Non-Toxic Therapeutic Strategies for Treatment of Pediatric Brain Cancers

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Kalkunte Srivenugopal
Kalkunte S. Srivenugopal, PhD (Venu) is a tenured Professor in the Department of Biomedical Sciences at Texas Tech University Health Sciences Center School of Pharmacy.
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Carcinogenesis-2014-Paranjpe-692-702.pdf [PDF]

MGMT is a DNA repair protein that interferes with the cytotoxic action of alkylating chemotherapy agents.  Because of the prevalence of this protein in tumors, especially brain tumors, there is a great need for the discovery of an inhibitor that will not harm bone marrow stem cells.  This invention has solved this problem through the discovery of a novel use for an existing FDA approved drug used for the treatment of alcoholism, disulfiram.

Market Applications:

• Cancer Therapeutics

Features, Benefits, and Advantages:

The alcohol aversion drug disulfiram (DSF) reacts and conjugates with the protein-bound nucleophilic cysteines and is known to elicit anticancer effects alone or improve the efficacy of many cancer drugs.  This invention investigated the effects of disulfiram on human MGMT, a DNA repair protein and chemotherapy target that removes the mutagenic O6-akyl groups from guanines, and thus confers resistance to alkylating agents in brain tumors.  Treatment with DSF inhibited the MGMT activity in two brain tumor cell lines in a rapid and dose-dependent manner.  DSF was a weaker inhibitor of MGMT, compared to the established O6-benzylguanine, nevertheless, the 24-36 h suppression of MGMT activity in cell cultures vastly increased the alkylation-induced DNA interstrand crosslinking, G2/M cell cycle blockade, cytotoxicity, and the levels of apoptotic markers.

• Increased efficacy of cancer treatment

• Decreased side-effects, as compared to existing MGMT inhibitors

Development Stage:

This technology has been produced and tested.