Enhancing the Efficacy of Docetaxel in Prostate Cancer

项目摘要 紫杉烷是第一种也是唯一一种可以延长男性去势转移患者生存时间的化疗药物-- 在雄激素剥夺治疗(ADT)后进展的耐药前列腺癌(MCRPC)。紫杉烷 不仅在mCRPC中显示出临床益处，而且在对去势敏感的转移瘤男性中也显示出好处 前列腺癌(MCSPC)患者在标准ADT时接受多西紫杉醇治疗。尽管有这些临床 紫杉烷治疗的好处，并不是所有男性的反应都一样，抵抗治疗会导致显著的发病率 和死亡率。目前，临床反应和耐药性的分子决定因素(固有的和获得性的) 紫杉烷化疗仍然知之甚少，而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对紫杉烷耐药的一种机制 而小鼠模型则是药物不能稳定微管。随后的微管束的丢失 可以量化为药物靶向结合(DTE)的丧失，并可能是患者耐药的生物标志物。 利用小鼠模型，我们发现FOXJ1的表达增加，FOXJ1是一种主要的转录调节因子 微管相关蛋白以及下游微管相关蛋白TPPP3是相关的 对紫杉烷产生抗药性。此外，我们还发现FOXJ1基因的扩增与紫杉烷治疗有关。 病人。最近，我们还发现FOXJ1在体内过表达会导致多西紫杉醇耐药， 多西紫杉醇治疗导致FOXJ1的RNA和蛋白质表达增加。目标1将专注于 增加FOXJ1和TPPP3作为抗性机制，并识别其中的潜在漏洞 肿瘤。在目标2中，我们将通过检测循环来探索紫杉烷耐药性的精确医学方法。 多西紫杉醇治疗前列腺癌患者的肿瘤细胞和浆细胞游离DNA鉴定 固有的或获得性抗性的机制。一个目标是开发靶向药物的临床试验。 这些患者的特异性耐药机制。多西紫杉醇耐药新机制的鉴定 可以立即转化为治疗组合的发展，以防止或延迟耐药性。我们的 最终目标是开发新的联合疗法，以提高转移性CRPC患者的反应和存活率。

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.