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Marek Zorawski

Marek Zowarski PDDS24
Predoctoral Fellowship in Drug Discovery, 2024 Duke University

Characterization and Targeting of the 3' Splice Site of Cryptic Exon 3 in the Androgen Receptor Pre-mRNA

Abstract

In castration-resistant prostate cancer (CRPC), a splice variant of the androgen receptor, AR-V7, can drive disease. The 3′ splice site (3’SS) of cryptic exon 3 (CE3), the unique alternative exon in AR-V7, is well-studied, but the impact of these pre-mRNA structures and their targetability are unknown. Here, I show the first experimental pre-mRNA secondary structure model of the CE3 3’SS. Based on this model and other data, I hypothesize RNA structures, such as stem loop 1 (SL1), become more single-stranded with androgen deprivation; RNA-targeted small molecules can modulate this splicing event; and this modulation occurs through SL1:HNRNPF binding. I will continue using chemical probing to deduce changes in pre-mRNA structures and functionally validate them; obtain and validate hit molecules that bind CE3 3’SS structures; and assess SL1 targeting via HNRNPF binding, revealing mechanisms of CE3 inclusion in CRPC that could lead to the first RNA-targeted splicing modulator in CRPC.

For many patients, the standard-of-care treatments we provide for prostate cancer in the clinic result in resistance to these drugs. This PhRMA Foundation award will help my work that focuses on targeting an RNA splicing process that contributes to this treatment resistance in many cases. I hope the development of these drugs will not only help patients with aggressive prostate cancer but will also pave a way toward the development of new RNA-targeting medicines for cancer patients more broadly.

Marek Zorawski

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