Treatment-Induced Phenotypic Reprogramming in Prostate Cancer

雄激素受体(AR)是转移性去势患者治疗反应的关键驱动因素。 耐药前列腺癌(MCRPC)。雄激素剥夺治疗(ADT)和AR靶向，特别是在 与微管靶向紫杉烷化疗相结合，可为mCRPC患者提供生存益处。 然而，治疗耐药性总是会产生，导致死亡。了解相关机制 潜在的耐药性是改善治疗结果的关键。我们的工作和其他人的工作建立了AR 多西紫杉醇(一线紫杉烷化疗)抑制雄激素敏感型前列腺的核定位 肿瘤。相比之下，CRPC表达的AR剪接变异体仍然能够进行核贩运，有助于 紫杉烷耐药性。雄激素/AR与转化生长因子-β(TGFR-β)的信号相互作用 通过调控细胞凋亡和上皮间质转化决定前列腺癌的生长和侵袭 (EMT)。我们最近发现卡巴紫杉醇(二线紫杉烷化疗)可以逆转EMT，导致 间充质-上皮转化(MET)和动蛋白介导的多核，而不影响核AR 体外和体内前列腺癌模型。这项工作首次提供了卡巴紫杉醇诱导 雄激素导致前列腺癌再分化的表型变化(除细胞凋亡外) 和转化生长因子-β。在这里，我们假设卡巴西紫杉醇治疗会导致一些前列腺肿瘤细胞的凋亡。 而且还可以使存活细胞多样化，使其进入重新分化状态(通过MET)，从而在 保留AR和Kinesin的活性。我们将通过评估MET介导的表型来检验这一假设 前列腺癌上皮细胞重编程导致对紫杉烷化疗/ADT的治疗耐药性 如果这种耐药性可以通过阻断转化生长因子-β来克服。将解决三个具体目标： 特定目标1将描述AR与转化生长因子-β的相互作用在编程前列腺癌方面的作用 慢性前列腺癌模型对卡氮紫杉醇的反应。特异性目标2将确定前列腺癌的机制 在临床前模型中，肿瘤细胞经历紫杉烷介导的再分化以克服治疗耐药性 晚期前列腺癌。特指目标3将测试动蛋白和中心体的抑制效果 聚集在微管上促进AR降解，使前列腺癌对卡氮紫杉醇敏感。建议数 该项目将为转化生长因子-β、AR和激动素在紫杉烷介导的表型中的作用提供新的见解 改变和确定治疗顺序，以克服复发疾病的耐药性。

The androgen receptor (AR) is a critical driver of therapeutic response in patients with metastatic castration- resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) and AR-targeting, particularly in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in mCRPC patients. However, therapeutic resistance invariably develops, leading to mortality. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes. Our work and others' established that AR nuclear localization is inhibited by docetaxel (1st line taxane chemotherapy) in androgen-sensitive prostate tumors. In contrast, CRPCs express AR splice variants that remain capable of nuclear trafficking, contributing to taxane resistance. Signaling interactions between androgens/AR and transforming growth factor-β (TGF-β) determine prostate tumor growth and invasion by regulating apoptosis and epithelial-mesenchymal transition (EMT). We recently found that cabazitaxel (2nd line taxane chemotherapy) can reverse EMT, resulting in a mesenchymal-epithelial transition (MET) and kinesin-mediated multi-nucleation, without affecting nuclear AR in in vitro and in vivo prostate cancer models. This work provided the first evidence that cabazitaxel induces phenotypic changes leading to prostate tumor re-differentiation (in addition to apoptosis) dictated by androgens and TGF-β. Here, we hypothesize that treatment with cabazitaxel causes apoptosis in some prostate tumor cells but also diversifies surviving cells into a re-differentiated state (via MET) that confers therapeutic resistance while retaining AR and kinesin activity. We will test this hypothesis by assessing if MET-mediated phenotypic reprogramming of prostate cancer epithelial cells drives therapeutic resistance to taxane chemotherapy/ADT combinations, and if this resistance can be overcome by TGF-β blockade. Three Specific Aims will be addressed: Specific Aim 1 will delineate the role of AR cross-talk with TGF-β in programming prostate tumor MET in response to cabazitaxel in models of CRPC. Specific Aim 2 will determine the mechanisms via which prostate tumor cells undergo taxane-mediated re-differentiation to overcome therapeutic resistance in pre-clinical models of advanced prostate cancer. Specific Aim 3 will test the effect of inhibition of kinesins and centrosome clustering on microtubule-facilitated AR degradation, to sensitize prostate tumors to cabazitaxel. The proposed project will provide new insights into the contribution of TGF-β, AR, and kinesins in taxane-mediated phenotypic changes and define treatment sequencing to overcome resistance in recurrent disease.