Document text
Principal Investigator: JUN LUO
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $355,850
Funding agency: National Cancer Institute
PROJECT SUMMARY
Homologous recombination (HR) deficiency (HRD), particularly from biallelic mutational loss of
BRCA1/BRCA2/ATM (BRCA/ATM), is significantly enriched in men with metastatic castration-resistant prostate
cancer (mCRPC). Such patients have multiple FDA-approved systemic life-prolonging therapies to choose
from, including abiraterone, enzalutamide, and taxane chemotherapies, as well as the possibility of poly(ADP-
ribose) polymerase (PARP) inhibitor therapy which currently remains investigational. A few recent studies
suggest that patients with germline and/or somatic HRD mutations may respond better (and for longer
durations of time) to novel hormonal therapies than their HRD-negative counterparts. These studies suggest
that in addition to PARP inhibition, potent AR suppression is also “synthetic lethal” with HRD in mCRPC.
However, the genetic/genomic determinants of HRD and their role in treatment selection remain unknown. We
propose a resource-driven, patient-centered study to determine the genetic/genomic drivers of HRD predicting
“deep” response to abiraterone and enzalutamide. We hypothesize that mCRPC patients can be categorized
into three groups according to HRD status defined by deleterious mutations in HRD genes: 1) germline/somatic
HRD; 2) somatic-only HRD; 3) negative HRD; and that these groups are molecularly distinct, and have
different clinical implications as predictive markers of response to AR-targeting therapies and taxane
chemotherapies. To address the overall hypothesis, it is necessary to establish clinical and tumor/normal
specimen cohorts that enable detailed molecular and clinical characterization of HRD in men with mCRPC. In
Specific Aim 1, we will seek to ascertain the HRD mutations status, both somatic and germline, in three
existing advanced/lethal prostate cancer cohorts enriched for HRD using blood-based assays. In Specific Aim
2, we will determine the association of HRD status defined by blood-based assays with treatment response to
first-line AR-directed therapy (abiraterone/enzalutamide) and taxane chemotherapies in mCRPC patients by
comparing treatment outcomes of men in these three groups. In Specific Aim 3, we seek to determine the
expression correlates of HRD status defined by blood-based assays and further ascertained by tissue-based
assays, by performing RNA-Seq in surgical specimens from men with lethal prostate cancer with: 1)
germline/somatic HRD; 2) somatic-only HRD; and 3) negative HRD. The proposed work addresses an unmet
need due to focus on liquid biopsy markers in a vulnerable patient population facing difficult treatment
decisions. Also, our effort in defining the clinical and functional implications of HRD status in established
cohorts of mCRPC patients will directly lead to treatment selection strategies to improve clinical management
as well as patient selection strategies for clinical trials.
Terms: <Address><Alleles><Allelomorphs><Androgen Receptor><Assay><BRCA1><BRCA1 Gene Product><BRCA1 Protein><BRCA1 gene><BRCA2><BRCA2 gene><Bioassay><Biological Assay><Blood><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Body Tissues><Breast Cancer 1 Gene><Breast Cancer 1 Gene Product><Breast Cancer 2 Gene><Breast Cancer Type 1 Susceptibility Gene><Breast Cancer Type 1 Susceptibility Protein><Breast Cancer Type 2 Susceptibility Gene><Breast-Ovarian Cancer Protein><Cancer Patient><Categories><Cell Body><Cells><Clinical><Clinical Management><Clinical Trials><DNA seq><DNA sequencing><DNAseq><Data><Development><Diagnosis><Disease><Disorder><Drug Targeting><Drugs><Early Onset Gene Breast Cancer 1><Early Onset Gene Breast Cancer 2><Early Onset Protein Breast Cancer 1><Endocrine Therapy><Evaluation><Event><FANCD1><FDA approved><Gene Expression><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Germ Lines><Goals><Hereditary><Hereditary Breast Cancer 1><Hereditary Breast Cancer 2><Hormonal Therapy><Inherited><Knowledge><Lesion><Life><Link><Local Therapy><Localized Therapy><Long-term cohort><Longitudinal cohort><Longterm cohort><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Medication><Molecular><Mutation><Operative Procedures><Operative Surgical Procedures><PARP Inhibitor><PARP Polymerase><PARP protein><PARP-1 inhibitor><PARPi><PARS><Patient Selection><Patients><Pharmaceutical Preparations><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) Polymerases><Poly(ADP-ribose) polymerase 1 inhibitor><Poly(ADPribose) Polymerase><Prediction of Response to Therapy><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><RNA Seq><RNA sequencing><RNAseq><RNF53><Rationalization><Recurrence><Recurrent><Research Resources><Research Specimen><Resistance><Resources><Role><SYS-TX><Sampling><Selection for Treatments><Specimen><Surgical><Surgical Interventions><Surgical Procedure><Systemic Therapy><Taxotere><Time><Tissues><Treatment outcome><Work><Xtandi><abiraterone><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><anti-cancer research><brca 1 gene><brca 2 gene><cancer research><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><chemotherapy><cohort><compare treatment><developmental><docetaxel><docetaxol><drug/agent><enzalutamide><gene testing><gene-based testing><genetic predictors><genetic testing><genome mutation><genomic biomarker><genomic marker><homologous recombination deficiency><homologous recombination repair deficiency><hormone refractory prostate cancer><hormone therapy><improved><inhibitor drug><inhibitor therapeutic><inhibitor therapy><liquid biopsy><men><molecular phenotype><mutation status><mutational status><novel><patient centered><patient oriented><patient population><poly ADP polymerase><poly ADP ribose synthetase><predict therapeutic response><predict therapy response><predictive biomarkers><predictive marker><predictive molecular biomarker><prospective><prostate cancer resistant to androgen><resistant><response><response biomarker><response markers><response to therapy><response to treatment><selection of treatment><social role><standard of care><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><taxane><therapeutic response><therapy prediction><therapy response><therapy selection><transcriptome sequencing><transcriptomic sequencing><treatment comparison><treatment prediction><treatment response><treatment response prediction><treatment responsiveness><treatment selection><tumor><tumor DNA><tumor cell DNA><tumor-specific DNA>