A new experimental approach to treating a type of brain cancer called medulloblastoma has been developed by researchers at Sanford-Burnham. The method targets cancer stem cells -- the cells that are critical for maintaining tumor growth -- and halts their ability to proliferate by inhibiting enzymes that are essential for tumor progression. The process destroys the ability of the cancer cells to grow and divide, paving the way for a new type of treatment for patients with this disease.
The research team, led by Robert Wechsler-Reya, Ph.D., professor in Sanford-Burnham's NCI-Designated Cancer Center and director of the Tumor Initiation and Maintenance Program, discovered that the medulloblastoma cancer cells responsible for tumor growth and progression (called cancer stem cells or tumor-propagating cells -- TPCs) divide more quickly than normal cells. Correspondingly, they have higher levels of certain enzymes that regulate the cell cycle (Aurora and Polo-like kinases). By using small-molecule inhibitors to stop the action of these enzymes, the researchers were able to block the growth of tumor cells from mice as well as humans. The research findings are described in an online paper published today by Cancer Research.
"One tumor can have many different types of cells in it, and they can grow at different rates. By targeting fast-growing TPCs with cell-cycle inhibitors, we have developed a new route to assault medulloblastoma. In this study, we have shown that cell-cycle inhibitors essentially block medulloblastoma tumor progression by halting TPC expansion, and have opened the window to preventing cancer recurrence," said Wechsler-Reya.
The team's first set of experiments used a mouse model for medulloblastoma. In-vitro studies of mouse tumor cells showed that cell-cycle inhibitors caused tumor cell death. In vivo, mice that were treated with the inhibitor had smaller tumors that weighed less compared to mice that were not treated, essentially halting the progression of the tumor.
The second set of experiments used human medulloblastoma cells. When the researchers treated these human tumor cells with cell-cycle inhibitors, they also observed a significant reduction in tumor growth and progression.
Finally, when the scientists combined cell-cycle inhibitors with treatments currently used for medulloblastoma, they found that the combination worked together to produce results that were greater than either inhibitor alone.
"These results strongly support an approach to treatment that combines current therapies with cell-cycle inhibitors to treat medulloblastoma. Our hope is that the combination of these inhibitors will prevent tumor progression and drug resistance, and improve the overall effectiveness of current treatment options. We look forward to clinical studies in human medulloblastoma patients as well as other cancers that are suitable for this approach," Wechsler-Reya said.
Medulloblastoma is the most common malignant brain tumor, affecting about 500 children under the age of 10 in the United States annually. Current treatment options for medulloblastoma include aggressive surgery, radiation, and chemotherapy. Today, over two-thirds of children are successfully treated. However, survivors generally suffer long-term side effects such as cognitive and developmental disabilities due to the aggressive treatment, and in many cases the tumor reappears within two years after treatment.
- Shirley L Markant, Lourdes a Esparza, Jesse Sun, Kelly Barton, Lisa M Mccoig, Gerald a Grant, John R Crawford, Michael L Levy, Paul Northcott, David Shih, Marc Remke, Michael D. Taylor, and Robert J Wechsler-Reya. Targeting Sonic Hedgehog-associated medulloblastoma through inhibition of Aurora and Polo-Like Kinases. Cancer Research, September 2013 DOI: 10.1158/0008-5472.CAN-12-4258
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