Scientists at St. Jude Children’s Research Hospital reversed an aggressive cancer, returning malignant cells to a more normal state. Rhabdoid tumors are an aggressive cancer that lacks a key tumor suppressor protein. The findings showed that with the tumor suppressor missing, deletion or degradation of the quality control protein DCAF5 reversed the state of the cancer cells. These results suggest that a new approach to curing cancer may be possible: returning cancer cells to an earlier, more normal state rather than killing cancer cells with toxic therapies. The results were published today in Nature.
“Rather than creating a toxic event that kills the rhabdoid cancer, we were able to reverse the state of the cancer by returning the cells to normal,” said senior author Charles WM Roberts, MD, PhD, executive vice president and director of St. Jude Comprehensive. Cancer Center. . “This approach would be ideal, especially if this paradigm could also be applied to other cancers.”
“We found a dependency that actually reverses the cancer state,” said first author Sandi Radko-Juettner, PhD, a former student at St. Jude’s Graduate School of Biomedical Sciences and now research program director of the Neoplasms Program. St. Jude Hematology. “Standard cancer therapies work by causing toxicities that also damage healthy cells in the body. Here, it appears that we are instead solving the problem caused by the loss of a tumor suppressor in this rhabdoid cancer.”
Drugging the unreachable
In many cancers, there is no easily druggable target. Often these cancers are caused by a lack of a tumor suppressor protein, so there is nothing to attack directly since the protein is missing. The loss of tumor suppressors is much more common than a protein gaining the ability to cause cancer. Consequently, finding a way to therapeutically intervene in these tumors is a high priority. Researchers were looking for a way to treat an aggressive set of cancers caused by loss of the tumor suppressor protein SMARCB1 when they found a new treatment approach.
The St. Jude group discovered that a poorly studied protein, DCAF5, was essential for rhabdoid tumors lacking SMARCB1. Initially, they identified DCAF5 as a target, using the Dependency Map (DepMap) portal, a database of cancer cell lines and genes critical for their growth. DCAF5 was one of the main dependencies in rhabdoid tumors. After the initial finding, scientists genetically deleted or chemically degraded DCAF5. The cancer cells returned to a non-cancerous state and persisted even in a long-term mouse model.
“We saw a tremendous response,” Roberts said. “The tumors melted.”
Eliminate quality control to reverse cancer
Normally, SMARCB1 is an essential component of a larger chromatin regulatory protein complex called the SWI/SNF complex. Unexpectedly, the study found that, in the absence of SMARCB1, DCAF5 recognizes SWI/SNF as abnormal and destroys the complex. When degraded by DCAF5, the researchers showed that SWI/SNF reforms and maintains its ability to open chromatin and regulate gene expression. Although the level of SWI/SNF activity in the absence of SMARCB1 was lower than usual, it was sufficient to completely reverse the cancer state.
“DCAF5 is doing quality control to ensure these chromatin machines are built well,” Roberts said. “Think of a factory assembling a machine. Quality checks are needed to examine and find faults and remove it from the line if it does not meet standards. DCAF5 is conducting quality assessments for the assembly of SWI/SNF complexes, he told the cell to get rid of the complexes if SMARCB1 is absent.
“Mutation of SMARCB1 turns off genetic programs that prevent cancer. By targeting DCAF5, we are turning those genetic programs back on,” Radko-Juettner said. “We are reversing the state of the cancer because the cell becomes more ‘normal’ when DCAF5 does not target these complexes for destruction.”
Future therapeutic opportunities to reverse cancer
“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 targetable by drugs. We showed that when DCAF5 is absent, the mice had no discernible health effects, so we could potentially target DCAF5. This can kill the cancer cells, but it should not affect healthy cells. “Therefore, targeting DCAF5 has the potential to avoid the toxicity of off-target radiation or chemotherapy, making it a promising therapeutic avenue to pursue.”
Beyond DCAF5, the findings could have implications for other cancers caused by the loss of a tumor suppressor.
“We’ve demonstrated a beautiful proof of principle,” Roberts said. “Many types of cancers are caused by the loss of tumor suppressors. We hope we have opened the door to thinking about new ways to address at least some of them by reversing, rather than killing, the cancer.”