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

基本信息

批准号：
9794237
负责人：
Dean G Tang
金额：
$ 44.45万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
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/9794237
关键词：
ABCG2 gene American Anabolism Androgen Antagonists Androgen Receptor Androgens Animals BCL2 gene Biological CD44 gene Cancer Patient Castration Cell Differentiation process Cell Survival Cell division Cells Chemotherapy-Oncologic Procedure Cisplatin Clinical Clinical Trials Coupled Cytotoxic Chemotherapy Differentiation Therapy Etoposide FDA approved Gene Activation Genes Goals Heterogeneity Inflammatory Investigational Therapies Knowledge Lead Malignant Neoplasms Malignant neoplasm of prostate Measures MicroRNAs Modeling Molecular Natural regeneration Patients Pharmaceutical Preparations Phase Phenotype Population Primary Neoplasm Proliferating Property Publications Radiation Receptor Cell Receptor Signaling Recurrence Refractory Regimen Reporting Resistance Stem cells Stimulus Testing Therapeutic Translating Translations Treatment Efficacy Undifferentiated Work Xenograft Model Xenograft procedure abiraterone androgen deprivation therapy cancer cell cancer stem cell castration resistant prostate cancer chemotherapy clinical care clinical effect combinatorial docetaxel experimental study genetic approach inhibitor/antagonist men novel novel strategies novel therapeutics pre-clinical prevent prostate cancer cell prostate cancer metastasis receptor function serum PSA standard of care stem-like cell stemness targeted agent taxane therapy resistant transcriptome sequencing treatment response tumor tumor microenvironment tumorigenic

项目摘要

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），通过减量实现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，报告的生存获益仅以月为单位来衡量大多数“阉割”患者最终会发展为 CRPC。同样，CT药物包括紫杉烷类（多西紫杉醇和卡巴他赛）和顺铂已被用于治疗晚期和复发性前列腺癌，但耐药性很快发展。支持出现、维持和发展的细胞起源和分子机制 CRPC 和 CT 耐药性 PCa 的进展仍知之甚少。我们实验室的系统研究在过去的 16 年里，我们对 PCa 细胞异质性和可塑性的剖析已经确定了一个群体表型未分化的 PCa 干细胞 (PCSC) 经常缺乏 AR 并且大部分处于休眠状态，这些因素共同使它们对 ADT 和 CT 具有固有的抵抗力。重要的是，PCSC 经常成为治疗抵抗性肿瘤中的主要细胞群，并且也可能充当起源细胞作为 CRPC 的肿瘤增殖细胞。这些观察结果引出了我们的总体假设：使用 ADT 或 CT 组合靶向大量 PCa 细胞，以及采用新策略的 PCSC，将抑制两者癌细胞干性和细胞可塑性，并达到卓越的治疗效果和预防/克服治疗抵抗。我们通过 3 个具体目标来检验这一假设。目标 1)：检验恩杂鲁胺与 Venetoclax（一种新的且唯一的 FDA- 已批准的 BCL-2 抑制剂）将延迟/预防 CRPC。我们最近的异种移植模型与 RNA-Seq 相结合实验疗法已将 BCL-2 确定为关键的 PCSC 生存因子和 CRPC 的驱动因素。目标 2)：检验恩杂鲁胺与抗 PCSC microRNA 联合使用会延迟/预防这一假设 CRPC。我们已经证明，包括 miR-34a 和 miR-141 在内的几种肿瘤抑制 miRNA PCSC 的关键负调节因子，可有效抑制 PCa 转移并延长动物存活时间。目标 3)：检验 CT 与抗 PCSC microRNA 或抗 BCL-2 联合使用可显着改善这一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相结合来实现机理研究。目标的实现应有助于建立重要原则、验证新颖性假设，阐明 PCa 亚群动态响应治疗的分子基础，并确定针对不同 PCa 亚群的新疗法和治疗方案。这些应该促进我们的临床前知识快速转化为临床试验。