Scientists at St. Jude Children's Research Hospital have achieved a pivotal advancement in the fight against cancer. Their groundbreaking research has led to the reversal of an aggressive form of cancer, steering malignant cells back towards a more normal state. The focus of this transformative study was on rhabdoid tumors, a particularly aggressive type of cancer characterized by the absence of a crucial tumor suppressor protein. The research findings, published in the esteemed journal Nature, have unveiled a promising new approach to combating cancer, potentially revolutionizing the existing treatment paradigm.
Lead researcher, Dr. Charles W.M. Roberts, MD, PhD, Executive Vice President and Director of St. Jude Comprehensive Cancer Center, expressed the profound significance of this breakthrough, stating, "Rather than making a toxic event that kills rhabdoid cancer, we were able to reverse the cancer state by returning the cells toward normal. This approach would be ideal, especially if this paradigm could also be applied to other cancers."
The study's first author, Dr. Sandi Radko-Juettner, PhD, emphasized the innovative nature of this research, highlighting the departure from traditional cancer therapies, which often result in harmful toxicities to healthy cells. "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," she stated.
The research team's groundbreaking approach focused on addressing a critical challenge in cancer treatment – the absence of easily targetable proteins in certain types of cancer. Specifically, they honed in on rhabdoid tumors caused by the loss of the tumor suppressor protein SMARCB1. In their quest to find a viable treatment strategy, the scientists identified a relatively obscure protein, DCAF5, as a key player in the progression of rhabdoid tumors missing SMARCB1. Through the use of the Dependency Map (DepMap) portal, a database of cancer cell lines and the genes crucial for their growth, the researchers pinpointed DCAF5 as a top dependency in rhabdoid tumors.
The pivotal discovery unfolded as the researchers genetically deleted or chemically degraded DCAF5, leading to the remarkable reversion of cancer cells to a non-cancerous state. Dr. Roberts described the response as "spectacular," as the tumors exhibited a significant regression, demonstrating the potential of this novel approach.
The study shed light on the intricate interplay between the tumor suppressor protein SMARCB1 and the quality control protein DCAF5. In the absence of SMARCB1, DCAF5 was found to recognize the chromatin-regulating complex of proteins called the SWI/SNF complex as abnormal, subsequently destroying it. However, the researchers observed that upon degradation by DCAF5, the SWI/SNF complex re-formed, effectively reversing the cancer state by maintaining its ability to open chromatin and regulate gene expression.
Dr. Radko-Juettner elaborated on the implications of this discovery, stating, "The mutation of SMARCB1 shuts off gene programs that prevent cancer. By targeting DCAF5, we're turning those gene programs back on. We're reversing the cancer state because the cell is becoming more 'normal' when these complexes aren't targeted for destruction by DCAF5."
Moreover, the research findings have illuminated a promising avenue for future therapeutic interventions. Dr. Radko-Juettner emphasized the potential of targeting DCAF5 as part of a larger family of drug targetable DCAF proteins, offering a tantalizing prospect of selectively eradicating cancer cells without detrimental effects on healthy cells. This approach holds the promise of mitigating the off-target toxicity associated with conventional cancer treatments such as radiation or chemotherapy, underscoring its potential as a transformative therapeutic avenue.
Dr. Roberts underscored the broader implications of this research, envisioning a new frontier in cancer treatment. "We have demonstrated a beautiful proof of principle. 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."
