Targeting the Core Transcriptional Regulatory Circuitry in Treating MPNSTs
Abstract
Rationale: The proposal presented here is in response to the FY19 Neurofibroma Research Program Early Investigator Research Award program announcement. This award will provide me the support and recognition needed to successfully launch the next phase of my research and career. I will focus on malignant peripheral nerve sheath tumors (MPNSTs) arising from patients with neurofibromatosis type 1 (NF1). These patients are at a much higher risk of developing MPNSTs than the general population (10% versus 0.01%, respectively). I will investigate the abnormal gene expression patterns caused by malfunctions in a protein complex (polycomb repressive complex 2 [PRC2]) that is responsible for keeping critical genes off. PRC2 malfunction is common in MPNSTs; over 80% of all MPNSTs exhibit PRC2 loss and, as a result, genes that are supposed to be kept off are overly activated. This proposal is investigating and targeting the novel targets that are overly activated in MPNSTs due to PRC2 loss. Although many attempts have been made to design new targeted therapy, MPNSTs respond poorly to existing chemotherapies (less than 20% response). Therefore, new treatment is desperately needed. Ultimately, the long-term goal of this project is to better treat MPNSTs by targeting the abnormal gene expression patterns caused by PRC2 loss. PRC2-targeted genes are kept silent by a functional PRC2, and its loss of function leads to over-activation of critical genes and abnormal gene expression patterns in MPNSTs. Among the PRC2 targets that are overly activated due to its loss, there is a small group of homeobox transcription factors that are uniquely over-expressed in human MPNSTs. Our compelling data show that they are essential for the survival of MPNSTs, and PRC2 restoration shuts down these transcription factors by inhibiting their super-enhancers. Therefore, I hypothesize that PRC2-regulated homeobox transcription factors are critical for MPNST survival and drugs that target this transcriptional control will be an effective treatment for human MPNSTs. Objective: Under the appropriate guidance of my mentors, I will first study how PRC2-regulated transcription factors govern their targets. I will perform a high-throughput drug screen searching for effective drugs that target the abnormal gene expression patterns in inhibiting the growth of MPNSTs. 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 that of the general population. Unfortunately, due to lack of effective treatment, more than 50% of these patients die within 5 years of diagnosis. Potential Clinical Applications, Benefits, and Risks: Targeting the essential master regulator is a novel and valuable approach in treating MPNSTs in patients with NF1. I predict that drugs coming out of the proposed high-throughput screen will be highly effective in treating MPNSTs, with very little effect on normal tissues. Since deletion of MPNST’s master transcription factor is so effective in killing MPNST cells, we also initiated an alternative approach to design small molecule inhibitors to directly degrade its protein. Projected Time Required to Achieve a Patient-Related Outcome: At the end of the 2-year period of this Early Investigator Research Award, I will have selectively effective drugs to treat PRC2-null MPNSTs. In the follow-up studies, I will test the safety and efficacy of these drugs in preclinical mouse models that we developed using established MPNST cell lines and patient-derived xenograft. Given the potential of effectively killing MPNSTs and our expertise in carrying out NF1 clinical trials, we foresee that these drugs will enter a Phase I clinical trial within a fairly short time.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010410
Entities
People
- Xiyuan Zhang
Organizations
- National Cancer Institute
- United States Army