Through the Drug Discovery Initiative, the Children’s Tumor Foundation is pleased to fund Sylwia Ammoun’s (University of Plymouth) study with an $85,000 grant to look at two newly-identified potential therapeutic targets in NF2-related tumors, AXL and MERTK. Inhibitors of these proteins successfully reduced growth and survival of patient-derived schwannoma and meningioma tumor cells in vitro. The goal of the present study is to examine the efficacy of these inhibitors in mouse models of NF2 schwannoma. The data thus generated would enable the testing of these inhibitors in human clinical trials.
Full abstract:
The inherited cancer predisposition syndrome neurofibromatosis type 2 (NF2) develops in childhood/early adolescence due to deficiency of a tumor suppressor (molecule that inhibits tumors development) called Merlin. NF2 patients develop multiple tumors of the nervous system called schwannoma, meningioma and ependymoma, that cause different neurological symptoms commonly deafness and facial paralysis. Schwannoma is the hallmark of NF2 and develops in all NF2 patients, meningioma develops in 50% of NF2 patients and ependymoma in 30%. Severe NF2 cases occur early in life and display a huge tumors load, leading to life threatening complications. Current treatments, surgery with adjuvant radiotherapy cannot always be used in all the patients, especially when the tumors burden is high, or tumors are surgically inaccessible, this highlights the need for novel drug-based treatments. Thanks to Children’s Tumor Foundation (CTF) initiatives to date, several potential therapeutic targets have been found and inhibited using different drugs at Maximum Tolerated Dose (MTD), in laboratory-cultured cells or animal models that accurately recapitulate NF2-related tumor biology. The most promising drugs are moved into clinical trials for NF2 patients, however, current or completed trials have had issues with either low efficacy or severe side effects. Brigatinib is effective in patients with meningioma but with strong side effects, and Avastin works in approximately 50% of patients with schwannoma. Our research has identified two new potential therapeutic targets in NF2-related schwannoma and meningioma tumors, called AXL and MERTK, two protein receptors that are more abundant in NF2-tumors compared to healthy cells and have multiple links to driving tumor growth. Using drug inhibitors of AXL called BGB324, and of MERTK called UNC2025, we successfully reduced growth and survival of patient-derived schwannoma and meningioma tumor cells in the laboratory (in vitro). Moreover, we tested an additional MERTK inhibitor called MRX2843, which strongly decreased growth of meningioma cells in vitro. Importantly, BGB324 and MRX2843 are both FDA approved, with BGB324 used for treatment of leukemia, and MRX2843 currently being used in human clinical trials.
