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：
10608079
负责人：
Natasha Kyprianou
金额：
$ 44.73万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608079
关键词：
Address Affect Androgen Antagonists Androgen Receptor Androgens Apoptosis Apoptotic Automobile Driving Cancer Patient Cell Death Cell Survival Cell model Cells Centrosome Clinical Trials Combined Modality Therapy Cytoplasmic Receptors Data Disease Epithelial Cells Epithelium FDA approved Gland Goals Growth Heterogeneity Human Impairment In Vitro Individual Kinesin Link Malignant neoplasm of prostate Mediating Mesenchymal Mesenchymal Cell Neoplasm Metastatic Neoplasm to the Prostate Metastatic Prostate Cancer Microtubule Polymerization Microtubules Mitotic Modeling Molecular Motor Nuclear Nuclear Receptors Patients Pharmaceutical Preparations Phenotype Population Pre-Clinical Model Process Property Prostatic Neoplasms RNA Splicing Receptor Cross-Talk Receptor Signaling Recurrent disease Recurrent tumor Resistance Resistance development Role Signal Transduction Testing Therapeutic Transforming Growth Factor beta Transforming Growth Factor beta Receptors 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 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抗性前列腺癌 (mCRPC) 和雄激素剥夺疗法 (ADT) 和 AR 靶向治疗，特别是在治疗中。与微管靶向紫杉烷化疗相结合，可为 mCRPC 患者提供生存获益。然而，治疗耐药性总是会出现，导致死亡。我们和其他人的工作都证实，潜在的耐药性对于改善治疗效果至关重要。雄激素敏感前列腺中的核定位被多西紫杉醇（第一线紫杉烷化疗）抑制相比之下，CRPC 表达的 AR 剪接变体仍然能够进行核运输，从而有助于紫杉烷抗性。雄激素/AR 和转化生长因子-β (TGF-β) 之间的信号相互作用。通过调节前列腺细胞凋亡和上皮间质转化来决定肿瘤生长和侵袭 (EMT)。我们最近发现卡巴他赛（二线紫杉烷化疗）可以逆转 EMT，从而导致间质-上皮转化 (MET) 和驱动蛋白介导的多核，不影响核 AR 这项工作提供了卡巴他赛诱导的体外和体内前列腺癌模型的第一个证据。雄激素决定的表型变化导致前列腺肿瘤再分化（除了凋亡）在这里，我们发现卡巴他赛治疗会导致一些前列腺肿瘤细胞凋亡。还使存活细胞多样化进入再分化状态（通过 MET），从而赋予治疗耐药性，同时我们将通过评估 MET 介导的表型来检验这一假设。前列腺癌上皮细胞的重编程导致对紫杉烷化疗/ADT的治疗耐药如果可以通过 TGF-β 阻断来克服这种耐药性，将实现三个具体目标：具体目标 1 将描述 AR 与 TGF-β 的串扰在编程前列腺肿瘤 MET 中的作用 CRPC 模型中对卡巴他赛的反应具体目标 2 将确定前列腺的机制。肿瘤细胞经历紫杉烷介导的再分化以克服临床前模型中的治疗耐药性具体目标 3 将测试驱动蛋白和中心体的抑制作用。聚集在微管促进的 AR 降解上，使前列腺肿瘤对卡巴他赛敏感。该项目将为 TGF-β、AR 和驱动蛋白在紫杉烷介导的表型中的贡献提供新的见解改变并确定治疗顺序以克服复发性疾病的耐药性。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Re: Regenerative Potential of Prostate Luminal Cells Revealed by Single-cell Analysis.

回复：单细胞分析揭示前列腺腔细胞的再生潜力。

DOI：
发表时间：
2021
期刊：
影响因子：
23.4
作者：
Kyprianou; Natasha
通讯作者：
Natasha

Impact of Circadian Rhythms on the Development and Clinical Management of Genitourinary Cancers.

昼夜节律对泌尿生殖系统癌症的发展和临床治疗的影响。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Kaur, Priya;Mohamed, Nihal E;Archer, Maddison;Figueiro, Mariana G;Kyprianou, Natasha
通讯作者：
Kyprianou, Natasha

Exosomes as A Next-Generation Diagnostic and Therapeutic Tool in Prostate Cancer.

外泌体作为前列腺癌的下一代诊断和治疗工具。

DOI：
发表时间：
2021-09-20
期刊：
影响因子：
5.6
作者：
Gaglani, Simita;Gonzalez;Lundon, Dara J;Tewari, Ashutosh K;Dogra, Navneet;Kyprianou, Natasha
通讯作者：
Kyprianou, Natasha

Anoikis in phenotypic reprogramming of the prostate tumor microenvironment.

前列腺肿瘤微环境表型重编程中的失巢凋亡。