2012

Alexander Stegh PhD

Northwestern University, Feinberg School of Medicine Assistant Professor, Neurology

Research Focus: Gene/Cell Mediated Therapies

Cancer Type: Brain Cancer

Award: Young Investigator

Dr. Stegh will define the role of a novel glioma oncoprotein, termed isocitrate dehydrogenase-1 (IDH1), in driving progression and therapy resistance of glioblastoma (GBM). Understanding the molecular basis of the therapy refractoriness of GBM is one of the most important areas of glioma research.

IDH1 is a critical enzyme of the citric acid cycle (CAC) and is a master regulator of metabolism. Building on his preliminary studies, Dr. Stegh will molecularly characterize the precise mechanism, by which IDH1 protects glioma cells from therapy-induced cell death using glioma cell and mouse models. To target IDH1 signaling in GBM, he will leverage these model systems and mechanistical knowledge to develop and preclinically characterize RNA interference RNAi-based nanomaterials. He will generate RNAi-functionalized spherical nucleic acids (SNAs) that neutralize IDH1 expression in established gliomas. Due to the negative charge of the RNA backbone, however, siRNA oligonucleotides have many downsides, such as they trigger auto-immune responses, and cannot cross the blood-brain-barrier (BBB).

In contrast, SNAs are able to transverse cellular membranes, do not require the use of toxic auxiliary reagents, and accumulate in cells and intracranial tumors very effectively. They also exhibit extraordinary stability in physiological environments, cross the BBB, are highly resistant to nuclease degradation, and thus, can move through biological fluids and avoid being destroyed as “foreign materials.” Dr. Stegh proposes to preclinically evaluate these IDH1-targeting nanoconjugates to provide a fundamentally novel treatment option of patients diagnosed with GBM, and will aid in successfully implementing RNAi-based therapies into neuro-oncological practice.

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