Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors

• Published in: Cancer gene therapy Vol. 24; no. 8; pp. 348 - 357
• Main Authors: Ambady, P, Wu, Y J, Walker, J M, Kersch, C, Pagel, M A, Woltjer, R L, Fu, R, Muldoon, L L, Neuwelt, E A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2017; Nature Publishing Group
• Subjects: 13/109; 14/19; 42; 42/34; 42/41; 631/67/68; 692/308/153; 692/699/67/1059/602; 82/51; 96; Analysis; Biomedical and Life Sciences; Biomedicine; Brain cancer; Cancer; Care and treatment; Cell proliferation; Chemoradiotherapy; Chemoresistance; Chemotherapy; Comparative analysis; Cytotoxicity; Diagnosis; DNA methylation; DNA methyltransferase; DNA repair; Endocytosis; Gene Expression; Gene Therapy; Glioblastoma; Glioblastomas; Ionizing radiation; Metastases; Methylguanine; Methyltransferases; O6-methylguanine-DNA methyltransferase; Oligonucleotides; Original; original-article; Solid tumors; Temozolomide; Tumor cells; Tumors
• ISSN: 0929-1903; 1476-5500; 1476-5500
• DOI: 10.1038/cgt.2017.27

The DNA repair enzyme O 6 -methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences. We demonstrate >40% reduction in the in vitro proliferation index and cell viability in radiation-primed MGMT-expressing human solid tumor cells treated with a single dose of AMONs and temozolomide. We further demonstrate the feasibility of using a non-ablative dose of radiation in vivo to guide and enhance the delivery of intravenously administered AMONs to achieve 50% MGMT knockdown only at radiation-primed tumor sites in a subcutaneous tumor model. Local upregulation of physiological endocytosis after radiation may have a role in radiation-guided uptake of AMONs. This approach holds direct translational significance in glioblastoma and brain metastases where radiation is part of the standard of care; our approach to silence MGMT could overcome the significant problem of MGMT-mediated chemoresistance.