Abstract 2007: Development of a clinical assay for predicting glioblastoma (GBM) patients most likely to respond to arsenic trioxide (ATO)

Glioblastoma (GBM) is the most frequently reported primary malignant brain tumor (29.6%). The prognosis for patients who develop GBM is bleak, with average survival after diagnosis of 12-16 months. Although conventional treatment with surgery, irradiation, and temozolomide postpones tumor progression and extends patients survival, these tumors universally recur and unrelentingly result in patient death. Personalized therapies against molecular targets that drive the growth of the bulk of primary tumors have so far been unsuccessful in clinical trials, due to lack of biomarker driven approaches. Thus, there is significant unmet need to begin biomarker driven precision medicine trials for treatment of GBM. Arsenic trioxide (ATO) is an inorganic compound that induces apoptosis via multiple pathways. Arsenic trioxide (TRISENOX®) is approved by the FDA for patients with acute promyelocytic leukemia (APL). Pre-clinical studies in brain tumors suggest that ATO is synergistic with radiation therapy (RT) and may enhance effects of radiation. In an earlier Phase II clinical trial (NCT00275067) using intravenous ATO and temozolomide in combination with radiation therapy for patients with newly diagnosed malignant gliomas, a subset of patients demonstrated notable benefit (Progression free survival (avg. = 638 days) and overall survival (avg. = 967 days)). Comparing RNAseq data from preclinical models and specimen from the Phase II clinical trial, the responder group could be confidently distinguished from the non-responder cohort leading to gene signatures of differential ATO sensitivity. Applying a Relative Expression Ordering (REO) Analysis framework, we pinpointed a probability-based roster of 28 top scoring pairs (TSP) as the classifier by which to identify patients with a higher likelihood to benefit from including ATO in combination with TMZ and radiation. This method is completely independent of platform on which data is collected and can be used for analysis of individual, newly-enrolled, n = 1 patients. We are advancing a protocol using the above gene classifier as enrollment criteria for an Adaptive clinical trial testing an oral formulation of ATO for newly diagnosed IDH1 WT Primary GBM patients; the trial will test whether patients whose tumors with ATO Classifier show 6-month PFS benefit by addition of ATO to Standard-of-Care. The trial will validate and refine the comprehensive biomarker panel that could identify most likely GBM responders to ATO and TMZ treatment in combination with radiation. Supported by a grant from the Baylor Scott & White Foundation. Citation Format: Sen Peng, Jinghua Gu, Xuan Wang, Sanhita Rath, Jacob Cardenas, Nicholas Schork, George Snipes, Harshil Dhruv, Karen Fink, Michael Berens. Development of a clinical assay for predicting glioblastoma (GBM) patients most likely to respond to arsenic trioxide (ATO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2007.