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

基本信息

  • 批准号:
    10613543
  • 负责人:
  • 金额:
    $ 43.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结/摘要 前列腺癌(PCa)是美国男性癌症相关死亡的第二大原因。典型地, 前列腺癌的治疗包括阻断雄激素合成或雄激素受体(AR)信号传导, 雄激素剥夺疗法(ADT)。虽然最初的反应率是有希望的,所有的人最终进展 接受ADT治疗并发生去势抵抗性前列腺癌(CRPC)伴转移性负荷。 转移性CRPC是不可治愈的,越来越多的男性正在发展CRPC的高致命性变体 称为侵袭性变异前列腺癌(AVPC)。AR信令在AVPC中丢失, 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) 前列腺癌属于神经内分泌性前列腺癌(NEPC),是我们研究的重点。非常 在这种情况下,存在很少的治疗方法并且仅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 可能是CRPC中有前途的治疗替代方案。我们研究的目的是了解 调节激酶基因表达增加的机制,导致激酶途径活化,以及如何 有效靶向NEPC中的这些激酶。我们的假设是RET mRNA和蛋白的上调是由 ASCL 1是一种主要的神经转录调节因子,RET激酶介导的活性作为一种 NEPC的治疗脆弱性。众所周知,RET突变是免疫缺陷综合征的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激酶信号在NEPC活力中的作用还没有完全阐明。我们的初步数据显示 RET激酶通过激活神经元分化转录因子ASCL 1而过表达, 在NEPC的小鼠模型和类器官、人细胞系和临床NEPC中酶促活化 肿瘤的我们的工作还表明,RET激酶抑制减少体内异种移植肿瘤生长和体外 NEPC的小鼠类器官模型。本项目的目标是:1)确认ASCL 1作为直接转录因子, RET的调节因子,2)定义RET活性特征并评估该特征与治疗的关联 临床样品中的耐药性和NEPC,以及3)优化与新型RET抑制剂的共靶向策略, NEPC模型系统。这些目标被共同设计来研究RET激酶作为一种 NEPC(PCa的一种不可治愈变体)中的关键治疗靶点。虽然激酶抑制剂被批准用于治疗 在几种上皮癌中,激酶抑制剂在PCa中的临床试验令人失望。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给药, 和不适当的联合治疗。因此,拟议工作的成果将为以下方面提供新的见解: 选择联合疗法治疗NEPC,使用可实施的再用途激酶抑制剂 在临床试验中迅速地应用于患有这种致命性前列腺癌的患者。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Justin Michael Drake其他文献

Justin Michael Drake的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Justin Michael Drake', 18)}}的其他基金

Development of a novel personalized medicine platform using apheretically isolated circulating tumor cells to assess drug responsiveness in prostate cancer
开发一种新型个性化医疗平台,使用非血浆分离的循环肿瘤细胞来评估前列腺癌的药物反应
  • 批准号:
    10384366
  • 财政年份:
    2022
  • 资助金额:
    $ 43.19万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 43.19万
  • 项目类别:

相似国自然基金

大肠癌发生机制的adenoma-adenocarcinoma pathway同serrated pathway的关系的研究
  • 批准号:
    30840003
  • 批准年份:
    2008
  • 资助金额:
    12.0 万元
  • 项目类别:
    专项基金项目

相似海外基金

Synergistic Radiosensitization of Hypoxic Pancreatic Adenocarcinoma using Gd-Texaphyrin Oxygen-Loaded Nanodroplets
使用 Gd-Texaphyrin 载氧纳米液滴对缺氧胰腺腺癌进行协同放射增敏
  • 批准号:
    478914
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
    Operating Grants
Expression mechanism of immune checkpoint molecules after carbon-ion radiotherapy in cervical adenocarcinoma specimens
宫颈腺癌碳离子放疗后免疫检查点分子的表达机制
  • 批准号:
    23K14913
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Study of fibrosis in pancreatic ductal adenocarcinoma (PDAC) and application of adipose-derived stromal/stem cells for PDAC treatment
胰腺导管腺癌(PDAC)纤维化的研究以及脂肪源性基质/干细胞在 PDAC 治疗中的应用
  • 批准号:
    23K15035
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Therapeutic Targeting of NSD2 in Lung Adenocarcinoma
NSD2 在肺腺癌中的治疗靶向
  • 批准号:
    10657069
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
IRAK4 AS A NOVEL IMMUNOTHERAPEUTIC TARGET IN PANCREATIC DUCTAL ADENOCARCINOMA
IRAK4 作为胰腺导管腺癌的新型免疫治疗靶点
  • 批准号:
    10442874
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
Control mechanisms of lung adenocarcinoma by SGLT2 inhibitors for treating diabetes mellitus.
SGLT2抑制剂治疗糖尿病对肺腺癌的控制机制。
  • 批准号:
    23K08326
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Establishment of histological transformation model from lung small cell carcinoma from adenocarcinoma to explore the therapeutic strategies of small cell lung carcinoma.
建立肺小细胞癌腺癌组织学转化模型,探讨小细胞肺癌的治疗策略。
  • 批准号:
    23K14614
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms of tumor progression controlled by tumor-initiating cells and cancer-associated fibroblasts in pancreatic adenocarcinoma.
阐明胰腺腺癌中肿瘤起始细胞和癌症相关成纤维细胞控制的肿瘤进展机制。
  • 批准号:
    23K15075
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Molecular mechanisms for development of pulmonary invasive mucinous adenocarcinoma
肺浸润性粘液腺癌发生的分子机制
  • 批准号:
    23H02698
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Elucidating the Cellular Origins of lung adenocarcinoma
阐明肺腺癌的细胞起源
  • 批准号:
    10743611
  • 财政年份:
    2023
  • 资助金额:
    $ 43.19万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了