The overall goal of this K08 application is to foster my development as an independent scientific investigator with a focus on translational research and drug development. To that end, my mentors and I have formulated a career development plan consisting of formal didactics, bench research, and involvement in the clinical trials program at the Ohio State University. The research focus of my proposal is the preclinical development of OSU-03012, a novel PDK1 inhibitor that targets AKT signaling in vestibular schwannomas (VS). OSU-03012 shall be used as a vehicle for my further training in drug development. VS are intracranial tumors that cause sensorineural hearing loss, balance abnormalities, tinnitus, vertigo, facial weakness, hydrocephalus, seizures, blindness, and even death. Current treatment options are surgery and/or radiation;however, complications remain major concerns. We have reported that the PI3-kinase/AKT pathway, a convergence point for many stimuli controlling cell proliferation and apoptosis, is active in VS. Our central hypothesis is that vestibular schwannomas rely on AKT activation to prevent apoptosis and promote cell proliferation, and molecular targeting of the AKT pathway may suppress VS growth, spare normal tissues, and be a viable therapeutic option for patients. Using a variety of in vitro laboratory techniques (cytotoxicity assays, flow cytometry, TUNEL, antibody arrays, caspase activity assays, proliferation indices, FACS, RNA interference, PCR and Western blots), we plan to better understand the end biologic effects of decreased AKT signaling on apoptosis and cell cycle regulation in VS. Simultaneously, we plan to validate the efficacy and molecular targets for OSU-03012 in vivo utilizing human malignant schwannoma xenografts, VS xenografts, and nestin-Cre Nf2-/- knockout mice that generate spontaneous peripheral schwannomas to test drug. Lastly, because treatment of VS may require long-term drug administration in order to sustain efficacy, we plan to evaluate clinically relevant pharmacodynamic (blood brain barrier penetration) and pharmacotoxicity (blood chemistries and organ toxicity) profiles for OSU-03012 during long-term dosing in rodent chow. These studies are vital to eventual FDA approval and human clinical trials for VS.
Vestibular schwannomas (VS) cause significant clinical morbidity due to their critical location in the posterior cranial fossa. Patients currently choose between surgery and radiation therapy to treat their disease;however, post-treatment complications remain a significant concern. OSU-03012 may represent the first medical treatment alternative for patients afflicted with VS.
