Novel Therapeutic Strategies to Co-Target Undifferentiated Prostate Cancer (PCa) Stem Cells and Bulk PCa Cells

耐阉割前列腺癌(CRPC)每年导致约28,000名美国男性死亡。护理标准 晚期前列腺癌(PCA)的临床治疗方法是雄激素剥夺疗法(ADT)和/或 化疗(CT)。ADT，旨在阻止雄激素合成(如阿比特龙)或抑制雄激素 受体(AR)信号转导(例如，苯扎鲁胺)，通过减容获得令人印象深刻的短期临床效果 原发肿瘤和血清PSA降低。然而，报道的生存益处仅以月为单位。 大多数被去势的患者最终都会发展为CRPC。同样，包括紫杉烷在内的CT药物(多西紫杉醇和 卡氮紫杉醇)和顺铂已被用于治疗晚期和复发的前列腺癌，但耐药性迅速 发展起来。细胞起源和分子机制支持的出现，维持和 CRPC和CT耐药PCa的进展仍然知之甚少。来自我们实验室的系统研究 在过去的16年里，对PCA细胞的异质性和可塑性进行了解剖，精确地发现了 表型未分化的PCA干细胞(PCSCs)，通常缺乏AR，大部分处于休眠状态， 这使得它们对ADT和CT都具有内在的抵抗力。重要的是，PCSC经常 成为耐药肿瘤的主要细胞群，也可能作为起源细胞发挥作用 作为CRPC的肿瘤增殖细胞。这些观察结果导致了我们的总体假设 用ADT或CT联合靶向Pca细胞，以及用新策略靶向PCSCs，将抑制两者 癌细胞干细胞和细胞可塑性，并取得优越的治疗效果和预防/克服 治疗抵抗。我们用三个具体的目标来检验这一假设。 目的1)：验证将苯扎鲁胺和万乃克拉克斯(一种新的也是唯一的FDA- 批准的bcl2抑制剂)将延迟/阻止CRPC。我们最新的结合RNA-Seq的异种移植模型 实验疗法已明确指出bcl2是PCSC生存的关键因素和CRPC的驱动因素。 目的2)：验证苯扎鲁胺与抗PCSC microRNAs联用将延迟/预防的假说 CRPC。我们已经证明了几个抑制肿瘤的miRNAs，包括miR-34a和miR-141是 PCSCs的关键负调控因子，并有效地抑制PCa转移和延长动物存活。 目的3)验证CT与抗PCSC microRNAs或抗bcl2联合应用的假设 延长化疗的疗效。 这些目标将通过将广泛的异种移植/PDX建模和治疗与深入的 机械学研究。目标的实现应该有助于建立重要的原则，验证小说 假说，阐明了PCA亚群动态对处理的反应的分子基础， 并针对不同的PCA亚群确定新的治疗方法和治疗方案。这些应该是 促进我们的临床前知识快速转化为临床试验。

Castration-resistant prostate cancer (CRPC) kills ~28,000 American men each year. The standard-of-care clinical therapies for advanced prostate cancer (PCa) have been androgen deprivation therapy (ADT) and/or chemotherapies (CT). ADT, aiming to block androgen synthesis (e.g., abiraterone) or to inhibit androgen receptor (AR) signaling (e.g., enzalutamide), achieves impressive short-term clinical effects by de-bulking primary tumor and reducing serum PSA. The reported survival benefit, however, is measured ONLY in months and most `castrated' patients eventually develop CRPC. Similarly, CT drugs including taxanes (docetaxel and cabazitaxel) and cisplatin have been used to treat advanced and recurrent PCa but resistance rapidly develops. The cellular origin and molecular mechanisms underpinning the emergence, sustenance, and progression of CRPC and CT-resistant PCa remain poorly understood. Systematic studies from our lab over the past 16 years on dissecting PCa cell heterogeneity and plasticity have pinpointed a population of phenotypically undifferentiated PCa stem cells (PCSCs) that frequently lack AR and are largely dormant, which, together, render them INHERENTLY resistant to both ADT and CT. Importantly, PCSCs frequently become the predominant cell population in therapy-resistant tumors and may function as a cell-of-origin as well as tumor-propagating cells for CRPC. These observations lead to our overarching hypothesis that combinatorial targeting of bulk PCa cells with ADT or CT, and PCSCs with novel strategies, will inhibit both cancer cell stemness and cellular plasticity, and achieve superior therapeutic efficacies and prevent/overcome therapy resistance. We test this hypothesis with 3 Specific Aims. Aim 1): To test the hypothesis that combining enzalutamide with Venetoclax (a newly and the ONLY FDA- approved BCL-2 inhibitor) will delay/prevent CRPC. Our recent xenograft modeling coupled with RNA-Seq and experimental therapies has pinpointed BCL-2 as a critical PCSC survival factor and a driver of CRPC. Aim 2): To test the hypothesis that combining enzalutamide with anti-PCSC microRNAs will delay/prevent CRPC. We have demonstrated that several tumor-suppressive miRNAs, including miR-34a and miR-141 are critical negative regulators of PCSCs and potently inhibit PCa metastasis and extend animal survival. Aim 3): To test the hypothesis that combining CT with anti-PCSC microRNAs or anti-BCL-2 will significantly extend the therapeutic efficacy of chemotherapies. These aims will be accomplished by combining extensive xenograft/PDX modeling and therapies with in-depth mechanistic studies. Accomplishment of the goals should help establish important principles, validate novel hypotheses, elucidate the molecular underpinnings of PCa subpopulation dynamics in response to treatments, and identify novel therapeutics and therapeutic regimens against different PCa subpopulations. These should facilitate rapid translation of our preclinical knowledge to clinical trials.