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Browsing by Author "Haggarty, Stephen J."
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Item Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK(PLOS, 2021-07-15) Chang, Long-Sheng; Oblinger, Janet L.; Smith, Abbi E.; Ferrer, Marc; Angus, Steven P.; Hawley, Eric; Petrilli, Alejandra M.; Beauchamp, Roberta L.; Riecken, Lars Björn; Erdin, Serkan; Poi, Ming; Huang, Jie; Bessler, Waylan K.; Zhang, Xiaohu; Guha, Rajarshi; Thomas, Craig; Burns, Sarah S.; Gilbert, Thomas S.K.; Jiang, Li; Li, Xiaohong; Lu, Qingbo; Yuan, Jin; He, Yongzheng; Dixon, Shelley A.H.; Masters, Andrea; Jones, David R.; Yates, Charles W.; Haggarty, Stephen J.; La Rosa, Salvatore; Welling, D. Bradley; Stemmer-Rachamimov, Anat O.; Plotkin, Scott R.; Gusella, James F.; Guinney, Justin; Morrison, Helen; Ramesh, Vijaya; Fernandez-Valle, Cristina; Johnson, Gary L.; Blakeley, Jaishri O.; Clapp, D. Wade; Pediatrics, School of MedicineNeurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.Item High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy(Springer Nature, 2021-08-23) Cheng, Chialin; Reis, Surya A.; Adams, Emily T.; Fass, Daniel M.; Angus, Steven P.; Stuhlmiller, Timothy J.; Richardson, Jared; Olafson, Hailey; Wang, Eric T.; Patnaik, Debasis; Beauchamp, Roberta L.; Feldman, Danielle A.; Silva, M. Catarina; Sur, Mriganka; Johnson, Gary L.; Ramesh, Vijaya; Miller, Bruce L.; Temple, Sally; Kosik, Kenneth S.; Dickerson, Bradford C.; Haggarty, Stephen J.; Pediatrics, School of MedicineMutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded tau protein that can propagate between neurons ultimately leading to cell death (tauopathy). Recently, a p.A152T tau variant was identified as a risk factor for FTD, Alzheimer's disease, and synucleinopathies. Here we used induced pluripotent stem cells (iPSC) from a patient carrying this p.A152T variant to create a robust, functional cellular assay system for probing pathophysiological tau accumulation and phosphorylation. Using stably transduced iPSC-derived neural progenitor cells engineered to enable inducible expression of the pro-neural transcription factor Neurogenin 2 (Ngn2), we generated disease-relevant, cortical-like glutamatergic neurons in a scalable, high-throughput screening compatible format. Utilizing automated confocal microscopy, and an advanced image-processing pipeline optimized for analysis of morphologically complex human neuronal cultures, we report quantitative, subcellular localization-specific effects of multiple kinase inhibitors on tau, including ones under clinical investigation not previously reported to affect tau phosphorylation. These results demonstrate the potential for using patient iPSC-derived ex vivo models of tauopathy as genetically accurate, disease-relevant systems to probe tau biochemistry and support the discovery of novel therapeutics for tauopathies.