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1.
Oncogene ; 43(13): 921-930, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38336988

RESUMEN

Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.


Asunto(s)
Indazoles , Neurilemoma , Neurofibromatosis , Neurofibromatosis 2 , Neoplasias Cutáneas , Sulfonamidas , Humanos , Animales , Ratones , Neurofibromatosis 2/tratamiento farmacológico , Neurofibromatosis 2/genética , Neurofibromatosis 2/metabolismo , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Fosfatidilinositol 3-Quinasas , Quinasas p21 Activadas/genética , Fosfatidilinositol 3-Quinasa/uso terapéutico , Neurilemoma/tratamiento farmacológico , Neurilemoma/genética
2.
Mol Cancer Ther ; 22(11): 1280-1289, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37527526

RESUMEN

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.


Asunto(s)
Antineoplásicos , Neurilemoma , Neurofibromatosis 2 , Humanos , Neurofibromatosis 2/tratamiento farmacológico , Neurofibromatosis 2/genética , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Dasatinib/farmacología , Fosfatidilinositol 3-Quinasa/farmacología , Fosfatidilinositol 3-Quinasa/uso terapéutico , Neurilemoma/tratamiento farmacológico , Neurilemoma/genética , Antineoplásicos/farmacología , Proliferación Celular
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