Imatinib Mesylate Reduces Plexiform Neurofibromas by Targeting the Hematopoietic Microenvironment

1. INDIANA UNIVERSITY Imatinib Mesylate Reduces Plexiform Neurofibromas by Targeting the Hematopoietic Microenvironment Shi Chen, Feng-Chun Yang, David Ingram, Kent Robertson, Xiaohong Li, Jin Yuan, Scott Knowles, Whitney Horn, Gary Hutchins, D. Wade Clapp. Indiana University School of Medicine, Indianapolis, IN. SCHOOL OF MEDICINE Overview Treatment of Krox20;Nf1flox/-mice treated with imatinib mesylate reduces plexiform neurfibroma size and histologic complexity Krox20;Nf1flox/flox mice transplanted with Nf1+/- bone marrow have plexiform neurofibromas • NF1 is a genetic disorder that affects approximately 250,000 individuals in the US, Europe, and Japan alone. Neurofibromas, the hallmark of NF1, are complex tumors characterized by tumorigenic Schwann cells, neoangiogenesis, fibrosis, and degranulating mast cells. • Studies in experimental models have emphasized the role of inflammatory cells in altering the microenvironment and facilitating malignant outgrowth. Similarly, Zhu et al (Science, 2002) found that nullizygosity of Nf1 in Schwann cells of conditional knockout mice (Krox20;Nf1flox/flox) was necessary but not sufficient for neurofibroma formation and haploinsufficiency of Nf1 in lineages within the tumor microenvironment was required for neurofibroma progression. • We previously provided the genetic, cellular, and biochemical evidence that haploinsufficiency of Nf1 alters ras activity and cell fates in mast cells (JEM, 2000, 2001) and identified a mechanism underlying the recruitment of mast cells to tumorigenic Schwann cells (JCI 2003). B A A AIM Figure 2. Dissection of spinal nerves and histologic sections from the indicated experimental groups. Arrow heads identify representative plexiform neurofibromas. Sections 2,3,7, and 8 identify neurofibromas. Collectively the histologic sections indicate that Nf1+/- BM is required for tumor progression. Examine the role of Nf1 haploinsufficient inflammatory cells and the C-Kit Kit ligand pathway in neurofibroma formation C-Kit/Kit ligand pathway has a key role in tumor progression B A B Background C • Figures 3A-C. • A. Kaplan-Meier curve of irradiated Krox20 Nf1flox/flox mice recipients transplanted with Nf1+/- or Nf1+/-; W/W BM that contains a mutation at the C-kit locus. • Dissection of the dorsal root ganglia from representative recipient mice. • Representative histologic sections from the indicated genotypes. Note: recipients containing Nf1+/- W/W BM do not have pathologic concentrations of mast cells or neurofibromas. Figure 6. Summary data of dorsal root ganglia from the indicated genotypes and treatment groups are shown in the upper panel. Bottom panel: histologic sections of the indicated genotypes treatment groups and stains are shown. Experimental design Krox20;Nf1flox/floxmice have increased fluoro-2-deoxy-d-glucose (FDG) uptake as compared to Krox20; Nf1flox/- mice CONCLUSION • Adoptive transfer data identify a key role for bone marrow derived cells in the initiation of tumor progression in this experimental model. • Genetic data support a key role for mast cells and the c- ki/kit ligand pathway in hematopoietic cells and identify a molecular target for therapy. • Pharmacologic intervention studies with imatinib mesylate reduces plexiform neurofibromas, the first ever therapy for this type of tumor. Indiana Institute for Biomedical Imaging Sciences (IIBIS) LIST OF SERVICES Figure 4. FDG PET uptake in increased in the lumbosacro spine region of Krox20; Nf1flox/- mice. Treatment with imatanib mesylate reduces FDG PET intensity in Krox20; Nf1flox/- mice RESULTS Krox20;Nf1flox/flox mice transplanted with Nf1+/- bone marrow but not WT bone marrow cells have increased mortality and motor abnormalities CONTACT INFORMATION A B D. Wade Clapp. Indiana University School of Medicine, Indianapolis, IN. 1044 West Walnut Street, R4 Rm 402, IUPUI Figure 1A. Kaplan Meier curve shows the lifespan of the mice in each group. Figure 1B. Representative mice following transplantation. Mouse 1 transplanted with WT BMMNCs looks healthy. Mice 2 and 3 transplanted with Nf1+/- BMMNCs developed paralysis after 5 months of transplantation. Figure 5. 9 month old Krox20; Nf1 flox/- mice were treated with imatanib mesylate or placebo. Representative images and summary data are shown.