RET Regulation and Targeting in Neuroendocrine Prostate Cancer

神经内分泌前列腺癌中的 RET 调节和靶向

• 批准号: 10419078
• 负责人: Justin Michael Drake
• 金额: $ 44.07万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419078
• 关键词: ASCL1 gene; Adenocarcinoma; American; Androgen Antagonists; Androgen Receptor; Androgens; Binding Sites; Biological Models; Cancer Etiology; Carcinoma; Cell Line; Cell Survival; Cessation of life; ChIP-seq; Clinical; Clinical Trials; Combined Modality Therapy; Data; Data Set; Development; Disease; Drug Targeting; Enhancers; FDA approved; Gene Expression; Genes; Genetic Transcription; Goals; Gonadotropin Hormone Releasing Hormone; Hormones; Human; Human Cell Line; In Vitro; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Manuscripts; Mediating; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neuroendocrine Therapy; Neuronal Differentiation; Neurosecretory Systems; Organoids; Outcome; Papillary thyroid carcinoma; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Platinum; Prostate Cancer therapy; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-akt; Publishing; RET gene; RET inhibition; Receptor Signaling; Regulation; Regulatory Element; Research; Resistance; Sampling; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Therapeutic; Transcriptional Regulation; United States; Up-Regulation; Variant; Western Blotting; Work; abiraterone; androgen deprivation therapy; cancer clinical trial; castration resistant prostate cancer; cell growth; chemotherapy; design; enzalutamide; genetic manipulation; improved; in vivo; ineffective therapies; inhibitor; inhibitor therapy; insight; kinase inhibitor; knock-down; lung small cell carcinoma; men; mortality; mouse model; novel; novel therapeutics; optimal treatments; overexpression; patient derived xenograft model; patient stratification; pharmacodynamic biomarker; phosphoproteomics; predictive signature; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer progression; protein expression; proto-oncogene protein c-ret; relating to nervous system; responders and non-responders; response; standard of care; targeted treatment; taxane; therapeutic target; therapy resistant; transcription factor; treatment responders; tumor; tumor growth; tumor xenograft

PROJECT SUMMARY/ABSTRACT Prostate cancer (PCa) is the second leading cause of cancer related death in American men. Typically, treatment for PCa involves blocking androgen synthesis or androgen receptor (AR) signaling known as androgen deprivation therapy (ADT). Although initial response rates are promising, all men eventually progress on ADT and develop castration resistant prostate cancer (CRPC) concomitant with metastatic burden. Metastatic CRPC is incurable and an increasing number of men are developing a highly lethal variant of CRPC known as aggressive variant prostate cancer (AVPC). AR signaling is lost in AVPC rendering the existing hormone targeting treatments ineffective. About a third of AVPC tumors also express neuroendocrine (NE) genes and are classified as neuroendocrine prostate cancer (NEPC), which is the focus of our studies. Very few therapies exist and only offer minimal survival benefits in this setting. Hence, functional assessment of other protein drug targets is needed to effectively treat NEPC. We have previously shown that kinase signaling pathways may be promising therapeutic alternatives in CRPC. The goal of our research is to understand the mechanisms regulating increased kinase gene expression, leading to kinase pathway activation, and how to effectively target these kinases in NEPC. Our hypothesis is that RET mRNA and protein up-regulation is driven by ASCL1, a master neural transcriptional regulator, and that RET kinase-mediated activity serves as a therapeutic vulnerability in NEPC. It is known that RET mutations are key drivers and therapeutic targets in other cancers with NE features such as papillary thyroid carcinoma and small cell lung cancer. Importantly, the contribution of RET kinase signaling in NEPC viability is not entirely elucidated. Our preliminary data shows that RET kinase is overexpressed via activation of a neuronal differentiation transcription factor, ASCL1, and enzymatically activated in mouse models and organoids of NEPC, in human cell lines, and clinical NEPC tumors. Our work also shows that RET kinase inhibition reduces in vivo xenograft tumor growth and in in vitro mouse organoid models of NEPC. The goals of this project are to: 1) confirm ASCL1 as a direct transcriptional regulator of RET, 2) define a RET activity signature and assess the association of this signature to treatment resistance and NEPC in clinical samples, and 3) optimize co-targeting strategies with novel RET inhibitors in NEPC model systems. These goals are collectively designed to investigate the mechanism of RET kinase as a key therapeutic target in NEPC, an incurable variant of PCa. While kinase inhibitors are approved for treatment of several epithelial cancers, clinical trials of kinase inhibitors in PCa have been disappointing. Our data indicate this is likely due to lack of appropriate patient stratification, administered in the wrong clinical context, and improper combination therapies. Hence, the outcomes of the proposed work will provide new insights into select combination therapies for treating NEPC, using re-purposed kinase inhibitors that may be implemented quickly in clinical trials of patients with this subset of lethal PCa.

