Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

Vaccination with EphA2-derived T cell-epitopes promotes immunity against both EphA2-expressing and EphA2-negative tumors

BACKGROUND: A novel tyrosine kinase receptor EphA2 is expressed at high levels in advanced and metastatic cancers. We examined whether vaccinations with synthetic mouse EphA2 (mEphA2)-derived peptides that serve as T cell epitopes could induce protective and therapeutic anti-tumor immunity. METHODS: C57BL/6 mice received subcutaneous (s.c.) vaccinations with bone marrow-derived dendritic cells (DCs) pulsed with synthetic peptides recognized by CD8+ (mEphA2(671–679), mEphA2(682–689)) and CD4+ (mEphA2(30–44)) T cells. Splenocytes (SPCs) were harvested from primed mice to assess the induction of cytotoxic T lymphocyte (CTL) responses against syngeneic glioma, sarcoma and melanoma cell lines. The ability of these vaccines to prevent or treat tumor (s.c. injected MCA205 sarcoma or B16 melanoma; i.v. injected B16-BL6) establishment/progression was then assessed. RESULTS: Immunization of C57BL/6 mice with mEphA2-derived peptides induced specific CTL responses in SPCs. Vaccination with mEPhA2 peptides, but not control ovalbumin (OVA) peptides, prevented the establishment or prevented the growth of EphA2+ or EphA2-negative syngeneic tumors in both s.c. and lung metastasis models. CONCLUSIONS: These data indicate that mEphA2 can serve as an attractive target against which to direct anti-tumor immunity. The ability of mEphA2 vaccines to impact EphA2-negative tumors such as the B16 melanoma may suggest that such beneficial immunity may be directed against alternative EphA2+ target cells, such as the tumor-associated vascular endothelial cells

The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation–arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field

Evidence of perturbations of cell cycle and DNA repair pathways as a consequence of human and murine <it>NF1</it>-haploinsufficiency

Abstract Background Neurofibromatosis type 1 (NF1) is a common monogenic tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Haploinsufficiency of NF1 fosters a permissive tumorigenic environment through changes in signalling between cells, however the intracellular mechanisms for this tumor-promoting effect are less clear. Most primary human NF1+/- cells are a challenge to obtain, however lymphoblastoid cell lines (LCLs) have been collected from large NF1 kindreds. We hypothesized that the genetic effects of NF1-haploinsufficiency may be discerned by comparison of genome-wide transcriptional profiling in somatic, non-tumor cells (LCLs) from NF1-affected and -unaffected individuals. As a cross-species filter for heterogeneity, we compared the results from two human kindreds to whole-genome transcriptional profiling in spleen-derived B lymphocytes from age- and gender-matched Nf1+/- and wild-type mice, and used gene set enrichment analysis (GSEA), Onto-Express, Pathway-Express and MetaCore tools to identify genes perturbed in NF1-haploinsufficiency. Results We observed moderate expression of NF1 in human LCLs and of Nf1 in CD19+ mouse B lymphocytes. Using the t test to evaluate individual transcripts, we observed modest expression differences in the transcriptome in NF1-haploinsufficient LCLs and Nf1-haploinsuffiicient mouse B lymphocytes. However, GSEA, Onto-Express, Pathway-Express and MetaCore analyses identified genes that control cell cycle, DNA replication and repair, transcription and translation, and immune response as the most perturbed in NF1-haploinsufficient conditions in both human and mouse. Conclusions Haploinsufficiency arises when loss of one allele of a gene is sufficient to give rise to disease. Haploinsufficiency has traditionally been viewed as a passive state. Our observations of perturbed, up-regulated cell cycle and DNA repair pathways may functionally contribute to NF1-haploinsufficiency as an "active state" that ultimately promotes the loss of the wild-type allele.</p