Inhibition of O6-methylguanine DNA methyltransferase (MGMT) in solid tumors by lomeguatrib

Abstract

3597 Background: MGMT is implicated in tumor resistance to O6-alkylating agents, since the protein repairs DNA damage before replication results in cell death. Lomeguatrib (LM) is an orally bioavailable pseudosubstrate for MGMT that inactivates the protein through transfer of a boromthenyl group to the active site cysteine. De novo synthesis is required to restore cellular MGMT levels. We determined the dose of LM needed reliably to deplete MGMT in 3 tumor types, to inform future combination studies with methylating agents. Methods: Patients due to undergo surgery for prostate, colorectal or primary CNS cancers were invited to take part. They were dosed with LM PO 6 to 18 hours before surgery, and a portion of the tumor specimen retained for assessment of total and active MGMT. Active MGMT was assessed by transfer of tritium from methylated DNA to the protein fraction, and total MGMT by ELISA. 3 patient cohort dose escalations were used, with expansion to 6 patients where total depletion was encountered. Dose levels were 20, 40, 80, 120, and 160 mg. Results: LM was well tolerated and depleted MGMT in all 3 tumor types (table 1). Prostate cancers had the highest levels of MGMT (550 Fmol/mg protein) but were the most readily depleted tumour type. CNS tumours required more LM to achieve 100% depletion. Conclusions: Lomeguatrib depletes MGMT in prostate, colorectal and CNS cancers after single oral doses of 120 mg, 120 mg, and 160 mg respectively. Mean MGMT depletion (%) with a single LM dose Dose Level (mg) Prostate Cancer Colorectal Cancer Glioblastoma 20 81.7 44.7 40 96.8 61 46 80 98.3 96.5 57 120 99.5 97.7 73.4 160 100 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cancer Research UK