Elucidating mechanisms of therapy response in BRCA2 mutant prostate cancers

阐明 BRCA2 突变前列腺癌的治疗反应机制

基本信息

批准号：
10678578
负责人：
Mia E Hofstad
金额：
$ 3.84万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678578
关键词：
ATAC-seq Address Affect BRCA2 gene Binding Biochemical Biological Biological Assay Biological Models Breast Cancer Treatment California Cancer Patient Cell Line Cell Survival Cessation of life Chromatin Clinical Clinical Trials Collagen Collagen Type I DNA Damage Data Deposition Extracellular Matrix Extracellular Matrix Degradation Failure Fibronectins Fibrosis Gene set enrichment analysis Genes Genetic Transcription Genomics Glean Goals Grant Hormonal Hour Impairment In Vitro Incidence Knowledge Laminin Link Malignant Neoplasms Malignant neoplasm of prostate Measures Metalloproteases Modeling Molecular Mutation Pathogenicity Pathologic Pathway interactions Patients Phosphotransferases Plasmin Plasminogen Activator Inhibitor 1 Poly(ADP-ribose) Polymerase Inhibitor Poly(ADP-ribose) Polymerases Polymerase Promoter Regions Prostate Proteins RNA analysis Recurrence Resistance Resistance development Risk Role SERPINE1 gene San Francisco Signal Pathway Signal Transduction Solid Neoplasm Stains System Tissues Transcriptional Activation Trichrome stain United States United States Food and Drug Administration Universities Up-Regulation Urokinase advanced breast cancer advanced prostate cancer cancer cell carcinogenesis castration resistant prostate cancer clinical prognosis clinically relevant in vitro activity in vivo in vivo Model inhibitor inhibitor therapy men mutant new therapeutic target novel overexpression patient derived xenograft model prevent prostate cancer model response small molecule therapy resistant transcription factor USF transcriptome sequencing treatment response tumor

项目摘要

ABSTRACT Prostate cancer is the most common non-skin malignancy in men and is projected to cause 34,500 deaths in 2022 in the United States alone. Sequencing studies of advanced lethal castrate resistant prostate cancer (CRPC) have identified a high incidence (~13%) of pathogenic BRCA2 mutations. These findings have enabled clinical trials and subsequent Food and Drug Administration (FDA) approval of the poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) olaparib and rucaparib in advanced CRPC patients harboring a pathogenic BRCA2 mutations. Despite initial responses, therapy resistance to PARPis is common. However, the molecular adaptations that occur in BRCA2 mutant CRPC in response to PARPi are poorly understood, due to a lack of biologically and clinically relevant models. Our proposed studies leveraging two new patient-derived model systems of pathogenic BRCA2 mutant CRPC will elucidate the biological mechanisms implicated in PARPi therapy response and help address a critical clinical unmet need to prevent or overcome resistance to PARPis. In this proposal, we will use two new models of pathogenic BRCA2 mutations in CRPC, including the 40511 cell line and matched PARPi-sensitive and resistant LTL-610 PDXs. Gene Set Enrichment Analysis (GSEA) and Over-Representation Analysis (ORA) of RNA-sequencing data utilizing these novel models point to significant upregulation in genes involved in Extracellular Matrix (ECM) modulation in response to both short and long term PARPi therapy. In particular, the ECM associated gene SERPINE1, which encodes for the protein Plasminogen Activator Inhibitor 1, (PAI-1) is the most significantly implicated gene after 72 hours of olaparib treatment via GSEA leading edge analysis. Since PAI-1 canonically prevents ECM degradation, we then used Masson’s Trichrome staining to evaluate the PARPi resistant LTL-610 PDX and found dramatically increased Type I Collagen deposition compared to its PARPi sensitive parental line. Since stromal alterations are known to affect cancer cell survival, we hypothesize that the induction of ECM genes like SERPINE1 by PARPis in BRCA2 mutant CRPC results in enhanced tumor stroma, and enables therapy resistance. Two specific aims are proposed in this grant to study this hypothesis: in Aim 1, we will elucidate the role of SERPINE1 signaling in ECM deposition in BRCA2 mutant CRPC in vitro, ex vivo, and in vivo. In Aim 2, we will investigate the mechanism of transcriptional activation of SERPINE1 in BRCA2 mutant CRPC in response to PARPi. The results from these studies will enable systematic approaches to modulate ECM alterations in response to PARPi in BRCA2 mutant CRPCs.

抽象的前列腺癌是男性最常见的非皮肤恶性肿瘤，预计将导致34,500人死亡仅2022年就在美国。晚期致命性castrate前列腺癌的测序研究（CRPC）已经确定了病原BRCA2突变的高入射（约13％）。这些发现已启用聚（ADP-核糖）聚合酶的临床试验和随后的食品和药物管理（FDA）批准（PARP）具有致病性BRCA2的晚期CRPC患者的抑制剂（Parpis）Olaparib和Rucaparib 突变。尽管有初步反应，但对PARPIS的抗药性很常见。但是，分子由于缺乏生物学和临床相关模型。我们提出的研究利用了两个新的患者衍生模型致病性BRCA2突变体CRPC系统将阐明PARPI实施的生物学机制治疗反应并有助于解决预防或克服对PARPIS的抵抗力的关键临床未满足的需求。在此提案中，我们将在CRPC中使用两种新的致病性BRCA2突变模型，包括40511 细胞系和匹配的PARPI敏感和抗性LTL-610 PDX。基因集富集分析（GSEA）和利用这些新型模型的RNA测序数据的过度代表分析（ORA）指向重要的响应短期和长期的细胞外基质（ECM）调节的基因上调 PARPI疗法。特别是，ECM相关基因serpine1，该基因编码为蛋白质基因激活剂抑制剂1（PAI-1）是在Olaparib治疗72小时后最显着实现的基因 GSEA领先分析。由于PAI-1可以防止ECM降解，然后我们使用了Masson的三色染色以评估抗PARPI的LTL-610 PDX，并发现I型大大增加了与其PARPI敏感父母线相比，胶原蛋白沉积。由于已知基质改变会影响癌细胞存活，我们假设parpis在BRCA2中诱导ECM基因等ECM基因突变的CRPC导致肿瘤基质增强，并具有耐药性。两个具体目标是在这笔赠款中提出的研究这一假设：在AIM 1中，我们将阐明Serpine1信号在 BRCA2突变体CRPC的ECM沉积在体外，离体和体内。在AIM 2中，我们将研究机制响应于PARPI的BRCA2突变体CRPC中serpine1的转录激活。这些结果研究将实现系统的方法来调节BRCA2突变体中PARPI的ECM改变 CRPC。