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OHSU # 2291 — Radiation-enhanced delivery of antisense oligonucleotides against MGMT

Summary

MGMT is a critical enzyme driving DNA repair, and down-regulation of this molecule in tumors is linked to increased efficacy of cancer therapies that promote DNA damage and apoptosis of cancer cells. Researchers at the Veteran’s Affair Hospital and Oregon Health & Science University have developed a new cancer therapeutic strategy consisting of anti-MGMT morpholino oligonucleotides (AMON), which, when used with traditional radiation therapy, can be locally-delivered and cross the blood brain barrier for treatment of brain cancer.

Technology Overview

Alkylating chemotherapy agents, which increase cancer cell cytotoxicity by inducing double-stranded DNA breaks, are powerful therapeutic agents in combined chemo-radiation therapy (CRT); however, endogenous DNA repair mechanisms can reduce the efficacy of these drugs.  The DNA repair enzyme O6-methylguanin DNA methyltransferase (MGMT) is a critical molecule initiating repair of double-stranded breaks, and low expression of this molecule in tumors is linked to a better cancer prognosis. Based on this observation, a novel therapeutic strategy has been developed to inhibit tis enzyme using anti-MGMT morpholino oligonucleotides (AMON) to promote the efficacy of traditional CRT. Importantly, this approach utilizes the radiation of traditional CRT to enhance as well as localize uptake of AMONs to the tumor site. In vitro data demonstrates that radiation-primed human solid tumors cells demonstrated a significant reduction in proliferation and viability when AMONs were combined with the chemotherapy agent temozolomide compared to temozolomide alone. The uptake of AMONs was highly localized, with a 50% MGMT knockdown limited to a radiation-primed tumor site in a subcutaneous tumor model, indicating the potential for this approach to reduce off-target effects. Furthermore, radiation pre-treatment also enhanced the targeted delivery of morpholino oligonucleotides across the blood-brain barrier, making this an important potential therapeutic approach for brain cancers. In conclusion, radiation delivered AMONs has the potential to limit endogenous DNA repair mechanisms and increase the efficacy of standard-of-care CRT and ultimately improve outcomes for cancer patients.

Publication

Ambady, P. et al., “Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors.” Cancer Gene Ther 24, 348–357 (2017). Link

Licensing Opportunity

Available for exclusive or non-exclusive licensing and/or collaborative co-development.

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Patents

Issued United States 11,679,121

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