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
- 来源:
- 关键词:ASCL1 geneAdenocarcinomaAmericanAndrogen ReceptorAndrogensBindingBinding SitesBiological ModelsCancer EtiologyCarcinomaCell LineCell SurvivalCessation of lifeChIP-seqClassificationClinicalClinical TrialsCombined Modality TherapyDataData SetDevelopmentDiseaseDrug TargetingEnhancersFDA approvedGene ExpressionGenesGenetic TranscriptionGoalsGonadotropin Hormone Releasing HormoneHormonesHumanHuman Cell LineIn VitroInstitutionLigandsMalignant NeoplasmsMalignant neoplasm of prostateManuscriptsMediatingMessenger RNAModelingMolecularMorbidity - disease rateMusMutationNeoplasm MetastasisNeuroendocrine Prostate CancerNeuroendocrine TherapyNeuronal DifferentiationNeurosecretory SystemsOrganoidsOutcomePapillary thyroid carcinomaPathway interactionsPatientsPhosphorylationPhosphotransferasesPlatinumProliferatingProstate Cancer therapyProtein Tyrosine KinaseProteinsProto-Oncogene Proteins c-aktPublishingRET geneRET inhibitionReceptor SignalingRegulationRegulatory ElementResearchResistanceSamplingSignal PathwaySignal TransductionSignaling ProteinTestingTherapeuticTranscriptional RegulationTumor Cell LineUnited StatesUp-RegulationVariantWestern BlottingWorkabirateroneandrogen deprivation therapyantagonistcastration resistant prostate cancercell growthchemotherapydesignenzalutamidegenetic manipulationimprovedin vivoineffective therapiesinhibitorinhibitor therapyinsightkinase inhibitorknock-downmenmortalitymouse modelneuralnovelnovel therapeuticsoptimal treatmentsoverexpressionpatient derived xenograft modelpatient stratificationpharmacodynamic biomarkerphosphoproteomicspredictive signaturepromoterprostate cancer cellprostate cancer cell lineprostate cancer modelprostate cancer progressionprotein expressionproto-oncogene protein c-retresponders and non-respondersresponsesmall cell lung carcinomastandard of caretargeted treatmenttaxanetherapeutic targettherapy resistanttranscription factortreatment responderstumortumor growthtumor xenograft
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/文摘
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
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:
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:
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: