PRMT5 is a Potential Therapeutic Target in Human MPNSTs
Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are one of the most common human sarcomas that are usually found in neurofibromatosis patients. MPNST prognosis is very poor, and current treatments are limited to surgical therapy and traditional chemotherapy, which generally cause many serious side effects. It is known that cancer is a genetic disease, as tumor cells acquire additional genetic changes in a sequential manner. Currently, targeted therapy has become the new hope of cancer treatments, as it has much less severe side effects. However, currently, there is no targeted therapy available for this type of malignancy. One of the significant barriers for MPNST-targeted therapy is the lack of essential cancer-related genes that are specifically present or absent in cancer cells. Recently, through human cancer genetic and genomic analysis, an exciting phenomenon named collateral lethality was discovered. When key tumor suppressor genes (whose functions are to repress tumor formation) are lost/deleted during cancer development, their neighbor genes are usually hijacked if their physical positions are close to the tumor suppressor genes. The CDKN2A gene is a frequently lost tumor suppressor in human MPNSTs (up to 75%). This CDKN2A deletion on the short arm of chromosome 9 generally causes its neighbor gene, MTAP (S-methyl-5 -thioadenosine phosphorylase), a key methylation catalyzing enzyme, also deleted through hijacking. Once MTAP is lost, the cell methylation metabolic pathway will be skewed. Thus, the cell’s survival and fitness will heavily depend on the overexpression of PRMT5, a Protein arginine N-methyltransferase 5, in cancer cells. If the PMRT5 is blocked in the MTAP deleted cells, a lethality will occur. PRMT5-based targeted therapy is currently being developed in many other types of human cancers, such as prostate, breast, and lung cancers. As CDKN2A is frequently lost in up to 75% of human MPNST patients, we hypothesized that MTAP is also deleted in these MPNSTs, and these cancer cells could be targeted by inhibiting PRMT5. In this proposal, we have two aims. Aim 1 is to establish the clinical relevance and significance of PRMT5 in human MPNSTs. We will evaluate the PRMT5 and MTAP expression in NF1-related and sporadic fixed MPNSTs and investigate MTAP genomic deletion frequency. In addition, we will assess the relationships of PRMT5 and MTAP expression levels with MPNST pathological grade and patient servals. Aim 2 is to investigate the therapeutic potential of targeting PRMT5 I n human MPNST cell lines. First, we will examine the PRMT5 cellular functions in MPNST in the cells with and without MTAP. Then we will evaluate PRMT5 therapeutic potential with chemical inhibitors, including the ones that are currently in clinical trials for other types of human cancers. Last, we will test the combinational therapeutic effect of PRMT5 inhibition with chemotherapy and radiotherapy. Upon finishing this project, we should obtain information on the PRMT5 and MTAP expression in human MPNSTs and evaluate the potential of PRMT5-based targeted therapies. This is particularly important since there is no current effective targeted therapy available yet for this type of malignant tumor.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210265
Entities
People
- GuangJun Zhang
Organizations
- Purdue University
- United States Army