Abstract B141: Degradation of the ETS transcription factor ERG by stabilized helical peptide (Helicon™) degraders enables pharmacological validation in ERG-fusion prostate cancer models

Abstract Each year in the United States, approximately 300,000 new prostate cancer cases are diagnosed, and about 35,000 deaths occur due to the disease. An estimated 40–50% of these cancers harbor the TMPRSS2-ERG fusion, which drives androgen receptor (AR)-dependent expression of the oncogene ERG. The TMPRSS2-ERG fusion generally occurs early on in oncogenesis and persists throughout the disease, meaning both hormone-sensitive and hormone-resistant patient populations could benefit from therapies targeting ERG. As a transcription factor, ERG promotes tumorigenesis by enhancing proliferation, invasion, and migration of cancer cells, supporting metastatic potential. ERG and AR functionally cooperate to balance proliferative signaling and luminal differentiation, while ERG also enhances stemness and resistance to AR therapies through interactions with epigenetic regulators such as PRC2 (EZH2/EED), MAT2A, and the SWI/SNF complex. Despite clear tumor dependence on ERG shown in genetic studies, its lack of ligandable pockets has limited traditional drug discovery approaches. To address this, we leveraged the Helicon platform, which uses stabilized helical peptides to target previously "undruggable" proteins. This platform has already yielded FOG-001, a β-catenin–TCF4 inhibitor currently in a Phase 1/2 trial (NCT05919264). Applying the same strategy, we developed ERG-binding Helicons that, upon conversion to heterobifunctional degraders, induce selective E3 ligase–dependent degradation of ERG via the ubiquitin-proteasome pathway. In both cell-based assays and xenograft models (CDX and PDX), these ERG-degrader Helicons achieved potent and durable ERG depletion, as well as reduced expression of ERG downstream targets. In pre-clinical efficacy studies, ERG-degrader Helicons were well-tolerated and substantially inhibited tumor growth comparable to or exceeding the standard of care AR pathway inhibitors, in part through downregulation of Myc protein and Myc transcriptional activity. Beyond their strong activity as single agents, ERG-degrader Helicons exhibit potential synergy with several clinically relevant small molecule drugs, such as inhibitors of PRC2, a known ERG interactor. These combination studies highlight the potential for an ERG degrader combination strategy independent of AR pathway inhibition. Further investigations will assess whether ERG-degrader Helicons, alone or with PRC2 inhibitors, could serve as frontline therapy for hormone-sensitive prostate cancer patients before initiating androgen deprivation treatment (ADT). These findings establish pharmacological proof of concept for ERG as a therapeutic target and support further study in prostate cancer patients. Citation Format: Amelia K. Luciano, Brian White, Graeme Lambert, Shelagh Fluharty, Aaron Fulgham, Ian Wallace, Miroslaw Lech, Dakota Hawkins, Pevindi Jayasuriya, Tara Travaline, Paula Ortet, Mallika Iyengar, Julia Bowers, Yusuf Vohra, Santosh Choudary, Olena Tokareva, Jean-Marie Smiecicki, Sean Litchman, John Santa Maria, Jason Hoki, Claire May, Jesper Andersson, Mark Ator, Brandon Nicolay, Diwakar R. 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 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B141.