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Treatment-Induced Phenotypic Reprogramming in Prostate Cancer

前列腺癌治疗诱导的表型重编程

基本信息

批准号：
10113564
负责人：
Natasha Kyprianou
金额：
$ 46.17万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2019-02-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113564
关键词：
Address Affect Androgen Antagonists Androgen Receptor Androgens Apoptosis Apoptotic Automobile Driving Cancer Patient Cell Death Cell model Cells Centrosome Clinical Trials Combined Modality Therapy Cytoplasmic Receptors Data Disease Disease model Epithelial Epithelial Cells FDA approved Gland Goals Growth Heterogeneity Human Impairment In Vitro Individual Kinesin Link Malignant neoplasm of prostate Mediating Mesenchymal Mesenchymal Cell Neoplasm Metastatic Prostate Cancer Microtubule Polymerization Microtubules Mitotic Modeling Molecular Motor Neoplasm Metastasis Nuclear Nuclear Receptors Patients Pharmaceutical Preparations Phenotype Population Pre-Clinical Model Process Property Prostatic Neoplasms RNA Splicing Receptor Cross-Talk Receptor Signaling Recurrence Recurrent disease Resistance Resistance development Role Signal Transduction Testing Therapeutic Transforming Growth Factor beta Transforming Growth Factors Transitional Epithelium Tumor Cell Invasion Variant Work Xenograft Model addiction advanced disease advanced prostate cancer androgen deprivation therapy androgen sensitive antitumor effect beta Tubulin castration resistant prostate cancer chemotherapy docetaxel epithelial to mesenchymal transition improved in vivo in vivo Model inhibitor/antagonist insight mortality overexpression patient derived xenograft model prostate cancer cell prostate cancer model prostate cancer progression response targeted treatment taxane therapeutic target therapy outcome therapy resistant tool trafficking translational impact treatment response treatment strategy tumor tumor growth tumor progression

项目摘要

The androgen receptor (AR) is a critical driver of therapeutic response in patients with metastatic castration- resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) and AR-targeting, particularly in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in mCRPC patients. However, therapeutic resistance invariably develops, leading to mortality. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes. Our work and others' established that AR nuclear localization is inhibited by docetaxel (1st line taxane chemotherapy) in androgen-sensitive prostate tumors. In contrast, CRPCs express AR splice variants that remain capable of nuclear trafficking, contributing to taxane resistance. Signaling interactions between androgens/AR and transforming growth factor-β (TGF-β) determine prostate tumor growth and invasion by regulating apoptosis and epithelial-mesenchymal transition (EMT). We recently found that cabazitaxel (2nd line taxane chemotherapy) can reverse EMT, resulting in a mesenchymal-epithelial transition (MET) and kinesin-mediated multi-nucleation, without affecting nuclear AR in in vitro and in vivo prostate cancer models. This work provided the first evidence that cabazitaxel induces phenotypic changes leading to prostate tumor re-differentiation (in addition to apoptosis) dictated by androgens and TGF-β. Here, we hypothesize that treatment with cabazitaxel causes apoptosis in some prostate tumor cells but also diversifies surviving cells into a re-differentiated state (via MET) that confers therapeutic resistance while retaining AR and kinesin activity. We will test this hypothesis by assessing if MET-mediated phenotypic reprogramming of prostate cancer epithelial cells drives therapeutic resistance to taxane chemotherapy/ADT combinations, and if this resistance can be overcome by TGF-β blockade. Three Specific Aims will be addressed: Specific Aim 1 will delineate the role of AR cross-talk with TGF-β in programming prostate tumor MET in response to cabazitaxel in models of CRPC. Specific Aim 2 will determine the mechanisms via which prostate tumor cells undergo taxane-mediated re-differentiation to overcome therapeutic resistance in pre-clinical models of advanced prostate cancer. Specific Aim 3 will test the effect of inhibition of kinesins and centrosome clustering on microtubule-facilitated AR degradation, to sensitize prostate tumors to cabazitaxel. The proposed project will provide new insights into the contribution of TGF-β, AR, and kinesins in taxane-mediated phenotypic changes and define treatment sequencing to overcome resistance in recurrent disease.

雄激素受体（AR）是转移性去势患者治疗反应的关键驱动因素