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Principal Investigator: Nicholas James Brady
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $196,745
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the
treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. Lineage plasticity has
been proposed as one mechanism of therapeutic resistance whereby patients with resistant disease develop
AR-negative, androgen signaling-indifferent prostate tumors that lose their luminal identity and display
neuroendocrine features (neuroendocrine prostate cancer, NEPC). While NEPC tumors share many genetic
alterations with prostate adenocarcinoma, the potential drivers of lineage plasticity remain understudied. Using
a novel genetically-engineered mouse model that faithfully recapitulates the transition to NEPC, I have
established an organoid-based allograft platform that is amenable to gene editing technologies. Using single-cell
based approaches, Furthermore, I have identified a previously undescribed tumor subpopulation with a unique
transcriptional regulator that may represent an transition between adenocarcinoma and NEPC. For the proposed
studies, I will modulate the expression levels of the identified transcriptional regulator using CRISPR-based gene
editing or overexpression strategies in prostate organoids and determine how the transition to NEPC is affected.
I will also assess the sensitivity of this tumor subpopulation to clinically-relevant treatment options, including
androgen withdrawal and AR-targeted therapy. Finally, I will reveal how targeting epigenetic modifiers changes
the composition of tumor subpopulations and reverses the development of therapeutic resistance. Alongside
these scientific aims, I will use the period of support to enhance my skillset and develop as an independent
researcher. Through a comprehensive plan, including workshops, course work, clinical case conferences, and
attendance at seminars and scientific conferences, I plan to develop a deeper understanding of bioinformatics
at the single cell level, expand my exposure to critical barriers facing clinicians and prostate cancer patients, and
successfully continue my transition to an independent research position. The environment at Weill Cornell
Medicine, and among its closely aligned neighboring institutions, is ideal for me to complete the proposed studies
and will help foster my continued research and career development success.
Terms: <Adenocarcinoma><Adenocarcinoma Cell><Affect><Allografting><Androgen Receptor><Androgenic Agents><Androgenic Compounds><Androgens><Antioncogene Protein p53><Back><Basal Transcription Factor><Basal transcription factor genes><Bio-Informatics><Bioinformatics><Biologic Models><Biological Models><CRISPR><CRISPR/Cas system><Cancer Patient><Castration><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Tumor Antigen P53><ChIP Sequencing><ChIP-seq><ChIPseq><Chromatin><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Data><Development><Development and Research><Disease Resistance><Dorsum><Drugs><ENX-1><EZH1><EZH2><EZH2 gene><Educational workshop><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Etiology><Exposure to><Fostering><Future><GEM model><GEMM model><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetically Engineered Mouse><Genomics><Histologic><Histologically><Histology><Human><In Vitro><Incidence><Institution><Intracellular Communication and Signaling><Intratumoral heterogeneity><Investigators><KMT6><KMT6A><Learning><MYCN><MYCN gene><Malignant Adenoma><Malignant Glandular Cell><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Medication><Medicine><Mice><Mice Mammals><Model System><Modern Man><Molecular><Murine><Mus><Mutate><Mutation><NMYC><NMYC Gene><Neuroendocrine><Neuroendocrine Cell><Neuroendocrine Prostate Cancer><Neuroendocrine System><Neurosecretory Systems><Oat cell carcinoma><Oncoprotein p53><Organoids><Outcome><P53><Patient Selection><Patients><Pharmaceutical Preparations><Phosphoprotein P53><Phosphoprotein pp53><Population><Position><Positioning Attribute><Process><Prostate><Prostate Adenocarcinoma><Prostate CA><Prostate Cancer><Prostate Gland><Prostate Gland Adenocarcinoma><Prostate Neoplasms><Prostate Tumor><Prostate malignancy><Prostatic Cancer><Prostatic Gland><Prostatic Neoplasia><Prostatic Neoplasms><Protein TP53><R & D><R&D><RB1><RB1 gene><RNA Expression><Research><Research Personnel><Researchers><Resistance><Resistance development><Resistant development><Role><Selection Criteria><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Small Cell Lung Cancer><Surgical Castration><TP53><TP53 gene><TRP53><Therapeutic Androgen><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Tumor Cell><Tumor Protein p53><Tumor Protein p53 Gene><Up-Regulation><Upregulation><Withdrawal><Work><Workshop><Xenograft Model><Xtandi><advanced prostate cancer><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><biological signal transduction><biomarker identification><career development><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><causation><chromatin immunoprecipitation-sequencing><clinical relevance><clinically relevant><combat><conference><convention><deprivation><developing resistance><developmental><disease causation><drug/agent><effective therapy><effective treatment><enzalutamide><epigenetically><gene editing platform><gene editing system><gene editing technology><gene editing tools><gene-editing toolkit><genetically engineered mouse model><genetically engineered murine model><genome editing><genome mutation><genomic editing><heterogeneity in tumors><hormone refractory prostate cancer><human model><identification of biomarkers><identification of new biomarkers><improved outcome><insight><intra-tumoral heterogeneity><intratumor heterogeneity><lentiviral-transduced><lentivirally transduced><lentivirus transduced><lung oat cell carcinoma><lung small cell neuroendocrine carcinoma><marker identification><men><model of human><mouse model><murine model><neoplastic cell><neuroendocrine phenotype><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><next generation><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oat cell cancer><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pharmacologic><potential biological marker><potential biomarker><prevent><preventing><prostate cancer model><prostate cancer resistant to androgen><prostate tumor model><prostatic adenocarcinoma><protein p53><research and development><resistance to disease><resistance to therapy><resistant><resistant disease><resistant to disease><resistant to therapy><retinoblastoma-1><scATAC sequencing><scATAC-seq><scRNA-seq><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell sequencing assay for transposase accessible chromatin><single cell transcriptomic profiling><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell RNA sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><skills><small cell lung carcinoma><small cell undifferentiated carcinoma><social role><success><summit><symposia><symposium><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutic resistance><therapy resistant><transcription factor><treatment resistance><tumor><tumor heterogeneity><xenograft transplant model><xenotransplant model>