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 2022 年仅在美国进行晚期致命性去势抵抗性前列腺癌的测序研究。 (CRPC) 发现致病性 BRCA2 突变的发生率很高（约 13%），这些发现使得这一结果成为可能。聚（ADP-核糖）聚合酶的临床试验和随后的食品和药物管理局 (FDA) 批准 (PARP) 抑制剂 (PARPis) olaparib 和 rucaparib 用于治疗携带致病性 BRCA2 的晚期 CRPC 患者尽管最初有反应，但对 PARPis 的治疗耐药性很常见。由于缺乏我们提出的研究利用了两种新的患者衍生模型。致病性 BRCA2 突变体 CRPC 系统将阐明 PARPi 涉及的生物学机制治疗反应并帮助解决临床未满足的关键需求，以预防或克服对 PARPis 的耐药性。在本提案中，我们将使用两种新的 CRPC 致病性 BRCA2 突变模型，包括 40511 细胞系和匹配的 PARPi 敏感和耐药 LTL-610 PDX 基因集富集分析 (GSEA) 和利用这些新颖模型对 RNA 测序数据进行过度表征分析 (ORA) 表明具有显着意义参与细胞外基质（ECM）调节的基因响应短期和长期的上调 PARPi 疗法尤其是 ECM 相关基因 SERPINE1，它编码纤溶酶原蛋白。激活剂抑制剂 1 (PAI-1) 是奥拉帕尼治疗 72 小时后最显着相关的基因由于 PAI-1 可以典型地防止 ECM 退化，因此我们使用了 Masson 的 GSEA 前沿分析。三色染色评估 PARPi 抗性 LTL-610 PDX，发现 I 型显着增加胶原沉积与其 PARPi 敏感亲本系相比，因为已知基质改变会影响。癌细胞存活，我们追踪 BRCA2 中 PARPis 对 SERPINE1 等 ECM 基因的诱导突变的 CRPC 会导致肿瘤基质增强，并产生治疗耐药性，这有两个具体目标。在本次资助中提出研究这一假设：在目标 1 中，我们将阐明 SERPINE1 信号传导在 BRCA2 突变体 CRPC 中的 ECM 沉积在体外、离体和体内在目标 2 中，我们将研究其机制。 BRCA2 突变体 CRPC 中 SERPINE1 响应 PARPi 的转录激活的结果。研究将实现系统方法来调节 ECM 改变以响应 BRCA2 突变体中的 PARPi CRPC。