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

P. Ambady, Y. J. Wu, J. M. Walker, C. Kersch, M. A. Pagel, R. L. Woltjer, R. Fu, L. L. Muldoon, E. A. Neuwelt

Research output: Contribution to journalArticle

Abstract

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.

LanguageEnglish (US)
Pages348-357
Number of pages10
JournalCancer Gene Therapy
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2017

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Morpholinos
Methyltransferases
Radiation
DNA
temozolomide
Neoplasms
Glioblastoma
O(6)-Methylguanine-DNA Methyltransferase
DNA Repair Enzymes
Chemoradiotherapy
Standard of Care
Endocytosis
Ionizing Radiation
Methylation
Cell Survival
Up-Regulation
Neoplasm Metastasis
Drug Therapy
Brain

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Cite this

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title = "Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors",
abstract = "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.",
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T1 - Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors

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AU - Wu,Y. J.

AU - Walker,J. M.

AU - Kersch,C.

AU - Pagel,M. A.

AU - Woltjer,R. L.

AU - Fu,R.

AU - Muldoon,L. L.

AU - Neuwelt,E. A.

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