# Safely Targeting Cancer, the Wound That Never Heals, Utilizing CBP/Beta-Catenin Antagonists

## TL;DR

This paper explores how targeting CBP/β-catenin interactions can safely treat cancer and related diseases by restoring normal cell behavior.

## Contribution

The paper introduces CBP/β-catenin antagonists as a novel approach to target quiescent cancer stem cells and restore lineage fidelity.

## Key findings

- CBP/β-catenin antagonists can induce differentiation and restore lineage fidelity in stem cells.
- Quiescent cancer stem cells are a critical target for therapy resistance and disease relapse.
- CBP and p300 have distinct roles in regulating stem cell quiescence and activation.

## Abstract

Unresolved wound healing is a critical factor in cancer. More generally, inappropriate wound healing can promote chronic progressive fibroinflammatory diseases, including organ fibrosis and neurodegeneration. Transient loss of lineage fidelity is important for wound healing however, persistent lineage infidelity is associated with cancer and fibrosis. CBP/β-catenin antagonists can safely target stem cells to induce differentiation and restore lineage fidelity to treat cancer, fibrosis and neurodegenerative diseases.

Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC.