Meningiomas are tumors that arise from the meningothelial arachnoid cap cells, and are the most common primary intracranial tumor in adults. WHO grade II (atypical) or WHO grade III (anaplastic or malignant) tumors display more aggressive clinical behavior with rapid growth and increased recurrence rates. The current standard of care for meningioma is maximal safe surgical resection with adjuvant radiation reserved for progressive tumors or those with aggressive features (e.g., WHO grades II or III). Meningiomas that progress despite surgery and radiation cause high morbidity. There is no proven effective chemotherapy for patients with aggressive meningiomas therefore, effective non-invasive therapies are much needed. The most common genetic alteration in sporadic meningiomas is bi-allelic NF2 gene inactivation in 50-60% of tumors. Our earlier studies established the NF2 protein merlin as a novel negative regulator of mTORC1 signaling, which led to clinical trials with the allosteric mTORC1 inhibitor rapamycin analog, RAD001/everolimus for NF2 and meningioma patients. The clinical outcome thus far appears to show cytostatic effects, which is consistent with our in vitro results with rapamycin. mTOR is an evolutionarily conserved Ser/Thr kinase that regulates cell growth, proliferation and survival through two distinct functional complexes, mTORC1 and mTORC2. In our recent studies, we have detected specific activation of the mTORC2-dependent AGC kinase SGK1 (serum and glucocorticoid-regulated kinase 1) in primary human meningioma cells with and without NF2 loss. These data are consistent with the elevated SGK1 transcriptional expression and elevated SGK1 protein expression that we observe in human meningiomas. These observations led us to test the selective dual mTORC1/mTORC2 inhibitor AZD2014, provided by AstraZeneca, in primary human meningioma cell lines. Our data convincingly show that activation of mTORC2-dependent SGK1 in human meningioma cells is sensitive to AZD2014, but insensitive to rapamycin. AZD2014 treatment of primary meningioma cells in vitro, whether NF2-deficient or NF2-expressing, leads to decreased cell proliferation with greater efficacy than rapamycin. Further, unlike rapamycin, AZD2014 does not cause activation of prosurvival pathway such as PI3K/Akt/SGK1. In this proposal, the investigators, in partnership with AstraZeneca, propose to test the effect of AZD2014 in patients with recurrent or progressive WHO grade II and III meningiomas. This will be a single-arm, multicenter, open label, phase II study to evaluate the efficacy, safety, and tolerability of AZD2014 in 30 patients with recurrent grade II-III meningioma after surgical resection and radiation. The primary objective of the study is to estimate 6-month progression-free survival for the cohort. Further, detailed molecular and immunohistochemistry analyses will be undertaken to define whether subgroups of meningiomas respond better to AZD2014. This study should firmly establish whether AZD2014 is an important candidate drug for future larger randomized meningioma trials.
Meningiomas are the most common primary intracranial tumors seen in adults and 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, AZD2104, supplied by AstraZeneca, in patients with recurrent or progressive grade II and grade III meningiomas and the results should establish whether it is an important candidate drug for future randomized trials of meningiomas. This study will be directly relevant for sporadic meningiomas, neurofibromatosis type 2 (NF2)-associated meningiomas and schwannomas as well as many other tumors where mTOR is often activated, thus having a significant impact on public health.
