Anti-Sense Might Make Sense For Treating Liver Cancer
COLUMBUS, Ohio - A new study shows that it is possible to selectively target and block a particular microRNA that is important in liver cancer. The finding might offer a new therapy for this malignancy, which kills an estimated 549,000 people worldwide annually.
The animal study, by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) and at Mayo Clinic, focused on microRNA-221 (miR-221), a molecule that is consistently present at abnormally high levels in liver cancer.
To control the problem molecule, the researchers designed a second molecule as a kind of mirror image of the first. That mirror molecule is called an antisense oligonucleotide, and it selectively bound to and blocked the action of miR-221 in human liver cancer transplanted into mice. The treatment significantly prolonged the animals' lives and promoted the activity of important tumor-suppressor genes.
"This study is significant because hepatocellular carcinoma, or liver cancer, generally has a poor prognosis, so we badly need new treatment strategies," says principal investigator Thomas Schmittgen, associate professor and chair of pharmaceutics at Ohio State's College of Pharmacy and a member of the OSUCCC - James Experimental Therapeutics program.
The findings are published in the journal Cancer Research.
For the study, Schmittgen and his colleagues injected liver cancer cells labeled with the luminescent lighting-bug protein luciferase into the livers of mice. The researchers used bioluminescence imaging to monitor tumor growth.
When the tumors reached the appropriate size, they gave one group of animals the molecule designed to block miR-221; the other group received a control molecule.
Key findings include the following:
· After treatment with the antisense oligonucleotide, half the treated animals were alive at 10 weeks versus none of the controls.
· The antisense oligonucleotide significantly reduced levels of miR-221 in both tumor and normal liver samples.
· Treatment with the antisense oligonucleotide caused a three-fold increase in the activity of three important tumor-suppressor genes that are blocked by miR-221 in liver cancer. (The tumor suppressors were p27, p57 and PTEN.)
"Overall, this study provides proof-of-principle for further development of microRNA-targeted therapies for hepatocellular carcinomas," Schmittgen says.
Funding from the National Cancer Institute and from the National Institute of Diabetes and Digestive and Kidney Diseases supported this research.
Other researchers involved in this study were Jong-Kook Park, Jinmai Jiang, Lei He, Ji Hye Kim, Mitch A. Phelps, Tracey L. Papenfuss and Carlo M. Croce of Ohio State; Takayuki Kogure and Tushar Patel of Mayo Clinic, Jacksonville, Florida; and Gerard J. Nuovo.
The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (cancer.osu.edu) strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only seven centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 210-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top 20 cancer hospitals in the nation as ranked by U.S. News & World Report.