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:
  • 金额:
    $ 3.84万
  • 依托单位:
  • 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

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.
摘要

项目成果

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