Growth suppressive and oncogenic transcriptional programs controlled by the androgen receptor in prostate cancer
Project Number1R01CA297829-01
Contact PI/Project LeaderBARBIERI, CHRISTOPHER E
Awardee OrganizationWEILL MEDICAL COLL OF CORNELL UNIV
Description
Abstract Text
PROJECT SUMMARY / ABSTRACT
The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling
normal, growth-suppressive gene expression associated with differentiation of prostate cells. It is also a key
driver of prostate tumorigenesis, becoming “hijacked” to drive oncogenic transcription. However, the key
factors that mediate this switch, and whether the growth suppressive program can be reactivated to
inhibit prostate cancer, remain unknown. Critically, AR also remains the key therapeutic target for prostate
cancer, even in advanced, treatment resistant disease, where genomic alterations such as massive amplification,
overexpression, mutations, and splice variants of AR drive continued reliance on androgen signaling. Therefore,
understanding how AR is reprogrammed from its normal growth suppressive role to an oncogenic factor has
major impact on our understanding of context-specific regulation of lineage-specific transcription factors and
responses to prostate cancer therapies targeting AR.
Our work has shown, in both published and unpublished preliminary data, that specific factors mediate the
balance of AR activity between normal and oncogenic transcriptional programs. In unpublished preliminary data,
we use a novel system to modulate canonical androgen receptor response element (ARE) motifs to show that
the normal AR transcriptional program is governed by AREs, and reactivation of this normal program is growth
suppressive in prostate cancer cells. We hypothesize that the growth-suppressive AR transcriptional
program can be reactivated in advanced prostate cancer, and specific genomic and epigenetic
modulators will mediate the transition between normal and oncogenic AR activity. We will test this
hypothesis with three Specific Aims: 1) Determine the context that allows engagement of growth suppressive
AR transcriptional programs in prostate cancer, 2) Establish the translational implications of oncogenic and
growth suppressive AR programs in human prostate cancer patients, and 3) Define the key cofactors and
modifiers that mediate the switch between normal and oncogenic AR programs.
With a combination of novel epigenomic modulation strategies, functional genomics, genetically engineered
mouse models, patient derived model systems, and human patient data, we will establish the potential of
reactivating the AR growth suppressive program in vitro and in vivo, examine the implications for patients, and
define novel AR cofactors and therapeutic targets. Together, these studies will evaluate an innovative,
potentially transformative treatment strategy for lethal prostate cancer, expose new biology and new therapeutic
targets, and define a new paradigm for cancers dependent on lineage-specific, multifunctional transcription
factors.
Public Health Relevance Statement
NARRATIVE
The androgen receptor (AR) defines and controls gene expression that is growth suppressive in the normal
prostate, but in prostate cancer cells, AR is converted to driving cancer-promoting gene expression. This
project will define the factors that mediate this switch, and explore the possibility of reactivating the normal,
growth suppressive AR gene expression programs in advanced prostate cancers, thereby halting progression.
These studies will evaluate an innovative, potentially transformative treatment strategy for lethal prostate
cancer, expose new biology and new therapeutic targets, and define a new paradigm for cancers dependent
on lineage-specific, multifunctional transcription factors.
NIH Spending Category
No NIH Spending Category available.
Project Terms
AR geneAndrogen ReceptorAndrogensAutomobile DrivingBiochemicalBiological ModelsBiologyCancer PatientCancerousCell LineCellsDNA MethylationDNA Sequence AlterationDNA-Binding ProteinsDataDisease ResistanceEpigenetic ProcessEquilibriumGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGenetically Engineered MouseGenomicsGrowthHumanIn VitroMalignant NeoplasmsMalignant neoplasm of prostateMediatingMediatorModelingMutationNucleic Acid Regulatory SequencesOncogenesOncogenicOrganoidsPatientsPhenotypePrognosisPrognostic MarkerProstateProstate Cancer therapyPublishingRNA SplicingReceptor SignalingRegulationRegulatory ElementResponse ElementsRoleSamplingSignal TransductionSystemTestingTissuesTranscriptional RegulationVariantWorkadvanced prostate cancercofactordisease heterogeneityepigenomicsfunctional genomicsin vivoinnovationinsightnew therapeutic targetnoveloverexpressionpatient populationpredicting responsepredictive markerprogramsprostate cancer cellprostate cancer modelprostate carcinogenesisreceptor expressionresponsetargeted agenttargeted cancer therapytherapeutic targettranscription factortreatment responsetreatment strategytumortumorigenesis
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