“Rather than making a toxic event that kills rhabdoid cancer, we were able to reverse the cancer state by returning the cells toward normal,” said senior author Charles W.M. Roberts, MD, Ph.D., Executive Vice President and St. Jude Comprehensive Cancer Center director. “This approach would be ideal, especially if this paradigm could also be applied to other cancers.”
“We found a dependency which actually reverses the cancer state,” said first author Sandi Radko-Juettner, Ph.D., a former St. Jude Graduate School of Biomedical Sciences student, now a Research Program Manager for the Hematological Malignancies Program at St. Jude. “Standard cancer therapies work by causing toxicities that also damage healthy cells in the body. Here, it appears that we’re instead fixing the problem caused by the loss of a tumor suppressor in this rhabdoid cancer.”
According to the scientists, they were looking for a way to treat an aggressive set of cancer cells caused by the loss of the tumor suppressor protein SMARCB1 when they discovered the new approach: with the missing tumor suppressor, deleting or degrading the quality control protein DCAF5 (essential to rhabdoid tumors missing SMARCB1) reversed the cancer cell state, even in a long-term mouse model, suggesting a potential new path to combat cancer and return cancerous cells back to an earlier more normal state rather than killing them with toxic therapies.
“We saw a spectacular response,” Roberts said. “The tumors melted away.”
“DCAF5 is doing a quality control check to ensure that these chromatin machines are built well,” Roberts said. “Think of a factory assembling a machine. You need quality checks to examine and find faults and to pull it off the line if it doesn’t meet standards. DCAF5 is doing such quality assessments for the assembly of SWI/SNF complexes, telling the cell to get rid of complexes if SMARCB1 is absent.”
“The mutation of SMARCB1 shuts off gene programs that prevent cancer. By targeting DCAF5, we’re turning those gene programs back on,” Radko-Juettner said. “We’re reversing the cancer state because the cell is becoming more ‘normal’ when these complexes aren’t targeted for destruction by DCAF5.”
“From a therapeutic perspective, our results are fascinating,” Radko-Juettner said. “DCAF5 is part of a larger family of DCAF proteins that have been shown to be drug targetable. We showed that when DCAF5 is absent, mice had no discernable health effects, so we could potentially target DCAF5. This can kill the cancer cells but shouldn’t affect healthy cells. Targeting DCAF5 thus has the potential to avoid the off-target toxicity of radiation or chemotherapy, making it a promising therapeutic avenue to pursue.”
“We have demonstrated a beautiful proof of principle,” Roberts said. “Myriad types of cancers are caused by tumor suppressor loss. We hope we may have opened the door to thinking about new ways to approach targeting at least some of these by reversing, instead of killing, cancer.”
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