Metabolic Vulnerabilities in NF1-Mutant Tumors
Abstract
Rationale: Cells generate energy to support growth, and this is especially true of tumors. In fact, tumors commonly reprogram their metabolism to support their abnormal growth. This proposal examines the poorly understood relationship between metabolism and tumors in the NF1 syndrome. Individuals with neurofibromatosis type 1 (NF1) are at risk for developing tumors such as optic pathway gliomas, plexiform neurofibromas, and malignant peripheral nerve sheath tumors, all of which can cause substantial neurologic deficits, pain, deformity, and death. Although NF1 mutations are associated with metabolic abnormalities, the responsible molecules and the particular metabolic contexts in which they operate remain unknown. Furthermore, the role of metabolism in the development of resistance to drug therapy in tumors, including NF1 tumors, is unknown. Thus, a potentially groundbreaking, but currently underdeveloped, paradigm in the management of NF1 is identifying and modifying disease using metabolically directed strategies. To realize this possibility, the experiments in this proposal will identify genes that modulate energy levels in Nf1 mutant tumors. This knowledge is fundamental to determining the metabolic vulnerabilities that develop in the cells and tissues of NF1 patients and designing metabolism-based diagnostic and therapeutic strategies to alter the disease course. Objective: Using state-of-the-art methodology to directly analyze energy levels in cells, we will perform a comprehensive genetics-based analysis of Nf1 mutant tumors and Nf1 mutant tumors that are drug-resistant to identify those genes that are essential for energy production and the metabolic conditions in which they operate. This will provide a basis for targeting metabolic vulnerabilities to cripple NF1 tumors. Ultimate Applicability: Metabolic approaches may potentiate a wide range of therapies in different tumors arising in NF1 patients. NF1 patients who currently have tumors causing symptoms may experience better tumor control and greater tumor regression when tumor metabolism is treated in conjunction with more conventional treatments. In one potential application, a patient undergoing drug therapy for a plexiform neurofibroma might at the same time make dietary modifications (reduce glucose intake and adopt a ketogenic diet) to coordinate drug therapy with a tumor’s metabolic response and improve the overall efficacy of the treatment. This approach could also help patients with recurrent tumors. This strategy could make sense if tumors (unlike normal tissues) reprogram their metabolism to use more glucose when they are subjected to therapy, and restricting glucose availability forces tumors to adopt alternative metabolic states that make them more vulnerable to death. NF1 patients often undergo body imaging to assess their disease. Currently, tumor metabolism is measured diagnostically using positron emission tomography (PET). However, there are developing approaches to non-invasively assess tumor metabolism using magnetic resonance spectroscopy (MRS). These technologies could be better used to analyze tumors in NF1 patients and determine which tumors might respond to specific therapies if more detailed information concerning tumor metabolic programming were available. Our proposal, by identifying genes and molecules that are specifically supporting energy production by tumors, raises the possibility of using imaging such as MRS and PET to detect these molecules and improve clinical decision-making. Tracking the accumulation of specific metabolites in particular tumors may justify earlier treatment of certain NF1 tumors. For example, in an NF1 patient with multiple plexiform neurofibromas, metabolic changes detected by non-invasive imaging may prioritize a specific tumor over other neurofibromas, leading to a personalized clinical plan for that individual. In individuals who may be very young and have a limited disea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810287
Entities
People
- Jean Nakamura
Organizations
- United States Army
- University of California, San Francisco