The Role of ATRX/DAXX Loss in NF1-Associated Solid Malignancies
Abstract
Tumors of the brain and nerves develop frequently in patients with neurofibromatosis type 1. Many are benign growths, like pilocytic astrocytomas in the brain and neurofibromas in the nerves. However, in some patients, the tumors become malignant and may cause local damage, disseminate to distant sites, and result in death. Under the microscope, they are identical to tumors that occur in patients without neurofibromatosis. Surgery in the locations where these tumors develop may not be able to remove all of the disease without resulting in severe handicaps, and even with aggressive surgeries, the tumors may still regrow. Furthermore, standard therapies such as radiation or chemotherapy are either associated with severe side effects or are not effective in these patients. The main goal of this proposal is to study the changes in the structure and levels of proteins associated with shaping chromatin, the scaffold that DNA in cells wraps around. Mutations and losses in these proteins have been proven by our group to affect the size of telomeres in brain tumors, which are the “caps” at the end of chromosomes and are required to be preserved for cells to proliferate indefinitely (an important property of cancer). We have also demonstrated that changes in these proteins and characteristic changes in telomeres are more frequent in tumors that are more likely to behave aggressively in patients with neurofibromatosis. Altered telomeres have been found to play a role in numerous diseases, including cancer, but their role in brain and nerve tumors in neurofibromatosis remains understudied. In this project, we will evaluate the levels of these chromatin proteins and changes in telomeres in cells obtained from mouse gliomas that are deficient in neurofibromin, as well as excess brain and nerve tumor tissue from patients with neurofibromatosis type 1. We will decrease the protein levels and reintroduce them under experimental conditions to see how they affect the biology and function of telomeres in tumor cells. We will also treat them with a panel of drugs to try to identify any that may be effective in killing these cells. Our research team, with multidisciplinary expertise in neuropathology, neuro-oncology, telomere biology, and bioinformatics, is in a unique position to uncover specific differences among groups that may be helpful in predicting tumors that either may behave more aggressively or respond to specific therapies. The use of drugs that target cells with specific alterations in chromatin proteins and telomeres may exploit a specific susceptibility of these cancers and represents a feasible, active area of biomedical research. We expect the results of our study to provide the rationale to extend these research efforts to the field of brain and nerve tumors associated with neurofibromatosis, particularly those tumors that are likely to behave more aggressively. Because we are planning to use pre-existing cells and tumor material that have already been collected for diagnosis or treatment purposes and de-identified, patient risks are minimal. In addition, many of the drugs that will be studied in this project are already available and have been studied in early clinical trials of actual cancer patients. After completion of this project, we expect our study to increase our knowledge in an understudied area of the biology of brain and nerve tumors associated with neurofibromatosis, resulting in improved, predictive biomarkers. We also expect our data to provide the rationale required for development of more accurate animal models to study neurofibromatosis, as well as specific molecularly based drugs for treatment as alternatives to the current, often devastating approaches of surgery, radiation, and chemotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810496
Entities
People
- Fausto J Rodriguez
Organizations
- Johns Hopkins University
- United States Army