Making a difference with young cancer patients

Backed by the KPCRTF funding, Dr. Daret St. Clair and her team are diving deeper into their research on using biomarkers to predict and prevent chemotherapy-induced cognition impairment in children and young adults with acute lymphoblastic leukemia (ALL), the most common childhood cancer.

“The success of today’s ALL chemotherapy is very good, with most children achieving remission,” said St. Clair, professor of toxicology and cancer biology and James Graham Brown Endowed

Chair in Neuroscience at UK. “However, a high percentage of these children experience treatment-related brain injury. So if we can recognize the potential for these adverse effects earlier, we can intervene earlier and spare them from a lifetime of quality-of-life issues.”

Building upon their previous discovery that a major cause of chemotherapy-induced brain injury involves the generation of reactive oxygen species (ROS) as well as that extracellular vesicles (EVs) carry proteins damaged by ROS – St. Clair and team are now investigating whether EVs are, in fact, early biological messengers that anticipate chemotherapy-induced brain injury in children with ALL. The team also aims to determine whether the use of an FDA-approved ROS-inhibiting drug during chemotherapy may prevent these associated adverse effects.

“We are hopeful that through our research, we’ll be able to predict and prevent cancer therapy associated cognitive impairment in children with ALL, and that we may be able to expand this therapy to other pediatric cancers,” St. Clair said.

Although current treatments for pediatric ALL have high remission rates, some patients will still experience disease relapse, and relapses occurring in the central nervous system (CNS) are associated with poor outcomes. With the support of the KPCRTF, Dr. Jessica Blackburn and her team are investigating the use of circulating tumor DNA (ctDNA) from patients’ blood to identify ALL relapse in the CNS earlier than current clinical tests.

Using this method to detect relapse and metastasis has shown promise in solid tumors, but it has yet to be applied to ALL or CNS relapse in leukemia. Blackburn and her team are also developing a rapid test that physicians can use to determine the best treatment plan for their patients.

“The idea is that if we can detect the ctDNA released by cancer cells earlier than physicians can actually see the cancer cells in the patient, then the physician could start treatment earlier, which may lead to a better outcome for the patient,” said Blackburn, assistant professor of molecular and cellular biochemistry at UK.

KPCRTF’s support has already paved the way for her team to expand its funding.

“We were able to submit some of our preliminary data from this study to apply for another grant with the National Institutes of Health to explore even more areas of this science and take our lab in a new and exciting direction,” she said.

With the incidence of pediatric brain and CNS tumors (PBCNST) signifi cantly higher in Kentucky than in the United States as a whole and even higher among the state’s children living in Appalachia, a novel study to identify factors contributing to this high incidence is under way.

Made possible by KPCRTF support, the population-specific study is led by Dr. Eric B. Durbin and his team. Durbin, assistant professor of biomedical informatics at UK, is director of Markey’s Cancer Research Informatics Shared Resource Facility and director of the Kentucky Cancer Registry (KCR).

“Our study has collected the available pathology tissues for all Kentucky children diagnosed with PCNCST between 2000 and 2017, which is unique and may be the fi rst truly population-based study of its kind in the United States.”

Dr. Eric B. Durbin

Using data and pathology specimens from the KCR, its Virtual Tissue Repository and the NIH Kids First Data Resource Center, the researchers are identifying potential environmental exposures, assessing the cancer mutational landscape underlying PBCNST in Kentucky, and determining how genetic risk factors for PBCNST among Kentucky children compare with other children represented in the Children’s Brain Tumor Tissue Consortium. They are also implementing informatics infrastructures for data sharing with national PBCNST consortia.

“Other pediatric brain cancer tissue research relies on samples collected as part of a consortium or at a single institution,” Durbin said. “Our study has collected the available pathology tissues for all Kentucky children diagnosed with PCNCST between 2000 and 2017, which is unique and may be the fi rst truly population-based study of its kind in the United States.”

Despite the COVID-19 pandemic slowing research efforts across the world, Durbin and his team have been able to make headway on their study and secured a second round of funding from the state. They also have received support as part of a supplement to the Markey Cancer Center P30 grant from the National Cancer Institute to contribute additional data to the National Childhood Cancer Registry.

Ewing sarcoma – a bone and soft tissue cancer most commonly diagnosed in children and young adults – is primarily treated with cytotoxic therapies that can have several adverse effects.

There have been no advances in treating this cancer in decades. Building on their previous research in this area, Dr. Markos Leggas and Dr. Jurgen Rohr, both professors in the Department of Pharmaceutical Sciences at UK, are investigating a new drug, which is selectively toxic to Ewing sarcoma tumors, while it spares normal cells.

“Ewing sarcoma is driven by a transcription factor fusion called EWS-FLI1,” Leggas said, and when it is eliminated from Ewing sarcoma cells, the cancer dies, making it an ideal therapeutic target.” He and Rohr are working to determine the efficacy and safety of an EWS-FLI1–targeted therapy, including “how to use the drug in terms of dosing and frequency of administration, and what happens to the drug once it’s inside the body,” he said. The team also believes that this preclinical research, funded by both the KPCRTF and the DanceBlue Foundation, will be applicable to the treatment of other cancers in the future.

“There are a variety of different cancers whose malignancy depends on similar transcription factors,” Leggas said. “Demonstrating that these novel compounds are efficacious in Ewing sarcoma will provide proof of concept that cancer-driving transcription factors can be targeted with our novel compounds. So, there’s a lot at stake with this drug development project.”