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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：
Justin Michael Drake
金额：
$ 43.19万
依托单位：
UNIVERSITY OF MINNESOTA
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：
https://reporter.nih.gov/project-details/10613543
关键词：
ASCL1 gene Adenocarcinoma American Androgen Receptor Androgens Binding Binding Sites Biological Models Cancer Etiology Carcinoma Cell Line Cell Survival Cessation of life ChIP-seq Classification 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 Institution 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 Proliferating 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 Tumor Cell Line United States Up-Regulation Variant Western Blotting Work abiraterone androgen deprivation therapy antagonist castration resistant prostate cancer cell growth chemotherapy design enzalutamide genetic manipulation improved in vivo ineffective therapies inhibitor inhibitor therapy insight kinase inhibitor knock-down men mortality mouse model neural 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 responders and non-responders response small cell lung carcinoma standard of care targeted treatment taxane therapeutic target therapy resistant transcription factor treatment responders tumor tumor growth tumor 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