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

联合靶向未分化前列腺癌 (PCa) 干细胞和大量 PCa 细胞的新治疗策略

• 批准号: 10415995
• 负责人: Dean G Tang
• 金额: $ 42.37万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415995
• 关键词: American; Androgen Antagonists; Androgen Receptor; Androgens; Animals; BCL2 gene; Biological; Cancer Patient; Castration; Cell division; Cell model; Cells; Chemoresistance; Cisplatin; Clinical; Clinical Trials; Coupled; Cytotoxic Chemotherapy; FDA approved; Goals; Heterogeneity; Investigational Therapies; Knowledge; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; MicroRNAs; Molecular; Natural regeneration; Patients; Pharmaceutical Preparations; Phase Ib/II Clinical Trial; Phenotype; Population; Primary Neoplasm; Proliferating; Property; Publications; Radiation; Receptor Signaling; Recurrence; Refractory; Regimen; Reporting; Resistance; Testing; Therapeutic; Translating; Translations; Treatment Efficacy; Undifferentiated; Work; Xenograft Model; Xenograft procedure; abiraterone; advanced prostate cancer; androgen biosynthesis; androgen deprivation therapy; cancer cell; cancer stem cell; castration resistant prostate cancer; chemotherapy; clinical care; clinical effect; combinatorial; docetaxel; enzalutamide; experimental study; genetic approach; inhibitor; men; novel; novel strategies; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; pre-clinical; prevent; prostate cancer cell; prostate cancer metastasis; receptor function; serum PSA; standard of care; stem cell survival; stem cells; stem-like cell; stemness; targeted agent; taxane; therapy resistant; transcriptome sequencing; treatment response; tumor; tumorigenic

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.

去势抵抗性前列腺癌（CRPC）每年杀死约28，000名美国男性。标准治疗 晚期前列腺癌（PCa）的临床疗法是雄激素剥夺疗法（ADT）和/或 化疗（CT）。ADT，旨在阻断雄激素合成（例如，阿比特龙）或抑制雄激素 受体（AR）信号传导（例如，恩杂鲁胺），通过减积达到令人印象深刻的短期临床效果 原发性肿瘤和降低血清PSA。然而，报告的生存益处仅以月为单位来衡量 并且大多数“阉割”患者最终发展为CRPC。类似地，包括紫杉烷类（多西他赛和紫杉醇）的CT药物也可用于治疗癌症。 卡巴他赛）和顺铂已被用于治疗晚期和复发性PCa，但耐药性迅速 发展起来的细胞起源和分子机制支持的出现，维持， CRPC和CT耐药PCa进展仍然知之甚少。我们实验室的系统研究 在过去的16年里，通过解剖PCa细胞的异质性和可塑性， 表型未分化的PCa干细胞（PCSC）经常缺乏AR并且大部分处于休眠状态， 这两个因素共同使它们对ADT和CT具有固有的抵抗力。重要的是，PCSC经常 成为治疗抗性肿瘤中的主要细胞群，并且也可以作为起源细胞发挥作用 作为CRPC的肿瘤增殖细胞。这些观察导致了我们的总体假设， 用ADT或CT联合靶向PCa细胞，以及用新策略联合靶向PCSC， 癌症细胞的干细胞性和细胞可塑性，并实现上级治疗功效和预防/克服 治疗抵抗我们用三个具体目标来检验这个假设。 目的1）：检验Enzalutamide与维奈托克（一种新的和唯一的FDA- 批准的BCL-2抑制剂）将延迟/预防CRPC。我们最近的异种移植模型结合RNA测序 实验性治疗已经确定BCL-2是关键的PCSC存活因子和CRPC的驱动因素。 目的2）：检验Enzalutamide与抗PCSC microRNA联合使用将延迟/预防 CRPC。我们已经证明了几种肿瘤抑制性miRNA，包括miR-34 a和miR-141， PCSC的关键负调节因子，并有效抑制PCa转移和延长动物存活。 目的3）：为了检验CT与抗PCSC microRNA或抗BCL-2的组合将显著地降低肿瘤细胞增殖的假设， 延长化疗的疗效。 这些目标将通过将广泛的异种移植物/PDX建模和治疗与深入的研究相结合来实现。 机械研究。目标的实现应有助于确立重要原则，验证新颖性， 假设，阐明PCa亚群动态响应处理的分子基础， 并鉴定针对不同PCa亚群的新型治疗剂和治疗方案。这些应该 促进我们的临床前知识快速转化为临床试验。