PAM-OBG: A monoamine oxidase B specific prodrug that inhibits MGMT and generates DNA interstrand crosslinks, potentiating temozolomide and chemoradiation therapy in intracranial glioblastoma

Oncotarget
Martyn A SharpeDavid S Baskin

Abstract

Via extensive analyses of genetic databases, we have characterized the DNA-repair capacity of glioblastoma with respect to patient survival. In addition to elevation of O6-methylguanine DNA methyltransferase (MGMT), down-regulation of three DNA repair pathways; canonical mismatch repair (MMR), Non-Homologous End-Joining (NHEJ), and Homologous Recombination (HR) are correlated with poor patient outcome. We have designed and tested both in vitro and in vivo, a monoamine oxidase B (MAOB) specific prodrug, PAM-OBG, that is converted by glioma MAOB into the MGMT inhibitor O6-benzylguanine (O6BG) and the DNA crosslinking agent acrolein. In cultured glioma cells, we show that PAM-OBG is converted to O6BG, inhibiting MGMT and sensitizing cells to DNA alkylating agents such as BCNU, CCNU, and Temozolomide (TMZ). In addition, we demonstrate that the acrolein generated is highly toxic in glioma treated with an inhibitor of Nucleotide Excision Repair (NER). In mouse intracranial models of primary human glioma, we show that PAM-OBG increases survival of mice treated with either BCNU or CCNU by a factor of six and that in a chemoradiation model utilizing six rounds of TMZ/2Gy radiation, pre-treatment with PAM-OBG more than doubled survival t...Continue Reading

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Citations

Oct 9, 2019·Current Opinion in Neurology·Jason M BecktaAnthony J Chalmers
Sep 27, 2018·International Journal of Molecular Sciences·Martina Da RosIacopo Sardi
Oct 10, 2020·Molecular Cancer Therapeutics·Sudhir RaghavanMartyn A Sharpe
Jun 15, 2021·Current Oncology Reports·Kevin B Elmore, Lauren R Schaff

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Methods Mentioned

BETA
biopsy
ubiquitination
Assay
RNA Seq
acylation
fluorescence microscopy
xenografts
xenograft

Software Mentioned

Nikon NIS - Elements
MAO
Elements

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