160 - Convection-Enhanced Drug Delivery and Radiosensitization for Diffuse Midline Glioma

M. Gallitto¹, G. De los Santos¹, X. Zhang², H. J. Wei¹, E. Calvo Fernández³, C. J. Kinslow¹, X. Berg³, P. Canoll⁴, J. N. Bruce⁵, R. Gartrell⁶, S. K. Cheng⁷, R. Wechsler-Reya⁸, Z. Zhang², and C. C. Wu⁷; ¹Department of Radiation Oncology, Columbia University Irving Medical Center, New York, NY, ²Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, ³Columbia University Irving Medical Center, New York, NY, ⁴Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, ⁵Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, ⁶Johns Hopkins University, Baltimore, MD, ⁷Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, ⁸Department of Neurology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY

Purpose/Objective(s): Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. The only approved standard of care is radiation therapy (RT). Studies examining the role of other systemic agents have failed to demonstrate a survival benefit, partially due to tumor extension into areas of the brain where the blood-brain barrier (BBB) remains intact. As our laboratory has recently determined active NAD(P)H Quinone Dehydrogenase 1 (NQO1) expression in patient-derived DMG tumor samples, and RT has been shown to induce NQO1 expression, we sought to investigate the NQO1 bioactivatable ROS inducing agent, Napabucasin, as a potential radiosensitizer in DMG. Furthermore, we explore the safety and feasibility of convection-enhanced drug delivery (CED) to overcome limitations of the BBB. Materials/

Methods: Using two DMG cell lines, we performed clonogenic survival assays with increasing doses of RT with and without Napabucasin. We then created subcutaneous xenograft mouse models, treating with (1) vehicle control, (2) Napabucasin 10mg/kg via intraperitoneal injection, (3) 2 Gy of RT daily, or (4) combination treatment with RT and Napabucasin. Flank tumor measurements were obtained weekly using ultrasound imaging. For our syngeneic orthotopic DMG mouse model, we implanted 7-day osmotic infusion pumps containing either vehicle or 80uM Napabucasin. Mice then underwent a second randomization with or without daily RT for 5 days. Weekly MRIs and daily weights were obtained to measure local control and overall survival (OS), respectively.
Results: We identified a robust radiosensitizing effect with Napabucasin using in vitro clonogenic survival assays (Bliss synergy score 16.6). In subcutaneous flank models, combination treatment led to a statistically significant decrease in tumor volume post-treatment completion when compared to any monotherapy (p<0.05). In our syngeneic orthotopic DMG mouse model, RT after osmotic pump implantation in the brainstem did not lead to significant morbidity or mortality. Combination RT and CED of Napabucasin led to a significant OS benefit when compared to monotherapy (median OS 46 days with combination treatment, 33 days with RT monotherapy, and 26 days with Napabucasin monotherapy, p<0.001).
Conclusion: In this study, we identify Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG. As RT is the cornerstone of DMG care, identifying novel radiosensitizing techniques in this devastating disease is paramount to clinical success.