No abstract

Development requires the expression of master regulatory genes necessary to specify a cell lineage. Equally significant is the stable and heritable silencing of master regulators that would specify alternative lineages. This regulated gene silencing is carried out by Polycomb group (PcG) proteins, which must be correctly recruited only to the subset of their target loci that requires lineage-specific silencing. A recent study by Erceg and colleagues (pp. 590–602) expands on a key aspect of that targeting: The same DNA elements that recruit PcG complexes to a repressed locus also encode transcriptional enhancers that function in different lineages where that locus must be expressed. Thus, PcG targeting elements overlap with enhancers.

Genetic and epigenetic alterations in the Wnt signaling pathway leading to constitutive activation of the driver oncogene Β-catenin occur in at least 20% of all human cancers. We have developed conformationally hyperstabilized α-helical peptides (Helicons) that bind directly to Β-catenin with picomolar affinity and block its interaction with TCF transcription factors. We describe here the characterization of anti-tumor efficacy, pharmacodynamic biomarkers and mechanism of action using multiple in vivo patient-derived xenograft (PDX) models treated with Helicons. Helicon treatment leads to dose-dependent anti-tumor effects and durable regressions in PDX models from multiple indications with Wnt pathway activating mutations. Anti-tumor responses are seen in the presence of additional driver mutations, including KRAS and PIK3CA. RNA-sequencing and Gene Set Enrichment Analysis confirm Helicon treatment inhibits both Wnt/Β-catenin and MYC-regulated gene sets. Inhibiting Β-catenin-TCF interaction with Helicons represents a first-in-class therapeutic approach for the treatment of cancers resulting from aberrant transcriptional signaling via Β-catenin. Citation Format: YaGuang Si, Minjung Choi, Xinwei Han, Brian White, Ziyang Wu, Erica Visness, Pieter Beerepoot, Elizabeth Jaensch, Jessica Ramirez, Charles Ponthier, Xiaogang Han, Paula Ortet, Peicheng Du, Sorabh Agarwal, Mirek Lech, Aaron Fulgham, Sarah Cappucci, Zhi Li, John McGee, Lihua Yu, Martin Tremblay, Keith Orford, Gregory Verdine, Jonathan Hurov. Anti-tumor activity of Helicon inhibitors of Β-catenin-TCF interaction in patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4972.

1405 Figure 4 Role of a top hit (IKZF1/Ikaros1) in T cell exhaustion validated using. A) rescue of cytokine secretion and B) tumor cell killing