Grants and Contracts Details
Description
Abstract:
Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer and the second-leading
cause of cancer mortality among American men. Castration-resistant prostate cancer (CRPC)
develops over a period of months to years, metastasizing to different organs and representing
the lethal stage of the disease. Molecular characterization of CRPC has paved a path for
discovery of novel therapeutic targets, and recent comprehensive genomic and transcriptomic
studies indicate that ~10–15% of CRPC cases harbor biallelic deletion or loss-of-function
alterations of RB1. Rb functions to repress the transcription activity of E2F activators by forming
an Rb-E2F transcription repressor complex but CDK4/6-mediated hyperphosphorylation of Rb
during G1/S cell cycle transition results in the gene’s disassociation with E2Fs, thus inducing
E2F-dependent transcriptional activation of DNA replication and cell cycle progression. While
the application of CDK4/6 inhibitors—which are currently in widespread clinical use—can restore
the Rb binding to E2F, the loss of RB1 has been implicated as a driver of resistance to CDK4/6
inhibitors. TRIM28 was identified as an interacting protein for Kruppel-associated box zinc finger
protein more than 2 decades ago, and the study team previously reported that TRIM28 is
aberrantly upregulated in CRPC and promotes PCa progression. Despite its longstanding
transcriptional repressive function, it has been shown that TRIM28 is also a transcriptional
activator under different cellular contexts. However, knowledge gaps remain regarding how
TRIM28 level is elevated in CRPC, what the key TRIM28-downstream pathways are, how
TRIM28 activates its targets, and most importantly whether the transcription activator activity of
TRIM28 can be exploited to develop treatment strategies against CRPC. Toward addressing
these gaps, the study team revealed that TRIM28 is overexpressed in RB1-loss CRPC and RSK-
driven pS473-TRIM28 promotes transcription activation of E2F1. The central hypothesis of the
proposed study is that aberrantly expressed TRIM28 promotes transcription activation of its
targets, which are dependent on RSK-mediated pS473-TRIM28, eventually contributing to
CRPC progression. This hypothesis will be tested by elucidating the mechanism of TRIM28
activation upon RB1-loss by cutting-edge CUT&RUN assay and ATAC-Seq (Aim1), investigating
the functional significance of RSK-directed TRIM28 phosphorylation in regulating TRIM28’s
interactome and transcriptome with use of affinity purification and RNA-Seq (Aim2) and testing
the efficacy of RSK inhibitor against RB1-loss CRPC with use of CRPC-derived xenograft and
next-generation patient-derived xenograft model (Aim3). Potential impact of project on tackling
therapeutic resistance: Direct pharmacological inhibition of E2F1 is not currently feasible, pS473-
TRIM28 will be targeted by pharmacologic inhibition of RSK to prevent E2F1 transcriptional
upregulation, resulting in innovative approaches to overcome CDK4/6 inhibitor resistance in
RB1-loss CPRC and to develop new biomarkers to follow disease progression.
Status | Active |
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Effective start/end date | 9/1/23 → 9/1/26 |
Funding
- V Foundation: $600,000.00
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