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Sagers, Jessica

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Sagers

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Jessica

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Sagers, Jessica
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    Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
    (Nature Publishing Group UK, 2017) Ren, Yin; Sagers, Jessica; Landegger, Lukas; Bhatia, Sangeeta; Stankovic, Konstantina
    Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-based or small molecule therapeutics. Tumor-targeted delivery of small interfering RNA (siRNA) therapeutics provides a direct and effective means to interrogate targets while minimizing off-target effects. To establish a preclinical model for therapeutic inhibition of putative targets in VS, archived tumor specimens, fresh tumor cells derived from patients with sporadic VS, and an established schwannoma cell line were screened. Nanoparticles directed by the tumor-homing peptide iRGD were selectively taken up by primary VS cultures in vitro via interactions with αvβ3/β5 integrins and neuropilin-1 (NRP-1). Cellular uptake was inhibited by a neutralizing antibody against αv integrin in a dose-dependent manner. When applied to primary VS cultures, iRGD-targeted nanoparticles delivered siRNA directed against TNFα in a receptor-specific fashion to potently silence gene expression and protein secretion. Taken together, our results provide a proof of principle for tumor-targeted, nanoparticle-mediated delivery of siRNA to VS and establish a novel platform for the development and pre-clinical screening of molecular therapeutics against VS.
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    Listening Into 2030 Workshop: An Experiment in Envisioning the Future of Hearing and Communication Science
    (SAGE Publications, 2017) Carlile, Simon; Ciccarelli, Gregory; Cockburn, Jane; Diedesch, Anna C.; Finnegan, Megan K.; Hafter, Ervin; Henin, Simon; Kalluri, Sridhar; Kell, Alexander J. E.; Ozmeral, Erol J.; Roark, Casey L.; Sagers, Jessica
    Here we report the methods and output of a workshop examining possible futures of speech and hearing science out to 2030. Using a design thinking approach, a range of human-centered problems in communication were identified that could provide the motivation for a wide range of research. Nine main research programs were distilled and are summarized: (a) measuring brain and other physiological parameters, (b) auditory and multimodal displays of information, (c) auditory scene analysis, (d) enabling and understanding shared auditory virtual spaces, (e) holistic approaches to health management and hearing impairment, (f) universal access to evolving and individualized technologies, (g) biological intervention for hearing dysfunction, (h) understanding the psychosocial interactions with technology and other humans as mediated by technology, and (i) the impact of changing models of security and privacy. The design thinking approach attempted to link the judged level of importance of different research areas to the “end in mind” through empathy for the real-life problems embodied in the personas created during the workshop.
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    Computational repositioning and preclinical validation of mifepristone for human vestibular schwannoma
    (Nature Publishing Group UK, 2018) Sagers, Jessica; Brown, Adam S.; Vasilijic, Sasa; M. Lewis, Rebecca; Sahin, Mehmet I.; Landegger, Lukas; Perlis, Roy H.; Kohane, Isaac; Welling, Duane; Patel, Chirag; Stankovic, Konstantina
    The computational repositioning of existing drugs represents an appealing avenue for identifying effective compounds to treat diseases with no FDA-approved pharmacotherapies. Here we present the largest meta-analysis to date of differential gene expression in human vestibular schwannoma (VS), a debilitating intracranial tumor, and use these data to inform the first application of algorithm-based drug repositioning for this tumor class. We apply an open-source computational drug repositioning platform to gene expression data from 80 patient tumors and identify eight promising FDA-approved drugs with potential for repurposing in VS. Of these eight, mifepristone, a progesterone and glucocorticoid receptor antagonist, consistently and adversely affects the morphology, metabolic activity, and proliferation of primary human VS cells and HEI-193 human schwannoma cells. Mifepristone treatment reduces VS cell viability more significantly than cells derived from patient meningiomas, while healthy human Schwann cells remain unaffected. Our data recommend a Phase II clinical trial of mifepristone in VS.