Imatinib Mesylate Reduces Plexiform Neurofibromas by Targeting the Hematopoietic Microenvironment.

Abstract Von Recklinghausen's neurofibromatosis type 1 (NF1) is the most common genetic disease in man with a predisposition to cancer, a disorder caused by mutations of the NF1 tumor suppressor gene that functions as a GTPase for p21ras. Affected individuals are predisposed to plexiform neurofibromas, congenital tumors that arise from cranial and peripheral nerves for which no effective therapies are available. We have recently utilized a genetically engineered murine model to demonstrate that mast cells and the c-kit/kitL pathway have a key role in plexiform neurofibroma formation. In the present study, we utilized this model to determine whether imatinib mesylate, an FDA approved drug that targets the c-kit ligand in mast cells and other cell lineages in the tumor microenvironment in inducing tumor regression. Krox20; Nf1flox/−mice begin to develop plexiform neurofibromas by 6 months of age, especially in the dorsal root ganglia involving the sciatic nerve. Fluoridinated PET/CT images were utilized to verify that experimental mice had developed plexiform neurofibromas and to evaluate tumor progression. Following a 12 week treatment, Krox20; Nf1flox/−mice who received the vehicle had an increase in FDG uptake in the tumor growth area. In contrast, mice received imatinib mesylate had a dramatic reduction in the FDG uptake. At autopsy, the spinal cords were examined and sections were prepared for histologic examination. Grossly, tumors from the vehicle control treated mice were consistent with plexiform neurofibromas, as previously described (Zhu, Science 2002). In contrast, dissection of the spinal cords from Gleevec treated mice revealed that the mean volume of the tumor was significantly reduced. In addition, though there is still hyperplasia observed in the dorsal root ganglia from imatinib mesylate treated mice, the overall architecture of the nerve is improved as compared to the hematoxylin and eosin stained sections from the placebo treated control. Serial sections from 10 tumors isolated from placebo treated mice and serial sections from all dorsal root ganglia in the FDG positive affected regions of imatinib mesylate treated sections were scored. There is variability in the number of mast cells from the placebo treated tumors. However, there is a consistent, significant reduction in the number of mast cells scored in the dorsal root ganglia from the imatinib mesylate treated mice, suggesting that imatinib mesylate is inhibiting the c-kit receptor kinase and thus reducing mast cell numbers in the neurofibroma. Finally, since there are anatomic reductions in tumor size of imatinib mesylate treated mice as compared to placebo control treated animals, we hypothesized that the FDG affected regions would have an increase in apoptosis as compared to the amount of apoptosis observed in tumors from placebo treated mice. While only rare TUNEL positive cells were observed in tumors treated with the placebo, up to 10% of cells were TUNEL positive in tumors received imatinib mesylate. Collectively, these studies provide direct evidence that targeting the microenvironment induces regression of a plexiform neurofibromas and provides the basis for conducting clinical trials for a tumor that affects approximately 10–15 thousand patients in the US alone.