC患者的反应和生存。