Wilms’ tumor is the most common type of kidney cancer in children. Almost 90% of children with this cancer can be cured with a combination of surgery, chemotherapy, and radiation. However, aggressive disease and cancer that returns after therapy are much more difficult to treat.
Researchers have been searching for a cause of Wilms’ tumor resistance to treatment. They have looked for a molecular indicator, or biomarker, so they can identify people with resistant disease earlier. This could help doctors precisely tailor treatment to overcome this resistance.
Now a team led by MSK Kids cancer biologist and pediatric oncologist Alex Kentsis has uncovered a biomarker for resistance in children with Wilms’ tumor. The researchers pinpointed the biomarker using a recently developed tool for molecular analysis called proteomics. They found that a protein in the urine of children with Wilms’ tumor can indicate the likelihood that the cancer will come back after treatment. If the protein, prohibitin, is present at high levels at diagnosis, the tumors are likely to develop resistance to chemotherapy and persist.
“This biomarker will help us know ahead of time those children for whom standard therapy should cure Wilms’ tumor and those for whom improved treatments are needed,” Dr. Kentsis says. “We also discovered how prohibitin causes treatment resistance, which should help in developing drugs to block this effect in Wilms’ tumor and other refractory cancers, many of which overexpress prohibitin.”
The results are published in the Journal of Clinical Investigation Insight.
A Long Collaboration
The finding is the result of a decade-long collaboration among Dr. Kentsis, Elizabeth Mullen of the Dana-Farber Cancer Institute, and Hanno Steen of Boston Children’s Hospital, in partnership with the Children’s Oncology Group.
The research team collected urine from children with various kidney tumors and from healthy children. Using an advanced technique called mass spectrometry proteomics, which can analyze thousands of proteins at once, they looked in the urine for specific proteins that are associated with certain tumors.
Early in the process, the researchers found that a protein called PGBD5 was a marker for rhabdoid tumors, a rare but very aggressive childhood cancer. This led to a landmark discovery by Dr. Kentsis’s Sloan Kettering Institute laboratory that an unanticipated genetic characteristic may be the cause of many childhood cancers. The breakthrough also pointed to new treatment strategies to target this process in cancer cells.
For Wilms’ tumor, the researchers hoped to find the best biomarker so that they could precisely tailor treatment for individuals and isolate targets for improved therapy. They looked for specific proteins that are present at high levels in the urine of children with Wilms’ tumor that has returned, or relapsed, after surgery and chemotherapy.
“We identified a number of biomarkers associated with tumor relapse,” Dr. Kentsis says. “After learning the significance of prohibitin, we wanted to understand exactly how it causes treatment resistance in cancer cells.”Back to top
Essential to Cancer Cell Survival
Michael Ortiz, a clinical investigator and pediatric oncologist at MSK Kids and first author of the JCI Insight paper, confirmed through laboratory experiments that prohibitin is overexpressed in Wilms’ tumor cells. This expression is even higher in people with advanced disease. Prohibitin is required for the survival and growth of cancer cells in response to chemotherapy. Normally, cancer cells treated with chemotherapy die, but high levels of prohibitin interfere with this process, helping cancer cells survive.
Prohibitin is also overexpressed in a variety of other solid tumors. In particular, recent work by Anton Henssen in Germany, in collaboration with Drs. Ortiz and Kentsis, demonstrated its importance in neuroblastoma, another common childhood tumor that remains difficult to treat. Drugs that target high levels of prohibitin are expected to improve cure rates for people with Wilms’ and other refractory tumors.
“Research like this will allow us to devise new therapeutic strategies to eliminate toxic chemotherapy for children who won’t benefit and to overcome treatment resistance for children for whom current therapy is not sufficient to be a cure,” Dr. Kentsis says.Back to top