项目概要/摘要 前列腺癌（PCa）是美国男性癌症相关死亡的第二大原因。通常， PCa 的治疗涉及阻断雄激素合成或雄激素受体 (AR) 信号传导，称为 雄激素剥夺疗法（ADT）。尽管最初的反应率很有希望，但所有男性最终都会取得进展 接受 ADT 并发展为伴随转移负担的去势抵抗性前列腺癌 (CRPC)。 转移性 CRPC 无法治愈，越来越多的男性正在开发一种高度致命的 CRPC 变体 称为侵袭性变异型前列腺癌 (AVPC)。 AR 信令在 AVPC 渲染现有内容时丢失 激素靶向治疗无效。大约三分之一的 AVPC 肿瘤也表达神经内分泌 (NE) 基因并被归类为神经内分泌前列腺癌（NEPC），这是我们研究的重点。非常 现有的治疗方法很少，并且在这种情况下只能提供最小的生存益处。因此，功能评估 需要其他蛋白质药物靶点来有效治疗 NEPC。我们之前已经证明激酶信号传导 途径可能是 CRPC 的有前途的治疗替代方案。我们研究的目标是了解 调节激酶基因表达增加、导致激酶途径激活的机制，以及如何 有效靶向 NEPC 中的这些激酶。我们的假设是 RET mRNA 和蛋白质上调是驱动的 由 ASCL1（一种主要的神经转录调节因子）控制，RET 激酶介导的活性充当 NEPC 中的治疗脆弱性。众所周知，RET 突变是关键驱动因素和治疗靶点 其他具有 NE 特征的癌症，如甲状腺乳头状癌和小细胞肺癌。重要的是， RET 激酶信号传导对 NEPC 活力的贡献尚未完全阐明。我们的初步数据显示 RET 激酶通过神经元分化转录因子 ASCL1 的激活而过度表达，并且 在小鼠模型和 NEPC 类器官、人类细胞系和临床 NEPC 中被酶促激活 肿瘤。我们的工作还表明，RET 激酶抑制可减少体内异种移植肿瘤的生长，并在体外 NEPC 小鼠类器官模型。该项目的目标是：1）确认ASCL1是直接转录的 RET 调节器，2) 定义 RET 活性特征并评估该特征与治疗的关联 临床样本中的耐药性和 NEPC，以及 3) 优化新型 RET 抑制剂的共同靶向策略 NEPC 模型系统。这些目标共同旨在研究 RET 激酶作为 NEPC（PCa 的一种无法治愈的变体）的关键治疗靶点。虽然激酶抑制剂被批准用于治疗 在多种上皮癌中，激酶抑制剂治疗前列腺癌的临床试验结果令人失望。我们的数据 表明这可能是由于缺乏适当的患者分层，在错误的临床背景下进行管理， 以及不适当的联合治疗。因此，拟议工作的成果将为以下方面提供新的见解： 选择治疗 NEPC 的联合疗法，使用可实施的重新用途的激酶抑制剂 很快就对患有这种致命 PCa 的患者进行了临床试验。