Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.
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Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target.
Researchers Julianne Huegel, Christine T. Dinh, Maria Martinelli, Olena Bracho, Rosa Rosario, Haley Hardin, Michael Estivill, Anthony Griswold, Sakir Gultekin, Xue-Zhong Liu, and Cristina Fernandez-Valle, from the University of Central Florida and the University of Miami Miller School of Medicine, conducted an unbiased chemical compound screen of the Library of Pharmacologically Active Compounds (LOPAC) as a pilot high-throughput screen to identify NF2 schwannoma targets for inhibition.
“Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells.”
The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG50) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5–100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 hours in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP.
In a 14-day treatment regimen, CUDC907 decreased tumor growth rate by 44%, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.
“In summary, we demonstrated that CUDC907 reduced the activity of three major signaling pathways in NF2 schwannomas (HDAC, PI3K, and YAP) and consistently reduced viability and induced apoptosis in several schwannoma cell models and in all five genetically unique primary VS studied. These consistent results offer the possibility that CUDC907 will promote schwannoma regression in patients with diverse NF2 mutations and support clinical evaluation of CUDC907 for NF2-associated schwannomas and potentially other cancers driven by NF2 pathogenic variants [45]. Current use of this drug in clinical trials for other indications reveals clinical interest in multi-modal drugs over monotherapies.”
Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.
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