Abstract 373: Silver nanoparticles are selectively cytotoxic to neurofibromin 1 deficient peripheral nerve sheath tumors
Authors: Alewine Garrett , Ghantae Adithya , Mamrega Christina , Knight Jerrica L. , Attiah Bashnona , Coover Robert A. , Fahrenholtz Cale D. 
Published: June 2022

Abstract
Neurofibromatosis type 1 (NF1) is the most common neurogenic disorder affecting 1 in every 3,000 people worldwide. NF1 is defined by heterozygous loss-of-function of the neurofibromin 1 gene (NF1). NF1 patients develop neurofibromas with near complete penetrance. These neurofibromas include peripheral nerve sheath tumors (PNSTs) such as plexiform neurofibromas (pNFs) and malignant PNSTs (MPNSTs). Current standard of care shows incomplete penetrance limiting clinical utility. Therefore, treatments to selectively and safely remove PNST cells would be advantageous. Biallelic loss of functional NF1 is the major driving force in the development of PNSTs. NF1 is a tumor suppressor gene responsible for suppressing Ras activity. Loss of NF1 increases Ras activity and subsequently increases intracellular reactive oxygen species (ROS). We and other groups have demonstrated that systemically administrable silver nanoparticles (AgNPs) are cytotoxic to a variety of cancers. We further showed that AgNP-mediated cytotoxicity is dependent upon intracellular ROS which induces rapid ionization (activation) of Ag0 to cytotoxic Ag+. Therefore, AgNPs represent a rational cancer-selective therapy for NF1-deficient PNSTs as these cells are enriched for ROS relative to non-cancerous cells. In this study, we found that AgNPs are significantly (~5-fold) more cytotoxic to NF1-null MPNST cells relative to tumor cell of origin Schwann cells and ~7-fold more cytotoxic to pNF cells relative to patient matched Schwann cells. Sporadic NF1 wild-type MPNST cells were not sensitive to AgNP. We further explored the relationship between oxidative stress and AgNP-mediated cytotoxicity in PNSTs. We found that co-administration of oxidative stress inducing cumene hydroperoxide with AgNP augments the cytotoxicity of AgNP in otherwise AgNP-tolerant cells (Schwann cells, NF1-wildtype MPNSTs). Importantly, either agent alone only showed modest cytotoxicity. As NF1 gene expression levels correlated with AgNP-sensitivity, we further studied this possible interaction by reintroducing NF1 into NF1-null MPNST. Remarkably, NF1 restoration decreased sensitivity to AgNP. This change is unique to AgNP as there was no altered sensitivity to standard of care chemotherapy doxorubicin. Conversely, knockdown of NF1 expression in Schwann cells increased sensitivity to AgNP with no corresponding change in sensitivity to pNF standard of care MEK inhibitor selumetinib. In conclusion, our work provides evidence that a therapeutic window exists for the safe use of AgNPs as a precision medicine to treat NF1-null PNSTs.
Citation Format: Garrett Alewine, Adithya Ghantae, Christina Mamrega, Jerrica L. Knight, Bashnona Attiah, Robert A. Coover, Cale D. Fahrenholtz. Silver nanoparticles are selectively cytotoxic to neurofibromin 1 deficient peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 373.