Efficacy of Novel Compound in Temozolomide-Resistant Brain Tumor Cell Lines in Mice
UP TO 50 PERCENT OF BRAIN TUMORS RESISTANT TO STANDARD CHEMOTHERAPEUTIC AGENT TMZ
When a patient presents with a malignant glioblastoma, the current standard therapy is total resection surgery followed by radiation, either alone or in combination with temozolomide (TMZ) chemotherapy.1 Used to treat several types of cancer, orally-administered alkylating agent TMZ is known to inhibit cell reproduction by blocking the replication of DNA.2 Although it is less toxic than other alkylating agents, TMZ does not display efficacy in as many as 50 percent of brain tumors.3 Because of this, as well as the high rate of chemotherapy resistance in recurrent brain malignancies, there is an urgent need for new drugs for treatment-resistant tumors.4
Researchers at Penn State Neurosurgery are currently working to develop such a compound. Led by Assistant Professor of Neurosurgery, Sang Y. Lee, PhD, the team is focusing on the two most common mutations found in the HFE gene, H63D and C282Y, which have shown a combined prevalence in the Caucasian population of 34 percent and have also been shown to correlate with increased cancer risk. According to Lee, these HFE mutations are frequently expressed in tumor cells that are resistant to TMZ. He and his team observed both in vitro and in vivo success of the novel compound “CC-1,” using immunodeficient nude mice to conduct the animal studies. They measured successful outcomes of CC-1 by both survival and MRI imaging in the murine population. Treatment with CC-1 inhibited tumor growth and was not lethal in any of the treatment groups.1 Conversely, Lee relates that in the control group, all of the mice died by the twenty-seven to thirty day mark.
This research, occurring exclusively at Penn State Hershey and partially funded by a grant from the National Institutes of Health, will continue in the animal-study phase for another two to three years. After those studies are completed, human trials will begin. The goal of human trials is to enhance efficacy of the compound, as well as discover alternate methods of drug delivery. Currently, CC-1 is administered via intraperitoneal injection; IV and oral formulations are of course preferred in the human population. Many improvements and refinements remain to be made to CC-1, but the compound shows great promise of being a viable option for brain tumor patients who do not respond to TMZ treatment.
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- Marchesi F (2007) Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol Res 56: 275-287.
- Hegi ME, Liu L, Herman JG, Stupp R, Wick W, et al. (2008) Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 26: 4189-4199.
- Lee SY, Slagle-Webb B, Rizk E, Patel A, Miller PA, et al. (2014) Characterization of a Novel Anti-Cancer Compound for Astrocytomas. PLoS ONE 9(9):e108166. doi:10.1371/journal.pone.0108166.