Metabolic Vulnerabilities in NF1-Mutant Tumors
[Technical Report, Final Report]
University of California
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A tumor cells ability to modulate its metabolism influences multiple key aspects of a tumors behavior, such as cellular signaling, differentiation and metastatic potential. Although the concept of targeting metabolic vulnerabilities in cancers has appeal from a therapeutic standpoint, delineation of critical vulnerabilities remains a barrier. NF1 encodes neurofibromin, a GTPase activating protein that negatively regulates Ras signaling. NF1 loss leads to activation of downstream Ras signaling effectors MEK and mTOR, which can be therapeutically targeted. NF1 loss is also associated with metabolic dysregulation, however the molecules primarily responsible for metabolic dysregulation in NF1-mediated tumorigenesis remain poorly defined. Additionally, the role of metabolic reprogramming in the development of drug resistance resistance to MEK inhibition-MEKi or mTOR inhibition-mTORi, for example is also unknown. Thus, a potentially groundbreaking but currently underdeveloped paradigm in the management of NF1 is identifying and treating disease on the basis of metabolic targets. These studies will identify candidate molecules that are critical participants in tumor metabolic reprogramming and outline the conditions of metabolically-targeted strategies.
- Medicine and Medical Research