First author Sandi Radko-Juettner, PhD, a former St. Jude Graduate School of Biomedical Sciences student, now a Research Program Manager for the Hematological Malignancies Program and senior author Charles W.M. Roberts, MD, PhD, Executive Vice President and St. Jude Comprehensive Cancer Center director.
Newswise — St. Jude Children’s Research Hospital scientists reversed an aggressive cancer, reverting malignant cells towards a more normal state. Rhabdoid tumors are an aggressive cancer which is missing a key tumor suppressor protein. Findings showed that with the missing tumor suppressor, deleting or degrading the quality control protein DCAF5 reversed the cancer cell state. These results suggest a new approach to curing cancer — returning cancerous cells to an earlier, more normal state rather than killing cancer cells with toxic therapies — may be possible. The results were published today in Nature.
“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, PhD, 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, PhD, 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.”
Drugging the un-targetable
In many cancers, there is no easily druggable target. Often, these cancers are caused by a missing tumor suppressor protein, so there is nothing to target directly as the protein is missing. Loss of tumor suppressors is much more common than a protein gaining the ability to drive cancer. Consequently, finding a way to intervene therapeutically in these tumors is a high priority. The researchers were looking for a way to treat an aggressive set of cancers caused by the loss of the tumor suppressor protein SMARCB1 when they found a new approach to treatment.
The St. Jude group found a little-studied protein, DCAF5, was essential to rhabdoid tumors missing SMARCB1. Initially, they identified DCAF5 as a target, using the Dependency Map (DepMap) portal, a database of cancer cell lines and the genes critical for their growth. DCAF5 was a top dependency in rhabdoid tumors. After the initial finding, the scientists genetically deleted or chemically degraded DCAF5. The cancer cells reverted to a non-cancerous state, persisting even in a long-term mouse model.
“We saw a spectacular response,” Roberts said. “The tumors melted away.”
Removing quality control to reverse cancer
Normally, SMARCB1 is an essential component of a larger chromatin-regulating complex of proteins 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 DCAF5 degrades them, the researchers showed that SWI/SNF re-forms and maintains its ability to open chromatin and regulate gene expression. While the SWI/SNF activity level in the absence of SMARCB1 was to a lesser extent than usual, it was nonetheless sufficient to reverse the cancer state fully.
“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.”
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 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.”
Beyond DCAF5, the findings could have implications for other cancers driven by the loss of a tumor suppressor.
“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.”
Authors and funding
The study’s other first author is Hong Yue of the Dana-Farber Cancer Institute and Harvard Medical School. The study’s other co-corresponding author is Eric Fischer, Dana-Farber Cancer Institute and Harvard Medical School. The study’s other authors are Katherine Donovan, Moritz Hunkeler, Shourya Burman and Anna Schmoker, Dana-Farber Cancer Institute and Harvard Medical School; Nada Mageed, Harvard Medical School; Behnam Nabet, Fred Hutchinson Cancer Center; Nathanael Gray, Stanford Cancer Institute; Jacquelyn Myers, Raymond Carter, Alexis Robertson, Priya Mittal, Zhexin Zhu, Baranda Hansen, Wojciech Rosikiewicz, Zhiping Wu, Meghan McReynolds, Scott Brown, Robert Mobley, Janet Partridge, Elizabeth Stewart, Shondra Pruett-Miller and Junmin Peng, St. Jude.
The study was supported by grants from the National Cancer Institute (NCI) (R01 CA113794, R01 CA273455 and R01 CA172152, K22 CA258805, R01 CA262188 and CCSG 2 P30 CA021765), the Garrett B. Smith Foundation, the St. Jude Children’s Research Hospital Collaborative Research Consortium on Chromatin Regulation in Pediatric Cancer, St. Jude Graduate School of Biomedical Sciences, Ruth L. Kirschstein National Research Service Award (F31 CA261150), National Institute on Aging (RF1AG068581) and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.
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