Browsing tumor library sparks understanding of drug resistance in childhood kidney cancer

When cancers relapse, especially ones with favorable outcomes, many questions need to be answered. What was the treatment plan? What is the molecular identity of the new tumor? How can it be treated now? Separate from these immediately urgent demands is the question that may impact countless future patients: Why did this happen?

Relapses represent a serious escalation in risk for patients. They usually originate from cells that bypassed previous treatment cycles and regrew into a tumor whose cells share the same resilient features. Drug resistance is one way tumor cells endure, meaning studies into how therapeutics and cancer cells interact are vital to providing patients with the most effective treatment programs at the outset.

Wilms tumor, which occurs in the kidneys, is the fourth most common type of cancer in children, but is still rare, with roughly 600 diagnoses per year in the U.S. About 90% of these cases have “favorable histology,” which means they should respond well to treatment based on tissue histology and tumor profiling. Andrew Murphy, MD, Department of Surgery, is exploring what happens when Wilms tumors do not fully respond to treatment and relapse. Through this work, he is helping clinicians gain the knowledge to explain to their patients why.

Wilms tumor samples set the stage for discovery

To begin this endeavor, Murphy needed a library, but rather than one filled with books, this library needed to contain patient-derived tumors, called xenografts. The rarity of Wilms tumor made this complicated, though, because samples for research are precious and hard to come by.

“For Wilms tumor, there is a real lack of model systems compared to other pediatric cancers, and very few commercially available cell lines,” Murphy said. “The ones that do exist are useful to a degree, but they lack many characteristics we know are present in patients’ tumors.”

In a 2019 paper published in Nature Communications, Murphy led the generation of a Wilms tumor xenograft library, complete with 45 patient-derived tumor samples. These samples spanned favorable histology tumors, those which appeared abnormal, called diffuse anaplastic tumors, relapsed tumors and bilateral tumors (affecting both kidneys).

“The purpose of developing that library was preclinical testing of novel therapies,” Murphy said. “We’ve since expanded the library and are now at over 120 xenografts available to the scientific community upon request.”

Library provides insight into drug sensitivity

Parallel to this, a multi-institutional phase 2 clinical trial called AREN1921, sponsored by the North America-based Children’s Oncology Group, launched in 2020. The trial tested new combination chemotherapies, including vincristine and irinotecan, for both favorable histology and diffuse anaplastic Wilms tumors. Due to the lack of model systems, the drug combinations lacked preclinical sensitivity data specific to Wilms tumor before the trial launched. However, Murphy’s library was well-positioned to provide these much-needed answers to prepare for future novel combination therapies.

In a 2025 paper published in the Journal of Pediatric Surgery, Murphy’s team characterized the sensitivity of diffuse anaplastic Wilms tumors to vincristine and irinotecan. This chemotherapy combo is often proposed as an effective option for relapsed or refractory (unresponsive) cancers. The researchers confirmed that diffuse anaplastic models generated from the xenograft library showed partial or complete response to the combination therapy.

“By defining the baseline response to vincristine and irinotecan in diverse anaplastic Wilms tumor patient-derived xenograft models, we’ve created a platform to design next-generation combination therapies rationally,” Murphy explained. “Integrating targeted agents with vincristine/irinotecan offers a compelling path toward more effective and durable treatments for anaplastic Wilms tumor.”

While the results were promising for these immediately high-risk cases, there was still the question surrounding drug resistance in favorable histology Wilms tumors: Why did this happen? To get answers, Murphy’s team exposed favorable histology Wilms tumors from the xenograft library to three commonly used chemotherapy agents — vincristine, actinomycin D and doxorubicin — until the cancer cells developed resistance.

Drug-resistant Wilms tumors tap into a drug pump

Published in 2026 in Cell Reports, the researchers identified two features that help drive chemotherapy resistance. First was the reactivation of gene programs that revert the kidney cells to an immature or stem cell–like state. Usually, tight restrictions are put in place at gene locations responsible for cell development once a cell finishes developing. The researchers found that this was not the case in drug-resistant cells.

“We noted reactivation of several developmental transcription factors which are characteristic of immature kidney cells during kidney development,” said Murphy.

This reactivation allowed the cells to proliferate with fewer guardrails but also released the tumor’s secret weapon: a drug pump. ABCB1 is a transporter protein that removes unnecessary chemicals from cells, protecting them from toxicity. This includes removing chemotherapies from cells. The researchers found that in drug-resistant Wilms tumors, ABCB1 production is elevated, enhancing the cell’s capacity to withstand chemotherapies.

The increase in ABCB1 is due to changes that alter how genes are expressed, called epigenetic changes. These changes thus appear to underlie the development of favorable histology Wilms tumor drug resistance.

“Our results imply that epigenetic transitions enable cells to shift into a stem-like state,” Murphy said. “To prevent the transitions that lead to chemotherapy resistance is the biggest takeaway. Using small-molecule inhibitors to block or reverse these transitions is how we aim to apply this knowledge.”

While these studies represent a vital step forward in understanding and treating Wilms tumors, many questions remain, especially regarding treatment for relapsed and refractory tumors. However, with the help of numerous collaborators, such as the ongoing SJWT21 trial exploring the use of proton therapy in patients with Wilms tumor, the xenograft library will continue to grow. As a result, the insights gained by Murphy and others into the biology of Wilms tumors will also continue to evolve and sharpen, paving the way for future clinical impact.