Abstract 4246: Degradation of the ETS transcription factor ERG by stabilized helical peptide (Helicon™) degraders enables pharmacological validation in ERG-fusion prostate cancer models

Abstract Approximately 300, 000 new prostate cancer patient diagnoses and 35, 000 deaths due to prostate cancer are documented annually in the United States. An estimated 40-50% of all prostate cancers harbor the TMPRSS2-ERG fusion, leading to androgen receptor (AR)-driven expression of the oncogene ERG. As a transcription factor, ERG induces tumorigenesis by increasing cell proliferation and both invasion and migration of tumor cells, promoting their metastatic ability. ERG and AR have interconnected functions in prostate cancer, where together they strike a balance between proliferative potential and luminal differentiation. ERG also enhances the stemness of prostate cancer cells by interacting with epigenetic modifiers such as EZH2, MAT2A, and the SWI/SNF complex, which may lead to increased therapeutic resistance after treatment with AR targeted therapies. While genetic deletion or knockdown demonstrates tumor dependence on ERG, the lack of small molecule ligandable pockets on ERG has limited preclinical target validation and pharmacological proof of concept. Using the Helicon™ (stabilized helical peptides) drug discovery platform, we can efficiently discover binders of traditionally undruggable targets lacking small-molecule binding pockets, like transcription factors. An example Helicon™ is our inhibitor of the β-catenin-TCF4 interaction, FOG-001, which is currently being evaluated in a Ph1/2 clinical trial (NCT05919264). ERG is a well-suited candidate for a Helicon™-based approach to targeting. Here we demonstrate the discovery of molecules that induce targeted ubiquitin-proteosome degradation of ERG by appending E3-ligase ligands to ERG Helicon™ binders. We demonstrate that ERG-degrader Helicons™ bind selectively and with high affinity to ERG in biochemical assays. In cells, ERG is potently degraded via an E3-ligase-dependent mechanism, reducing downstream expression of its target genes. Using both human cell line- (CDX) and patient-derived xenograft (PDX) models, we demonstrate deep and durable degradation of ERG with our Helicon™ degraders and have confirmed for the first time that pharmacological reduction of ERG protein levels leads to substantial tumor growth inhibition. Collectively these data demonstrate preclinical proof of concept for this therapeutic target and mechanism of action. Ongoing optimization of these Helicons™ may allow clinical application of ERG degraders in a patient population with high unmet need. Citation Format: Amelia K. Luciano, Brian White, Graeme Lambert, Aaron Fulgham, Ian Wallace, Shelagh Fluharty, Miroslaw Lech, Dakota Hawkins, Pevindi Jayasuriya, Tara Travaline, Paula Ortet, Mallika Iyengar, Julia Bowers, Yusuf Vohra, Santosh Choudary, John Santa Maria, Jason Hoki, Claire May, Mark Ator, Brandon Nicolay, Diwakar Pattabiraman, Alexander W. Hird, Markus Haeberlein, Jonathan Hurov. Degradation of the ETS transcription factor ERG by stabilized helical peptide (Helicon™) degraders enables pharmacological validation in ERG-fusion prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4246.