Exploiting Aneuploidy in NF1-MPNST: Prognostication and Understanding Pathogenesis
Abstract
Neurofibromatosis type 1 is an inherited disease, affecting 1:3,000 individuals worldwide. Diagnosis, usually malignant peripheral nerve sheath tumor (MPNST), which arises from a benign precursor (PN), is the most feared and deadly of these cancers. Sadly, for those individuals with NF1 who develop these cancers, there are limited treatment options, and to date, no clinical trials have yielded positive results. Current mouse models of NF1-MPNST used to discover and evaluate new therapies are largely engineered with one set of genetic changes, limiting their ability to fully represent the human condition. For this reason, we believe that the failure to discover effective treatments is partly due to the inability of these preclinical models to accurately model the genetic landscape of the human tumors. To address this problem, we have started to develop and characterize a set of patient-derived MPNST cell lines grown only in mice and directly obtained from actual human tumors. Through the study of these lines, we identified several important points: (1) MPNST have extra copies of chromosomes (aneuploidy) compared to PN which tend to have only two copies of each chromosome (which is what normal cells should have); (2) all MPNST examined have extra copies of a large piece of chromosome 8; and (3) there are several genes on chromosome 8 that have been implicated in promoting cancer. Based on these studies, we propose to determine which genes on chromosome 8 are important in MPNST and whether or not the number of extra copies of chromosome 8 correlates with poor overall survival and other patient outcomes. This project is directly in line with the NFR areas of interest in terms of (a) biomarker discovery, utility, development, and validation and (b) novel disease and treatment response markers using genetics, genomics, and epigenetics. We hypothesize that Chr8 gain is a critical driver of MPNST progression, functions by increasing the expression of a set of genes responsible for tumor growth, and correlates with poor overall survival. We will test this hypothesis through the following aims: 1. We will define the genes on Chr8 that are essential for MPNST progression. 2. We will define the dysregulated signaling pathways in cells with Chr8 gain. 3. Determine whether the degree of Chr8 gain observed in FISH correlates with OS or development of resistance. The experiments outlined in this proposal will define the genes and pathways mediated by Chr8q gain that are responsible for driving MPNST progression, which may be relevant for determining patient survival. With a deeper understanding of the molecular pathogenesis of MPNST, we will be able to uncover new opportunities for the development of novel therapeutic strategies that may improve clinical outcomes. While there are no immediate risks or benefits to patients with NF1, we believe these experiments are critical for better understanding this aggressive cancer and ultimately uncovering better therapies. By the end of this funding period, we should have a better understanding of MPNST biology, which we hope will guide preclinical studies and subsequent clinical trials. Additionally, we hope to have validated a potential biomarker (degree of Chr8 gain) that can inform clinical prognosis discussions. Finally, we will evaluate the utility of Chr8 gain as a prognostic biomarker by performing DNA-Fluorescent In Situ Hybridization (FISH) on a clinically annotated collection of tumors from MPNST patients. We will determine whether there is a correlation between the percentage of cells with Chr8q gain by DNA-FISH and OS as well as response to therapy in patients with MPNST. Impact: The experiments outlined in this proposal will provide a deeper understanding of the molecular pathogenesis of MPNST, which is required to uncover new opportunities for the development of novel therapeutic strategies that may improve clinical outcomes. Additionally, the work
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210324
Entities
People
- Angela Hirbe
Organizations
- United States Army
- Washington University in St. Louis