Developing a new drug will cost about $1 billion and take more than 15 years to reach the clinic. But repositioning an existing FDA-approved drug accelerates development and reduces risks and expenses for pharmaceutical companies by using pharmacokinetic and toxicity data on current treatments. Currently, an urgent and unmet treatment need exists for patients with NF2-related Schwannomatosis (NF2), as there is no FDA-approved treatment available. In this case, Nelfinavir is an antiretroviral drug designed to treat NF2 and can efficiently block the activity of retroviral protease, an enzyme crucial for the final stages of viral replication. This drug has been safely tested for over two decades on both adult and pediatric patients with HIV.

Retroviral protease divides the viral polyproteins (Group-specific antigen (Gag)-Polymerase (Pol)) into functional, mature proteins that are essential for assembling new infectious viral particles to promote tumorigenesis. But instead of cleaving the viral protease, Nelfinavir binds with the protease active site of Gag-Pol elements (polyproteins) of retrovirus. This inhibition forms non-infectious, immature viral particles that are unable to infect new cells and grow neoplasm. This process has gained attention in cancer research due to its potential role in inhibiting phosphoinositide 3-kinase (PI3K)/Akt prototypic survival pathway, a common upregulated pathway in many cancers and NF2. NF2 gene product-Merlin has a pleiotropic effect on several downstream pathways that control cell proliferation and prevent tumorigenesis. However, most NF2 treatment strategies focus on targeting a single pathway, rather than multiple. Nelfinavir holds broader applications, not only for HIV-related sarcoma and cancer, but also for central nervous system (CNS) and peripheral nervous system (PNS) tumors.

The in-vitro fibroblast-derived Schwann cells (iSCs) model shows that patient cells that are heterozygous for loss of function NF2 mutations already display defects that are prone to tumors, like reduced expression of mature Schwann cell markers and upregulation of immature stem cell markers. Additionally, elevated retroviral elements at the transcriptional level explain the higher proliferation of induced Schwann cell's (iSCs). Thus, anti-retroviral drugs might be therapeutic in NF2-related Schwannomatosis by reducing the growth of existing tumors and preventing/slowing the generation of new tumors. Compared to seven other anti-retroviral drugs, Nelfinavir is the most successful in preventing aberrant cell growth and future tumor formation. Using Flow cytometry, the S and G2 phase-specific cell cycle arrest in both healthy and NF2 mutant iSCs and verify Nelfinavir's cytostatic role on cell proliferation. When using immunofluorescence (IF) staining, Nelfinavir (at 15um dose) sufficiently reduces the C-MYC and SOX2 phenotypes at a healthy level. Nelfinavir’s innovative and pleiotropic qualities reveal a new therapeutic treatment avenue for rare CNS and PNS-related tumors. It provides an in-depth view into the effectiveness at both preclinical and clinical application, beyond NF2-related Schwannomatosis or NF2-related somatic cancer.