Document text
Principal Investigator: Aadel Chaudhuri
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $596,475
Funding agency: National Cancer Institute
PROJECT SUMMARY
The deadliest form of advanced-stage prostate cancer is treatment-resistant metastatic castration-
resistant prostate cancer (mCRPC), which occurs in ~35% of patients after exposure to androgen
receptor (AR)-directed therapies such as Abiraterone and Enzalutamide, resulting in a dismal median
survival of only ~5.5 months. Unfortunately, detection of treatment-resistant disease typically occurs
too late, when patients are already progressing on AR-directed drugs, after which they succumb rapidly
to their disease. There is therefore a critical need to detect AR resistance more sensitively and earlier
in the disease course. To address this, our team designed a novel cell-free DNA assay called Enhancer
and Neighboring Loci of Androgen Receptor Sequencing (EnhanceAR-Seq), built upon the Cancer
Personalized Profiling by deep Sequencing (CAPP-Seq) platform, and demonstrated superb sensitivity
for detecting AR gene body and enhancer locus alterations in plasma collected from mCRPC patients.
Notably, we applied our EnhanceAR-Seq technology to mCRPC patient plasma and showed that the
results correlate strongly with clinically verified resistance to AR-directed therapy, and significantly
outperform circulating tumor cell (CTC) AR-V7 detection. Building upon this, the current proposal will
evaluate whether our EnhanceAR-Seq technology can be used to predict both (Aim 1) pre-treatment
and (Aim 2) on-treatment resistance to AR-directed therapy in mCRPC patients. Further, in Aim 3 we
will investigate whether integrating EnhanceAR-Seq with genome-wide methylation sequencing can
granularly refine our ability to predict treatment resistance and monitor both clonal and phenotypic
evolution in mCRPC. We are uniquely positioned to accomplish this through our interdisciplinary team
comprised of cell-free DNA genomicists, bioinformaticians, oncologists, and statisticians. Overall, this
study has significant translational impact by establishing cell-free genomic and epigenomic biomarkers
of tumor evolution and resistance to AR-directed therapy in men with lethal prostate cancer.
Terms: <AR gene><Address><Androgen Receptor><Androgen Therapy><Assay><Bioassay><Biological Assay><Biological Markers><Biometrics><Biometry><Biostatistics><Blood Plasma><Blood Plasma Cell><CAPP-seq><Cancer Patient><Cancer Personalized Profiling by Deep Sequencing><Cell Body><Cells><Clinic><Clinical><Computational Biology><DNA Alteration><DNA Sequence Alteration><DNA analysis><DNA methylation profiling><DNA mutation><Data><Detection><Development><Diagnosis><Dihydrotestosterone Receptor><Disease><Disease Progression><Disease Resistance><Disorder><Drugs><Enhancers><Evolution><Exposure to><Genetic mutation><Genomics><Goals><Lead><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Measures><Medication><Metastatic Prostate Cancer><Methyl-Seq><MethylSeq><Methylation sequencing><Monitor><NR3C4><Neoplasm Circulating Cells><Oncologist><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Pharmaceutical Preparations><Phenotype><Plasma><Plasma Cells><Plasma Serum><Plasmacytes><Position><Positioning Attribute><Prognosis><Prostate CA><Prostate Cancer><Prostate Carcinoma Metastatic><Prostate malignancy><Prostatic Cancer><Resistance><Resistance development><Resistant development><Resolution><Reticuloendothelial System, Serum, Plasma><SMAX1><Sequence Alteration><TM-MKR><Technology><Time><Tumor Markers><Tumor Tissue><Upstream Enhancer><Variant><Variation><Work><Xtandi><abiraterone><analyze DNA><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen receptor gene><androgen resistance in prostate cancer><androgen resistant prostate cancer><bio-markers><biologic marker><biomarker><cancer genomics><cancer type><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><cell free DNA><cell free circulating DNA><circulating neoplastic cell><circulating tumor cell><computer biology><design><designing><detection sensitivity><determinants of therapy resistance><determinants of treatment resistance><develop therapy><developing resistance><developmental><drug/agent><enzalutamide><epigenomics><gene locus><genetic locus><genome scale><genome wide methylation><genome-wide><genomewide><genomewide methylation><genomic alteration><genomic location><genomic locus><global methylation><heavy metal Pb><heavy metal lead><hormone refractory prostate cancer><human tissue><improved><intervention development><liquid biopsy><men><multiomics><multiple omics><novel><oncogenomics><panomics><patient oriented outcomes><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><plasmocyte><predictive biomarkers><predictive marker><predictive molecular biomarker><predictors of therapy resistance><predictors of treatment resistance><prospective><prostate cancer resistant to androgen><resistance to disease><resistance to therapy><resistant><resistant disease><resistant to disease><resistant to therapy><resolutions><response><sequencing platform><standard of care><survival outcome><therapeutic resistance><therapy development><therapy resistant><translational impact><treatment development><treatment resistance><treatment strategy><tumor><tumor biomarker><tumor specific biomarker>