Background: Wilms’ tumor is the most common type of kidney cancer in children. Almost 90 percent of people with this cancer can now be cured with a combination of surgery, chemotherapy, and radiation, but aggressive or recurrent disease is much more difficult to treat. In collaboration with the Children’s Oncology Group, researchers from MSK have been searching for a cause of treatment resistance and a molecular indicator, or biomarker, that would enable them to identify children with resistant disease earlier and tailor treatment to overcome drug resistance.
Findings: The MSK Kids research team, led by cancer biologist and pediatric oncologists Alex Kentsis, MD, PhD, and Michael Ortiz, MD, together with colleagues from Harvard Medical School, used proteomics, a recently developed tool for molecular analysis, to identify urine biomarkers in children with kidney cancer. They found that a protein in the urine of children with Wilms’ tumors can indicate the likelihood that the cancer will relapse. If prohibitin is present at high levels, the tumors are likely to develop resistance to chemotherapy and persist. Prohibitin is also overexpressed in a variety of other solid tumors. Drugs that target high levels of prohibitin are expected to improve cure rates for people with Wilms’ and other refractory 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 about an unanticipated genetic mechanism that may be the cause of many childhood cancers, along with new treatment strategies to target this process in cancer cells. For Wilms’ tumors, the researchers hoped to find the best biomarkers to precisely tailor treatment for individuals and to identify targets for improved therapy. They looked for specific proteins that are present at high levels in the urine of children whose Wilms’ tumors returned, or relapsed, after surgery and chemotherapy treatments.
Bottom Line: MSK Kids researchers discovered that a protein, prohibitin, in the urine and tumors of people with Wilms’ tumors can indicate the likelihood that the cancer will relapse. If prohibitin is present at high levels, the tumors are likely to develop resistance to chemotherapy and persist.
Journal: “Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumor” was published in JCI Insight on August 8, 2019. Dr. Kentsis is the senior and corresponding author, along with Hanno Steen and Elizabeth Mullen from Harvard Medical School.
Expert Commentary: “This biomarker will help us identify ahead of time those children for whom standard therapy should cure Wilms’ tumors 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’ and other refractory cancers, many of which overexpress prohibitin.
“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 cure,” Dr. Kentsis continues.
About MSK Kids
MSK Kids, Memorial Sloan Kettering’s pediatric program, is here for all children, young adults, and families facing childhood cancer. With our specialized expertise and care focused on the individual child, we’re proud to say that more families turn to us for cancer care than any other hospital in the United States. And as pioneers in research, our physicians and scientists fight harder than anyone else to develop and deliver more-effective strategies to prevent, treat, and ultimately, cure childhood cancer — for all of our patients at MSK Kids and those everywhere. www.mskcc.org/pediatrics
About Memorial Sloan Kettering
We are the world’s oldest and largest private cancer center, home to more than 18,000 physicians, scientists, nurses, and staff united by a relentless dedication to conquering cancer. As an independent institution, we combine 130 years of research and clinical leadership with the freedom to provide highly individualized, exceptional care to each patient. We are consistently ranked the number-one hospital for cancer care in the Northeast and among the top two cancer hospitals nationwide. And our always-evolving educational programs continue to train new leaders in the field, here and around the world. www.mskcc.org.