Targeting EP300 epigenomic control in neuroblastoma

St. Jude Children'S Research Hospital, Memphis TN

Investigators

Abstract

Resistance to conventional therapy is a common source of cancer morbidity and mortality. Many tumors show intratumoral heterogeneity in cell state, where cells shift between epigenetically-controlled cell states under the selective pressures of treatment. These states may have differential resistance to therapy, and are marked by distinct epigenetically-controlled transcriptomes. The processes by which tumors convert between epigenetically-specified states has been challenging to study, since tumors are commonly marked by a high mutational load, which can obscure the contribution of cell state. Intriguingly, the pediatric high-risk tumor neuroblastoma (NB) is a heterogenous and lethal tumor associated with epigenetically-plastic cell states, and is marked by a low mutational burden. This makes NB an ideal system to study the mechanisms of cell state plasticity. By studying NB through the lens of cell state, we identified a role for the histone acetyltransferases EP300 and CBP in controlling responsiveness to chemotherapy and tumor cell differentiation and apoptosis. Our collective long-term goal is to capitalize on transcriptional control to identify mechanism-based, targeted cancer therapies. The objective of this proposal is to dissect how EP300 and CBP proteins control state-specific phenotypes and chemosensitivity in high-risk NBs, and capitalize on these to enforce chemosensitivity and differentiation. Our hypothesis for this study is that EP300/CBP are master regulators of cell state that control cell-state-specific malignant behaviors in NB. This hypothesis is formulated based on preliminary data using new systems and tools including cell state reporters and domain-specific inhibitors and selective small molecule degraders of EP300/CBP. This preliminary data supports the rationale that that these proteins play state-specific roles, controlling cell state plasticity in NB. This hypothesis will be tested in two parallel specific aims: 1) Interrogating how EP300 represses the differentiation of “adrenergic” cells and 2) Dissecting how EP300/CBP maintain the relatively chemoresistant “mesenchymal” state. First, we will use chemical and genetic methodologies to perturb EP300 and identify the domains responsible for repressing cellular phenotypes, such as differentiation and apoptosis, in vitro and in vivo. Then, we will use analogous methods, alongside cell state reporter systems, to identify the roles of EP300 and CBP on the mesenchymal cell state. These approaches are innovative as they use new approaches, including cell state reporter systems and new pharmacologic tools, to dissect the control of cell state plasticity in neuroblastoma. We expect to identify new methods to engender chemosensitivity, thereby achieving new research horizons. This approach is significant because it will expand our understanding of how EP300 and CBP, master controllers of histone acetylation, are able to control cell state and drive resistance to chemotherapy. These studies have the potential to change management of children with NB, while also impacting our understanding of chemoresistant cell state regulation broadly in cancer.