Discovering novel therapies for glioma patients

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This project includes both preclinical and clinical studies of the combination of TG02 and TMZ in recurrent high-grade gliomas. In the preclinical studies, we extensively investigated TG02, a novel agent known to cross the blood-brain barrier. Our investigations uncovered the single agent effect and several complementary mechanisms of action that underlie the synergy with an oral alkylating agent, temozolomide. We demonstrated that in addition to suppressing transcription through inhibition of cyclin-dependent kinase 9 (CDK9), TG02 also decreases cellular ATP levels by suppression of glycolysis and mitochondrial function, inducing cell death in glioblastoma cells but not in normal astrocytes. Cellular ATP production is further decreased with the combined treatment of TG02 and temozolomide by inhibiting glycolysis, which could explain the synergistic effects. The synergy is further characterized by a prolonged survival that was observed in a syngeneic mouse glioblastoma model receiving combined treatment of TG02 and temozolomide. In summary, TG02 targets multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in refractory glioblastoma. The findings in these preclinical findings, providing the rationale for clinical testing of the combination therapy, have led to the launching of phase I/II clinical trial (NCT02942264). The primary objective of Phase I trial is to determine the maximum tolerate dose (MTD) of TG02 plus TMZ using both dose-dense (dd) and metronomic (mn) schedules in adult patients with recurrent high-grade astrocytoma. The phase I part is conducted in two stages: the MTD finding and cohort expansion. After MTDs of TG02 in a combination of TMZ with two doing schedules (dd and mn) are obtained, the cohort expansion of both arms will be performed at each MTD and the treatment arm with a better progression-free survival at 4 months will be selected for the combination treatment arm for phase II. Pharmacokinetic, pharmacogenetic studies and neutrophil analysis are planned during the cohort expansion phase. The phase II study is to determine the efficacy of TG02 plus TMZ versus TMZ alone in the recurrent high-grade glioma patients, using the dosage that is derived from the phase I part. At the disease progression, patients that are randomized to control arm will be offered the opportunity to cross-over to the treatment arm. Currently, the preclinical studies that let to this investigator-initiated clinical trial have been published in Clinical Cancer Research. Both primary and secondary endpoints are met for the phase 1 study. A manuscript is in preparation. We have also developed preclinical research to identify the resistance mechanisms of TG02 in treating gliomas and the selective vulnerability of a subset of glioma to TG02 treatment.