IDH Mutations and the Effects of Metabolism on Chromatin and Solid Tumor Differentiation
Abstract
The majority of the cells in our body specialize, or differentiate, into non-dividing cells that carry out the diverse functions of each tissue. This process involves reading certain parts of the genome that instruct a cell to differentiate into its correct fate while shutting off instructions to differentiate into other fates. To continue dividing, cancer cells learn to ignore these signals that would otherwise instruct them to differentiate. How cancer cells, in particular in the context of solid tumors, avoid these signals has not been well understood. The discovery of mutations in the enzyme isocitrate dehydrogenase (IDH) in a diverse group of cancers led to the finding that changes in how a cell uses nutrients could affect its ability to differentiate. Mutations in isocitrate dehydrogenase are believed to prevent differentiation by blocking the ability of cells to open parts of the genome required for differentiation. In a cell’s nucleus, DNA wraps around histone proteins in a beads-on-a-string like structure known as chromatin. Histones can be modified by metabolic enzymes and these modifications, epigenetic marks, influence whether genes are turned on or off. In my recently published work, I found that IDH mutations prevent normal cells from removing a chromatin mark that is associated with the inability to access genes. Because IDH mutant cells cannot access these genes, they are unable to differentiate. Cells with IDH mutations have also been found to have a large number of DNA breaks. This has been proposed as a separate mechanism by which cells with IDH mutations become tumors, accumulating more mutations because they are unable to repair DNA breaks. However, in analysis of data from the Cancer Genome Atlas (TCGA), I found that IDH-mutant tumors have fewer mutations than other cancers. An answer to this seeming contradiction is that the compacted chromatin of IDH-mutant cells leads to difficulty in copying DNA (known as replicative stress) and to DNA breaks, but that these breaks are repaired with little further consequence. I propose to study how IDH mutations lead to tumor formation. I will study whether IDH-mutant inhibitors being investigated in clinical trials result in the differentiation of IDH-mutant cancers (Aim 1) and how IDH mutations change chromatin and sensitize it to accumulate DNA breaks (Aim 2). By using samples from patients treated with mIDH inhibitors and comparing tissue obtained prior to therapy with that obtained on therapy, I will determine whether the mutant-IDH inhibitor results in changes in the ability to access and or read the genes needed for differentiation and whether it results is replicative stress and genomic damage. My career goal is to become a physician-scientist leading a laboratory that investigates how metabolism influences cellular behaviors. Chondrosarcomas and cholangiocarcinomas are two clear examples where a metabolic abnormality affects cancer growth and where changing metabolism can lead to effective and safe treatment. The outlined research and career development plans, underscored by the mentorship of Craig Thompson will allow me to transition towards an independent research position. The Fiscal Year 2020 Peer Reviewed Cancer Research Program (PRCRP) Career Development Award will be critical in my goal, providing me with the necessary support to carry out the proposed experiments. Differentiation therapy has been successful in some leukemias but has never been possible in solid tumors. By studying IDH-mutant chondrosarcomas and cholangiocarcinomas, malignancies that form part of the Topic Areas of Liver Cancer and Young Adult Cancers, I aim to identify ways that we can target these cancer cells to force them to re-acquire their original non-malignant state. Because IDH mutations also lead to replicative stress, they may serve as safe and affordable markers of response to other already approved agents. Finally, metabolic changes like those seen with IDH mu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110292
Entities
People
- Juan Schvartzman
Organizations
- Sloan-Kettering Institute
- United States Army