Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer

利用 RB1 缺陷治疗致命性神经内分泌前列腺癌

• 批准号: 9152986
• 负责人: Leigh Ellis
• 金额: $ 50.58万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152986
• 关键词: Accounting; Acetates; Acute; Address; Androgen Receptor; Androgens; Autopsy; CYP17A1 gene; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chromatin; Clinical; Clinical Management; DNA Sequence Rearrangement; Data; Diagnosis; Disease; Disease Resistance; Drug Targeting; Effectiveness; Engineering; Epigenetic Process; Exhibits; Gene Expression; Generations; Genetically Engineered Mouse; Goals; Growth; Health; Histology; Human; Human Cell Line; In Vitro; Incidence; Life; Ligands; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Target; Mus; Mutation; Neoplasm Metastasis; Neuroendocrine Carcinoma; Neurosecretory Systems; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Prevalence; Process; Prostate Adenocarcinoma; Publishing; RB1 gene; Receptor Activation; Receptor Signaling; Recurrence; Recurrent disease; Relapse; Research; Resistance; Resistance development; Role; Societies; Testing; Therapeutic; Tumor Burden; Tumor Suppressor Genes; Variant; Visceral; abiraterone; base; clinically relevant; combat; deprivation; design; effective therapy; genetic approach; improved; in vivo; inhibitor/antagonist; innovation; loss of function; men; mortality; mouse model; novel; novel therapeutic intervention; pre-clinical trial; preclinical study; receptor expression; research study; resistance mechanism; response; steroid metabolism; targeted treatment; therapeutic target; therapy resistant; tumor; tumor progression

Metastatic prostate cancer is incurable with available therapies and accounts for all prostate cancer mortality. This is a significant health problem given that prostate cancer is the most common visceral cancer in men and the second leading cause of cancer death in western societies. Androgen deprivation therapy (ADT) is the most generally useful therapy available. Despite the initial effectiveness of this molecularly targeted therapy, however, patients will inevitably relapse with ADT resistant disease. Well characterized forms of ADT resistance include alterations in androgen receptor (AR) leading to persistent and sometimes ligand independent AR signaling as well as changes in steroid metabolism that maintain intratumoral androgen levels sufficient for AR signaling. Newer generation drugs like the superior AR antagonist enzalutamide or the CYP17A1 inhibitor abiraterone acetate counter these ADT resistance mechanisms and extend life in men with recurrent disease, but responses have proven short lived. Delaying or reversing ADT resistance, therefore, is an important therapeutic goal as it is proven to extend patient survival. As AR blockade has improved, a unique form of resistance involving trans differentiation to an AR negative cancer with neuroendocrine features (NEPC) is increasingly observed. NEPC progresses with atypical visceral metastasis in the absence of rising PSA, and is observed currently in about 25% of prostate cancer autopsies. Incidence is likely to increase as more patients benefit from improved ADT. Molecular mechanisms underlying NEPC trans differentiation are not clear, nor are there targeted therapies available to treat it. We present data from human cell lines and mouse models suggesting RB1 loss is a key determinant facilitating NEPC trans differentiation. We suggest Rb1 loss relieves a constraint on epigenetic reprogramming of gene expression thereby facilitating trans differentiation to AR negative, ADT resistant NEPC. If true, NEPC trans differentiation should be reversible. Consistent with this prediction, preliminary data indicates some epigenetic modulating drugs restore AR expression and enzalutamide sensitivity in NEPC. The specific goals of the proposed research are to challenge the central hypothesis, characterize mechanisms causing NEPC trans differentiation, assess their clinical relevance by cross-species analysis, and test their utility as therapeutic targets using pre-clinical trials. Successful completion of these goals will address a critical issue in the clinical management of prostate cancer and will fill major current gaps in our fundamental understanding of prostate cancer progression, therapeutic resistance, and the role that RB1 loss of function plays in these processes.

转移性前列腺癌是无法治愈的，可用的治疗方法，并占所有前列腺癌死亡率。