Exploiting Frequent Alterations in Polycomb Repressive Complex 2 in MPNSTs for Translational Benefit
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) affect 10% to 15% of individuals with neurofibromatosis 1 (NF1). These tumors have limited treatment options and have a five-year survival rate as low as 20%. The best outcomes still are found in individuals where the tumor is discovered early and can be completely surgically resected. However, promising clinical trials are underway, including some with novel therapies that target an alteration found specifically within tumor cells. Challenges currently facing clinicians caring for individuals with MPNST include the ability to diagnose the disease early, track disease burden and response to therapy and limit patients exposure to radiation from recurrent imaging studies. The current "gold standard" of PET/CT imaging has false positive results, is expensive, time consuming, and far from universally available. CT and MRI are ineffective because of the large number of benign neurofibromas that are difficult to distinguish from cancerous MPNSTs. Surgical removal of an MPNST still remains the best chance for a cure, making detection prior to metastasis or invasion of critical structures of paramount importance. To improve early detection, we are proposing to develop novel non-invasive biomarkers based on the molecular characteristics of MPNSTs. We have found that nearly all solid tumors shed fragments of DNA into the bloodstream. These pieces of tumor DNA have been coined "ctDNA" and can be detected and quantified using sensitive molecular biology techniques. The premise of ctDNA is that all tumor but not normal cells harbor mutations and other changes within its DNA. These alterations should be exquisitely specific for tumor cells and found only in DNA derived from the malignancy. By detecting and quantifying levels of these alterations within the bloodstream, we hypothesize that we will be able to detect and monitor MPNSTs in a sensitive and specific fashion. Some MPNSTs will arise from a pre-existing plexiform neurofibroma. However, plexiform tumors are now very well understood. Therefore, we will study the global genetic landscape of these tumors and study whether they shed tumor-derived DNA into the circulation as well. This would provide the opportunity to develop plexiform-specific biomarkers and will help inform scientists how to develop future screening tests for individuals with NF1, where any one person may harbor both a plexiform neurofibroma and MPNST. We hope to generate tests that in the future can detect changes at the DNA level directly in the plasma without any knowledge of the specific tumor. If a suspicious change is found in any of the MPNST-specific driver genes, it would raise the possibility of a malignancy and suggests that the individual should be further tested. This will hopefully enable MPNSTs to be detected at an earlier stage when chances of cure are highest. In addition, these assays can be used after the diagnosis has been made to monitor disease burden and detect recurrence. This is especially important as more individuals are being treated with targeted therapies. The approach we employ will potentially allow clinicians to monitor the plasma for the development of resistance mutations to these therapies so that treatment regimens can be altered in real time. If the proposal is successful, the results will have an immediate impact and will greatly aid in our ability to diagnose, detect, and track MPNSTs, which are a leading cause of morbidity and mortality in individuals with neurofibromatosis 1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610078
Entities
People
- Chetan Bettegowda
Organizations
- Johns Hopkins University
- United States Army