Using Single-Cell CRISPR Screen to Decipher the Function of Core Transcription Factors in Driving NF1-Deficient MPNST
Abstract
Rationale: The proposal presented here is in response to Fiscal Year 2021 (FY21) Rare Cancers Research Project (RCRP) Concept Award. I will focus on malignant peripheral nerve sheath tumors (MPNSTs) arising from patients with neurofibromatosis type 1 (NF1). MPNST is a cancer of the Schwann cells, which serve as the protective sheath sitting outside of the nerve in the peripheral nervous system. MPNST is a type of soft tissue sarcoma that accounts for 10% of all soft tissue sarcomas. MPNST arises predominantly in patients with neurofibromatosis type 1 (NF1), among whom the lifetime incidence is between 8%-13%. MPNST can also arise sporadically in general population with a lifetime risk that is 1,000 times lower than patients with NF1. MPNST is a rare cancer, with an overall incidence of 1 in 100,000 in the general population, and the prognosis of this rare cancer is poor, with about 20%-50% of patients surviving 5 years after diagnosis. Currently, the only possible cure for MPNST is complete surgical removal with wide negative margins. Advances of next generation sequencing have allowed researchers to discover recurrent genetic alterations in patient samples of MPNST. Loss-of-function mutations in tumor suppressor genes, including NF1, CDKN2A, TP53, SUZ12, and EED, have been reported in the majority of MPNST samples. Given the dismal prognosis of MPNST and the lack of effective treatment for patients, it is urgent to search for targeted therapy based on the current knowledge of this disease. Here in the current study, I propose to study the oncogenic feature of a group of highly expressed transcription factors. Our preliminary data indicate that targeting the abnormal transcriptional activation of these oncogenes is effective in treating MPNST. Objective: I will first understand how a group of transcription factors govern their targets. I will next assess the tumorigenic potentials of these transcription factors and find out how they, together with commonly used chemotherapies, cause the malignant transformation of Schwann cells. This project will address the following FY21 RCRP Focus Areas: Biology and Etiology and Therapy. Impact: Results of this proposed study will be applicable to any NF1 patient who develops MPNSTs. For patients with NF1, their lifetime risk of developing MPNSTs is 1,000 times higher than the general population. Unfortunately, due to the lack of effective treatment, more than 50% of these patients die within 5 years of diagnosis. The method developed in this study can also be utilized in other rare cancers. Potential Clinical Applications, Benefits, and Risks: Targeting the essential master regulator is a novel and valuable approach in treating MPNSTs in patients with NF1. By learning more about the abnormal gene expression patterns and control, I predict that results from the proposed study will nominate highly effective strategy to treat MPNSTs, with very little effect on normal tissues. Projected Time Required to Achieve a Patient-Related Outcome: At the end of the 1-year period of this Concept Award, I will have a fully depicted gene regulation network for MPNST. In the follow-up studies, I will test the safety and efficacy of targeting the transcription control in preclinical mouse models that we developed using patient-derived xenograft. Given the potential of effectively killing MPNSTs and our expertise in carrying out rare tumor clinical trials, we foresee that knowledge learned from this study will benefit future phase 1 clinical trials within a fairly short time. Contributions to Advancing Rare Cancers Research: The experimental approaches proposed here can be readily applicable in other rare cancer research. From preliminary bioinformatic analysis, we nominated a group of candidate master transcription factors, which will be assessed in this study using a robust gene perturbation followed by phenotype-readout system. The new technique and innovat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210770
Entities
People
- Xiyuan Zhang
Organizations
- National Cancer Institute
- United States Army