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Principal Investigator: Boyang Wu
Organization: WASHINGTON STATE UNIVERSITY
Fiscal Year: 2024
Award: $332,489
Funding agency: National Cancer Institute
Project Summary/Abstract (Parent Grant Application)
Prostate cancer (PC) is the most common non-skin cancer in American men, with a lifetime incidence of 1 in 7,
and also the second leading cause of cancer death in American men. Androgen receptor (AR) is the primary
oncogenic driver of PC growth, survival and progression. AR-directed therapy is currently the principal
treatment regimen. Despite initial response rates exceeding 90%, PC eventually relapses and progresses to
fatal castration-resistant PC (CRPC), where reactivation of AR signaling occurs in a low-androgen environment.
Recent introduction of FDA-approved next-generation antiandrogens, including enzalutamide (ENZ) and
abiraterone acetate (ABI), have improved the CRPC treatment landscape, but emergence of drug resistance
remains nearly universal, with no AR-targeted therapeutic options afterwards. These dismal facts underscore
the pressing clinical need to identify new molecular targets and develop effective therapies to combat
advanced PC. Through integrated analysis of publicly available clinical PC data sets coupled with functional
studies in AR-positive PC cells, we propose monoamine oxidase A (MAOA), which synergizes with AR to
promote PC, as an ideal therapeutic candidate to complement AR-targeted therapy in CRPC. We identified a
novel reciprocal interaction between MAOA and AR in PC cells. MAOA expression is induced by androgen
treatment; and conversely, MAOA silencing significantly reduces AR activity by lowering AR target gene
expression and responsiveness to androgen stimulation in PC cells under both androgen-replete and depleted
conditions as well as in a CRPC xenograft model. We showed significant positive co-expression of MAOA and
AR target genes (PSA, TMPRSS2, NKX3.1) in multiple clinical data sets, including CRPC. Importantly, we
found MAOA genomic amplification and/or epigenetic activation in 64% of samples in a CRPC data set,
reinforced by elevated MAOA protein expression in our CRPC patient cohort. Additionally, we demonstrated
that inhibition of MAOA by genetic or pharmacological approaches enhanced the growth-inhibiting effects of
ENZ and ABI in androgen-sensitive, CR and antiandrogen-resistant PC cells. Based on these findings, we will
test the hypothesis that MAOA synergizes with AR through reciprocal crosstalk and convergent downstream
signaling to amply MAOA/AR effects promoting AR-driven PC growth and progression, and that co-targeting
MAOA/AR is an actionable, effective strategy to treat CRPC and reverse antiandrogen drug resistance. To
address this hypothesis, three aims are proposed. In Aim 1, we will elucidate the mechanistic basis of MAOA-
AR reciprocal interaction in PC cells. In Aim 2, we will characterize the role of MAOA in regulating the
development and progression of CRPC in xenograft models. In Aim 3, we will determine the efficacy of MAOA
inhibitors for treating CRPC and reversing resistance to next-generation antiandrogens in vitro and in vivo.
These studies will provide fundamental innovative insights into AR regulation in CRPC and illuminate a path
toward the development of new combination therapy for advanced PC.
Terms: <Acetates><Active Oxygen><Address><American><Androgen Antagonists><Androgen Receptor><Androgen Response Element><Androgenic Agents><Androgenic Compounds><Androgens><Anti-Androgen><Anti-Androgen Agents><Applications Grants><Assay><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biochemical><Biological Assay><CPT7><CYP17><CYP17A1><CYP17A1 gene><Cancer Cause><Cancer Etiology><Cancer Patient><Cancer Relapse><Cancers><Castration><Cell Communication and Signaling><Cell Signaling><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Chemicals><Clinical><Clinical Data><Clinical Management><Combined Modality Therapy><Complement><Complement Proteins><Complex><Coupled><Data Set><Death><Dependence><Development><Disease><Disease Resistance><Disorder><Drug resistance><Drugs><E-Box Elements><E-Box Motifs><E-Box Sequences><E-Box Sites><Enhancers><Environment><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epitheliasin Gene><Evaluation><FDA approved><Foundations><Gene Expression><Gene Transcription><Gene set enrichment analysis><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Genetic Transcription><Genomics><Grant Proposals><Growth><H2O2><Homeobox Protein NKX-3.1><Homeobox Protein NKX3A><Human><Hydrogen Peroxide><Hydroperoxide><In Vitro><Incidence><Intracellular Communication and Signaling><Journals><Knowledge><Link><MAO-A><Magazine><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Mediator><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mitochondria><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Molecular Target><Monoamine Oxidase A><Multimodal Therapy><Multimodal Treatment><NK Homeobox Family 3 Subunit A Homolog><NK3 Transcription Factor Homolog A><NK3 Transcription Factor Related Protein><NKX3-1 gene><NKX3.1><NKX3A><Nature><Neoplasm Metastasis><New Agents><Nkx-3.1 protein><Oncogenic><Operative Procedures><Operative Surgical Procedures><Oxygen Radicals><P450C17><PRSS10><Patients><Pharmaceutical Preparations><Pro-Oxidants><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate malignancy><Prostatic Cancer><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reactive Oxygen Species><Receptor Signaling><Regulation><Relapse><Reporting><Resistance><Resistance development><Resistant development><Role><S17AH><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Surgical><Surgical Castration><Surgical Interventions><Surgical Procedure><Survey Instrument><Surveys><System><TMPRSS2><TMPRSS2 gene><Testing><Tetracyclines><Therapeutic Androgen><Tissue Growth><Transactivation><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Translations><Treatment Protocols><Treatment Regimen><Treatment Schedule><Type A Monoamine Oxidase><Xenograft Model><Xtandi><abiraterone><advanced prostate cancer><androgen ablation therapy><androgen biosynthesis><androgen blockade therapy><androgen dependent><androgen deprivation therapy><androgen deprivation treatment><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen inhibitor><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><androgen responsive><androgen sensitive><antagonism><antagonist><biological signal transduction><cancer cell><cancer initiation><cancer metastasis><cancer prevention><cancer progression><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><chromatin immunoprecipitation-sequencing><clinical investigation><cohort><combat><combination therapy><combined modality treatment><combined treatment><complementation><determine efficacy><developing resistance><developmental><dietary><drug resistant><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><enzalutamide><epigenetically><evaluate efficacy><examine efficacy><hormone refractory prostate cancer><improved><in vivo><inhibitor><innovate><innovation><innovative><insight><knock-down><knockdown><mRNA Expression><malignancy><men><mitochondrial><molecular profile><molecular signature><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><monoamine><multi-modal therapy><multi-modal treatment><neoplasm progression><neoplasm/cancer><neoplastic progression><new combination therapies><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><ontogeny><parent grant><pharmacologic><promoter><promotor><prostate cancer cell><prostate cancer cell line><prostate cancer progression><prostate cancer resistant to androgen><prostate cancer treatment><prostate tumor cell><protein expression><resistance to Drug><resistance to disease><resistant><resistant disease><resistant to Drug><resistant to disease><response><shRNA><short hairpin RNA><small hairpin RNA><social role><surgery><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic candidate><therapeutic target><trans-activation><transcription factor><transcriptome sequencing><transcriptomic sequencing><translation><treatment strategy><tumor><tumor cell metastasis><tumor growth><tumor progression><xenograft transplant model><xenotransplant model>