[R01] The role of early oncogenic drivers in maintaining lineage fidelity in prostate cancer
Ente: National Cancer Institute
Scadenza: 2030-04-30
Importo max: 656.000 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Prostate cancer (PCa) is a clinically and molecular heterogenous disease, with biologically distinct subtypes
driven by characteristic genomic alterations in both early, untreated disease and treatment resistant castration-
resistant prostate cancer (CRPC). However, whether early alterations affect fidelity to prostate lineage,
shape the specific resistance patterns that emerge with treatment, and the underlying mechanisms,
remain unclear.
We hypothesize that specific molecular features of early, untreated PCa establish distinct pathways to
progression and therapeutic resistance through transcriptional control and fidelity to luminal prostate
lineage. Preliminary data generated by our multi-institutional, multidisciplinary, collaborative group suggest
specifically that the subclass of PCa defined by recurrent mutations in SPOP maintain strong fidelity to prostate
lineage, and are therefore preferentially reliant on androgen receptor (AR) signaling and possibly resistant to
conversion to AR-indifferent subtypes of CRPC.
The overall objective of this proposal is to define the propensity of prostate cancers harboring SPOP mutations
to progress to specific subtypes of treatment resistant CRPC, and to define the mechanisms that shape these
resistance patterns. Using novel models and human prostate cancer samples, our preliminary data demonstrate
that SPOP mutation reprograms AR function, altering chromatin accessibility and transcription driven by AR and
making these cancers highly reliant on AR activity. In contrast, N-Myc induction combined with RB1-loss is a
strong driver of AR-indifferent CRPC that functions to rewire and deactivate the AR transcriptional program. Our
central hypothesis is that opposing effects on rewiring of the AR-directed epigenomic and transcriptional
programs mediate the downstream impact on biology and therapeutic sensitivity shown with SPOP mutation and
drivers of AR-indifferent disease.
This project will elucidate the molecular details underlying these phenomena through the following Aims: 1)
defining the propensity of SPOP mutant PCa to progress to AR-indifferent disease in response to specific driver
alterations, 2) mechanistically, determining the contribution of FOXA1 and TRIM24 in lineage fidelity and
plasticity downstream of SPOP, and 3) establishing if drivers of luminal lineage fidelity can prevent or reverse
resistance to AR-targeting therapies. To accomplish this, we will leverage unique, biologically and clinically
relevant model systems, innovative approaches to epigenomic and transcriptomic discovery, and data from
human prostate cancer samples. This project will define the critical transcriptional processes in specific subtypes
of prostate cancer and the broader applicability to treatment resistance, and provide the foundation for precision
clinical trials.
Istituzione: WEILL MEDICAL COLL OF CORNELL UNIV
PI: Christopher E Barbieri, David S. Rickman
Progetto: 5R01CA301637-02
Settori: National Cancer Institute
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