Hyperactive RAS SPOREs
Tumorigenesis has been viewed as a process in which normal developmental programs are dysregulated, leading to aberrant cellular proliferation and differentiation. These processes lead to a failure to respect normal tissue boundaries and abnormal response to multiple inhibitory microenvironmental cues. The RASopathies are developmental syndromes caused by mutations in various genes capable of altering the function of RAS family proteins and Mitogen-activated Protein Kinases (MAPKs) that control intracellular signal transduction. Neurofibromatosis type 1 (NF1) is the most frequent RASopathy syndrome and occurs in one in every 3000-4000 live births. This syndrome is caused by mutation of a tumor suppressor gene encoding a protein called neurofibromin that functions as a GTPse activating protein for p21RAS. Individuals with NF1 have a high predisposition to plexiform neurofibromas, a premalignant tumor that causes major morbidity and mortality with life expectancy reduced by 8-15 years.
The Developmental and Hyperactive RAS Tumor (DHART) SPORE focuses on developing better treatment for cancers and pre-malignant conditions associated with NF1 mutations including plexiform neurofibroma (pNF), malignant peripheral nerve sheath tumors (MPNST), NF1-associated gliomas, and juvenile myelomonocytic leukemia (JMML).