(P 252) STUDY OF NUTRACEUTICAL INTERVENTION WITH HIGH PHENOLIC EXTRA VIRGIN OLIVE OIL AND CURCUMIN FOR NEUROFIBROMATOSIS TYPE 1

Objective: Neurofibromatosis Type 1 (NF1), a common genetic disorder caused by mutations in the tumor suppressor gene NF1, causes patients to develop Schwann cell tumors of the peripheral nervous system (neurofibromas). These can progress to malignant peripheral nerve sheath tumors (MPNSTs), a deadly soft tissue sarcoma.

The development of MEK inhibitors for the treatment of plexiform neurofibromas has been a major milestone in the NF1 field, and they may be useful for other manifestations of the disease. However, many patients are unable to benefit from this therapeutic approach, possibly lacking a qualifying indication. Moreover, MEK inhibitors can have complex side effect profiles to manage, do not show efficacy in all patients, and the response is not durable if therapy is discontinued. There has been much interest in the NF1 patient community in exploring nutraceutical interventions which have been shown to mimic pharmaceutical inhibition of Ras and other NF1 relevant pathways including inflammation. These interventions could conceivably treat or prevent benign tumors in NF1 from developing or progressing.

Methods: Two nutraceutical compounds, oleocanthal and curcumin, have garnered particular attention. Oleocanthal is found in high phenolic extra virgin olive oil (HP-EVOO) and has been shown to have anti-inflammatory and anti-cancer properties. Curcumin is a bioactive compound found in turmeric and has been shown to have anti-inflammatory, antioxidant, and anti-cancer properties. Previously, a small clinical trial was conducted (Espositio et al, 2017), using dietary intervention with high phenolic olive oil and curcumin, which showed promising results in NF1 patients.

This study builds on the previous trial observations in the following ways: 1. We have an open and enrolling clinical trial to establish the safety and preliminary activity of a novel and more bioactive form of curcumin (SLCP Longvida®) and HP-EVOO supplementation in adult NF1 patients with cutaneous and plexiform neurofibromas (NCT05363267). The trial will establish plasma levels of curcumin and oleocanthal, monitor changes in inflammatory cytokines, utilize skin imaging to track cutaneous neurofibroma changes, and incorporate quality-of-life measurements. 2. We have examined signaling pathways and neurofibroma-relevant cell phenotypes impacted by curcumin and oleocanthal using human plexiform-like neurofibroma cells in vitro and animal models.

Results: In our pre-clinical work, we investigated the effect of curcumin, oleocanthal and their combination on signaling pathways in NF1-related cell lines. Our results show that the combination of the compounds at doses achievable in humans, but not single agents, produced potent inhibition of mTORC1 as evidenced by dramatically reduced pS6K, in NF1-deficient, immortalized human Schwann cells, comparable to the FDA approved mTOR inhibitor, everolimus. The combination treatment also inhibited activating phosphorylation of STAT3 and ERK in NF1-deficient Schwann cells. Strong inhibition of signaling pathways known to be important for neurofibroma formation by this combination prompted in vivo follow-up investigation.

When used in an in vivo model of neurofibroma growth, promising results were again observed. Using NF1-deficeint immortalized human Schwann cells implanted into immunodeficient mice, control of tumor growth and an overall survival benefit was observed in animals receiving the oleocanthal/curcumin combination. Signaling pathway targets were also examined in treated tumor tissues vis immunohistochemistry.

Conclusion: The combination of oleocanthal and curcumin shows promise as a chemopreventive treatment for NF1 patients that could slow tumor growth and improve outcomes. We look forward to the results of our clinical trial.