Molecular, Cellular and Genetic Analyses of Malignancies Associated with NF1

Division Of Basic Sciences - Nci

Investigators

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Abstract

During FY25 we completed drug screening of human malignant peripheral nerve sheath tumor (MPNST) cells with NFkappa-B inhibitors in combination with inhibitors of MAPK, PI3K, or AKT/mTORC1 signaling. We found some synergistic interactions between these drugs inhibiting human tumor cell growth, suggesting that NFkappa-B inhibitors could improve the response of MPNSTs to drugs that currently are unsuccessful. Given the newly released roadmap to reduce preclinical testing in animals by the FDA and NIH, we will investigate new approach methodologies (NAMS) for confirming the activity of these drugs in MPNST in the upcoming year. To investigate novel drug targets in MPNST, we are expanding our studies to ion channels and solute transporters. We have found in that drugs blocking sodium and calcium channels can inhibit the growth of human MPNST cells. We also find that blocking gene expression of some ion channels can also inhibit MPNST cell growth. Others have demonstrated that dysregulation of ion channels in breast cancer led to a transition in cell state that we also see in MPNST. We are examining which ion channels are expressed in MPNST cells and whether drugs developed against these channels can play a role in treating MPNST. Solute transporters play an important role in cell metabolism, transporting building blocks for cellular processes in and out of the cell. We hypothesize that some tumors may develop "addiction" to specific nutrients and could be treated by modulating the function of transporters. Alternatively, over-expression of cell surface proteins may be useful as biomarkers to diagnose and follow tumor growth and progression. Publicly available data shows that certain solute transporters are expressed on MPNST cells and that inhibiting expression of some transporters will block the growth of MPNST cells. We are investigating metabolism and the cell surface proteins in MPNST as a potential target for developing therapies. Continuing our work from last year on the role of the immune system in peripheral nerve sheath tumors, we have completed our analysis of circulating cytokines and chemokines from patients with plexiform neurofibromas treated with pegylated-interferon (pegIFN). To understand whether blood biomarkers predict who responds to pegIFN with tumor volume shrinkage, we have used a machine learning approach to identify factors that influence models of response. This gives us insight into interactions between the immune system and the tumor that may be harnessed to improve responses to therapy.