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Principal Investigator: Mia E Hofstad
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $39,711
Funding agency: National Cancer Institute
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.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Address><Affect><Assay><Assay for Transposase-Accessible Chromatin using sequencing><BRCA2><BRCA2 gene><Binding><Bioassay><Biochemical><Biologic Models><Biological><Biological Assay><Biological Models><Body Tissues><Breast Cancer 2 Gene><Breast Cancer Treatment><Breast Cancer Type 2 Susceptibility Gene><California><Cancer Induction><Cancer Patient><Cancers><Cell Communication and Signaling><Cell Line><Cell Signaling><Cell Survival><Cell Viability><Cell-Extracellular Matrix><CellLine><Cessation of life><Chromatin><Clinical><Clinical Trials><Cold-Insoluble Globulins><Collagen><Collagen Type I><DNA Damage><DNA Injury><Data><Death><Deposit><Deposition><ECM><Early Onset Gene Breast Cancer 2><Extracellular Matrix><Extracellular Matrix Degradation><FANCD1><FN1><Failure><Fibrinolysin><Fibronectin 1><Fibronectins><Fibrosis><Food and Drug Administration><Gene Transcription><Gene set enrichment analysis><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Glean><Glu-Plasmin><Glycoprotein GP-2><Goals><Grant><Hereditary Breast Cancer 2><Hormonal><Hour><Impairment><In Vitro><Incidence><Intracellular Communication and Signaling><Kinases><Knowledge><LETS Proteins><Laminin><Large External Transformation-Sensitive Protein><Link><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Measures><Metallopeptidases><Metalloproteases><Metalloproteinases><Model System><Modeling><Molecular><Molecular Interaction><Mutation><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><PAI-1><PAI1><PARP Inhibitor><PARP Polymerase><PARP protein><PARP-1 inhibitor><PARPi><PARS><PDX model><PLANH1><Pathogenicity><Pathologic><Pathway interactions><Patient derived xenograft><Patients><Phosphotransferase Gene><Phosphotransferases><Plasmin><Plasminogen Activator Inhibitor 1><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) Polymerases><Poly(ADP-ribose) polymerase 1 inhibitor><Poly(ADPribose) Polymerase><Polymerase><Promoter Regions><Promotor Regions><Prostate><Prostate CA><Prostate Cancer><Prostate Gland><Prostate malignancy><Prostatic Cancer><Prostatic Gland><Protease F><Proteins><RNA Expression><RNA Seq><RNA analysis><RNA sequencing><RNAseq><Recurrence><Recurrent><Resistance><Resistance development><Resistant development><Risk><Role><SERPINE1><SERPINE1 gene><San Francisco><Serine or Cysteine Proteinase Inhibitor Clade E Member 1><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Staining method><Stains><Strains Cell Lines><System><Tissues><Transcription><Transcription Activation><Transcriptional Activation><Transphosphorylases><Trichrome stain><Type 1 Collagen><Type 1 Plasminogen Activator Inhibitor><U-PA><U-Plasminogen Activator><USFDA><United States><United States Food and Drug Administration><Universities><Up-Regulation><Upregulation><Upstream Stimulatory Factor><Upstream Transcription Factor><Urinary Plasminogen Activator><Urokinase><Urokinase Plasminogen Activator><Urokinase-Type Plasminogen Activator><advanced breast cancer><advanced prostate cancer><advanced stage breast cancer><alpha 2-Surface Binding Glycoprotein><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biologic><biological signal transduction><brca 2 gene><cancer cell><carcinogenesis><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><clinical prognosis><clinical relevance><clinically relevant><cultured cell line><developing resistance><genetic promoter element><genetic promoter sequence><genome mutation><helix-loop-helix activator USF><hormone refractory prostate cancer><in vitro activity><in vivo><in vivo Model><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><malignancy><men><mutant><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><overexpress><overexpression><pathway><patient derived xenograft model><poly ADP polymerase><poly ADP ribose synthetase><prevent><preventing><promoter sequence><prostate cancer model><prostate cancer resistant to androgen><prostate tumor model><resistance to therapy><resistant><resistant to therapy><response><response to therapy><response to treatment><small molecule><social role><therapeutic resistance><therapeutic response><therapy resistant><therapy response><transcription factor MLTF><transcription factor USF><transcriptome sequencing><transcriptomic sequencing><treatment resistance><treatment response><treatment responsiveness><tumor>