Neurofibromatosis 2 (NF2) is an inherited disease characterized by multiple nervous system tumors, such as bilateral vestibular schwannomas and meningiomas. Loss of function mutations in the NF2 gene is also seen in the majority of sporadic meningiomas and almost all schwannomas. These tumors cause compression of the brainstem, adjacent brain or spinal cord resulting in severe pain, neurological morbidity and mortality. The current treatment for NF2 is maximal surgical resection;however, tumors that progress despite surgery remain a significant problem and drug-based therapies are much needed for NF2. Based on our recent studies that established NF2 protein merlin as a novel negative regulator of mTORC1 signaling, clinical trials with the allosteric mTOR inhibitor rapamycin analog, RAD001 are underway for NF2 patients. However, recent evidence indicates that rapamycin and its analogs (rapalogs) incompletely inhibit mTORC1 signaling, which may be the reason for their limited success in the treatment of many tumors. Rapalogs also cause activation of prosurvival and mitogenic pathways such as PI3K/Akt and MAPK/ERK, and these concerns have led to the development of improved mTOR kinase inhibitors, which effectively inhibit both mTORC1 and mTORC2 and downstream targets such as Akt. We therefore recently tested the mTOR kinase inhibitor Torin1 and observed that it is more effective than rapamycin in inhibiting proliferation of NF2-deficient meningioma cells, which strongly suggests that treatment with mTOR kinase inhibitors will be more beneficial for NF2 patients. In addition to mTOR activation, we and others have observed activation of MAPK/ERK in NF2-associated meningiomas and schwannomas. Our objectives in this preclinical translational research proposal are to test AstraZeneca compounds, mTOR kinase inhibitor (AZD2014), and MEK inhibitor (selumetinib) alone and in combination in human-derived meningioma models. AstraZeneca has kindly provided these drugs to us free of cost on a collaborative basis. Employing our well-characterized in vitro culture model of meningiomas, we will examine benign (WHO grade 1) as well as atypical (WHO grade 2) primary meningioma cells derived from NF2 patients for response to AZD2014 and selumetinib in cell signaling, proliferative, apoptotic and autophagic assays. These drugs will also be evaluated for preclinical in vivo efficacy in mouse models implanted with human NF2-deficient meningioma cells derived from benign as well as recurrent atypical tumors. Successful findings from this project should set the stage for further consideration of the mTOR kinase inhibitor and /or the MEK inhibitor individually or in combination for the treatment of NF2-associated tumors as well as sporadic meningiomas and schwannomas. These studies will have impact not only on NF2, but also on sporadic meningiomas and schwannomas, which are quite common in the general population.
NF2 is an inherited disorder associated with nervous system tumors such as meningiomas and schwannomas and these tumors are also frequently seen in the general population without NF2. A key signaling pathway known as mTOR is abnormally activated in these tumors. This project will test the efficacy of a novel mTOR pathway inhibitor in preclinical models of meningiomas and will be directly significant to NF2, sporadic meningiomas, schwannomas as well as other tumors where mTOR is often activated and thus will be of relevance to public health.
|Li, Lin; Walsh, Ryan M; Wagh, Vilas et al. (2015) Mediator Subunit Med28 Is Essential for Mouse Peri-Implantation Development and Pluripotency. PLoS One 10:e0140192|
|Beauchamp, Roberta L; James, Marianne F; DeSouza, Patrick A et al. (2015) A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas. Oncotarget 6:16981-97|