Radiation Biology

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SU_39_2392 - Therapeutic implications of targeting Notch pathway in glioma

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Therapeutic implications of targeting Notch pathway in glioma
R. Singh1, S. J. Haque2, E. H. Bell3, and A. Chakravarti4; 1The Ohio State University-Comprehensive Cancer Center, COLUMBUS, OH, 2Ohio State University, Columbus, OH, 3The Ohio State University Comprehensive Cancer Center, Columbus, OH, 4Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH

Purpose/Objective(s): The purpose of this study is to evaluate the effects of targeting Notch pathway on the glioma pathobiology. Gliomas are the most common cancer of central nervous system (CNS) and are highly invasive and vascularized. Given the critical role of Notch pathway in gliogenesis and maintenance of neural progenitors, its pivotal role in CNS carcinogenesis is also substantiated. Additionally, the products of Notch pathway are also known to modulate hypoxia and angiogenesis, which are well-known hallmarks of glioma. Therefore, we sought to investigate how Notch pathway and its interactome can drive the gliomagenesis, and the therapeutic insinuations associated with targeting specific component(s) of the pathway.

Materials/Methods: We used specific γ-secretase inhibitors to block the cleavage of Notch Intracellular domain and the subsequent activation of the Notch signaling. This was followed by the assessment of the downstream effects on cell proliferation and the targeting of Notch effector proteins and associated pathways. Additionally, we probed the synergistic effects of Notch inhibition with radiation treatment (RT), and in combination with Temozolomide. Lastly, we used RNAi to target the Notch receptors individually, in order to probe the effects on glioma pathogenesis and evaluate their therapeutic potential.

Results: We observed a significant decline in cell proliferation after treatment with γ-secretase inhibitors, and in combination with RT and temozolomide. In addition, we observed a comprehensive targeting of Notch pathway, both at canonical and non-canonical levels. All these phenotypic effects were augmented with a synergy of these inhibitors with both RT and temozolomide. Lastly, we observed context-specific effects of targeting Notch receptors on cell proliferation, invasion, EMT, and their cross-talk with other radioresistance pathways

Conclusion: Targeting notch pathway modulates the vital cellular processes that are implicated in the tumorigenesis of the gliomas. All these endeavors may lead to better treatment outcomes for the patients. Further studies to authenticate the druggability of notch effectors and their interacting partners should be investigated to determine if this combinatorial targeting could be used to design personalized therapeutic interventions for GBM patients.

Author Disclosure: R. Singh: None. S.J. Haque: None. E.H. Bell: None. A. Chakravarti: None.

Rajbir Singh, PhD

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