Molecular, Cellular and Genetic Analyses of Malignancies Associated with NF1

Division Of Basic Sciences - Nci

Investigators

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Abstract

Malignant Peripheral Nerve Sheath Tumors (MPNST) affect between 5-13% of Neurofibromatosis type 1 (NF1) patients and is a leading cause of mortality in this disease. We are using tumor cell lines from both mouse and human MPNSTs to test drugs for growth inhibition. We are focusing on late phase and FDA approved drugs and comparing their ability to inhibit MPNST growth to doxorubicin, one of the standard treatment options for MPNST. We are studying the changes in transcriptome and kinome caused by these drugs for rational design of synergistic combinations. Because all the drugs we're testing have been through phase I clinical testing, we are comparing inhibitory effects at the Cmax found in patient serum at the maximum tolerated dose in humans. During FY23, we tested additional combinations with NF-kappa-B pathway inhibitors, and revised a manuscript we hope to submit in the upcoming months. In addition to our examination of drugs that inhibit tumor signaling pathways, we are looking at the role of the immune system in MPNST tumorigenesis. The neurofibromin protein that is mutated in NF1 patients downregulates RAS signaling. Not only is RAS signaling important for MPNST growth, it also plays multiple important roles in the immune system. NF1 patients and mice that lack one copy of the gene for neurofibromin (NF1) have been shown to have several alterations in immune system with implications for tumorigenesis. Myeloid cells haploinsufficient for NF1 are hypersensitive to signaling through the RAS pathway and NF1 patients have higher levels of inflammatory cytokines in their blood. For these and other reasons, it is not clear whether MPNST patients would be amenable to immune therapies currently being developed for other cancers. We are using immune-competent mouse models of MPNST to characterize the interaction between the tumor and the immune system. We have found changes in the myeloid and lymphoid compartments in MPNST-bearing mice and are currently testing immune checkpoint therapy in immune competent syngenic orthografts of mouse MPNST. Depending on our findings, we will examine how immune-based therapies could complement therapies targeting tumor cell signaling for combination therapy in MPNST. During FY23, we analyzed differential spatial profiling of MPNSTs from immune-competent mice to look at the distribution of immune cells within the tumor. NF1 patients are also at an increased risk for malignant gliomas and a subset of glioblastomas have mutation of the NF1 gene. New therapeutic options for malignant gliomas are desperately needed. Glioblastomas are more common in males than in females, but the mechanism of this difference is not understood. We have identified a modifier of gliomagenesis in our mouse model of NF1-associated brain tumors that affects males and females differently. Using human and mouse glioblastoma and astrocytic astrocytoma tumor lines and primary astrocytes, we are dissecting the mechanism of the sex-specific action of this modifier. In addition, because our mouse brain tumor lines are on purebred strain backgrounds, they are a powerful tool to study the immune system role in brain cancer. Our extramural collaborators are using these tumor lines to test candidate therapies for glioblastoma.