Reprogram Cancer Cell and Cancer Microenvironment for Antitumor Immunity in NF1-Associated MPNST
Abstract
Neurofibromatosis type 1 (NF1) is one of the most common genetic cancer predisposition disorders that affects approximately 1 in 3,000 people. Although those afflicted can suffer from multiple cancer and non-cancer health defect, malignant peripheral nerve sheath tumor (MPNST) represents the most common and deadly malignancy, leading to significant morbidity and mortality. To date, there are no effective molecularly targeted therapies and immunotherapies for NF1-associated MPNST. The central obstacles that limit effective therapeutic development are deeply rooted in the molecular underpinning of MPNST. MPNSTs harbor mutations that inactivate three tumor suppressor pathways: NF1, CDKN2A, and PRC2. PRC2 is critical to maintain correct gene expression by suppressing the inappropriate expression of a multitude of genes and loss of PRC2 leads to enhanced cellular adaptation. Efforts at rationally targeting activated MAPK and CDK4/6 driver pathways because of NF1 and CDKN2A inactivation, respectively, have largely failed due to the enhanced adaptation conferred by PRC2-lossmediated epigenetic changes. In addition, PRC2 loss MPNSTs exhibit an immune desert tumor microenvironment characterized by lack of immune cells that are thought to mediate tumor killing in response to immune checkpoint blockade (ICB). Loss of PRC2 represents a clear barrier to effective therapeutics in MPNST. Our efforts have focused on identifying epigenetic drugs that can reverse the immune desert phenotype by inducing gene expression signatures involving antigen presentation and immune responses, and/or by reprograming the epigenome to induce re-expression of key regulatory cytokines involved in antigen presentation. We identified two potential candidates: (1) DNMT1 inhibitor (GSK862/GSK032) and (2) bromodomain CBP/P300 inhibitor (GNE049). The DNMT1 inhibitor was of particular interest since DNMT1 has emerged as a synthetic lethal candidate with PRC2 loss in MPNST; further, we have observed enhanced programmed cell death accompanied by augmented innate immune responses and proinflammatory cytokine production by DNMT inhibitor treatment in PRC2 loss MPNST cells and tumors. These observations have motivated an investigator-initiated clinical trial of evaluating an oral pan-DNMT inhibitor (ASTX727, combination of decitabine and cedazuridine, recently FDA-approved for treatment of myelodysplastic syndrome) in patients with PRC2 loss MPNST (Clinicaltrials.gov NCT04872543, Principal Investigator, Ping Chi). They have also compelled us to further investigate the impact of epigenetic drugs on reprogramming the epigenome and the tumor microenvironment. Recent studies point to cancer cell plasticity and heterogeneity as well as tumor microenvironment as key factors in cancer pathogenesis and therapeutic resistance. The proposed research follows our understanding of molecularly-driven MPNST and aimed to (1) further understand the MPNST cancer cell heterogeneity and plasticity in MPNST pathogenesis in the relevant tumor microenvironment and under selective therapeutic pressure by novel and selective epigenetic drugs (DNMT1 and bromodomain CBP/P300 inhibitors) using cutting edge single cell- sequencing (scRNA-seq and scATAC-seq) coupled with CellTag-mediated clonal tracking; (2) evaluate the epigenetic reprograming effects by GSK862/GSK032 and GNE049 on chromatin landscape, transcriptomes, and tumor microenvironment; and to identify novel combination immunotherapies in established in vitro and in vivo MPNST models. These synergistic investigations will be conducted by a team of two investigators with complementary expertise in epigenetics and chromatin biology (Chi, Leslie), NF1 and MPNST biology, clinical management (Chi), and computational and systems biology (Leslie) to ensure success. They focus on multiple areas of emphasis in NF research, including heterogeneity of NF-related tumors (MPNST) and novel disease treatment markers, using genet
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210326
Entities
People
- Ping Chi
Organizations
- Sloan-Kettering Institute
- United States Army