Dr. Nemechek’s study plans to build on recent findings from her team’s whole genome CRISPR-based screen studies targeting leukemia stem cells.

Treatment of pediatric leukemia often involves the use of high doses of anthracyclines, such as doxorubicin (DXR). Doxorubicin is immunosuppressive and often results in severe side-effects including cardiotoxicity, when cancer treatments damage the heart, and development of secondary cancers. Low-dose DXR has shown promise in targeting therapy-resistant leukemia stem cells (LSCs) and reducing immune checkpoint (IC) gene expression, such as PD-L1, making LSCs more vulnerable to immune attack.

While the study team has had success in eliminating therapy resistant LSCs by using low dose doxorubicin as a targeted therapy, recent advances in cutting-edge whole genome screens has allowed them to investigate different dosing effects of this treatment in the context of knocking down each individual gene in the genome.

The team conducted a whole genome CRISPR screen to identify mechanisms and genetic collaborators of drug sensitivity vs. resistance in leukemia cells. This led to the identification of the epigenetic “reader” ZMYND8, which has known roles in the DNA Damage Response (DDR), transcriptional regulation, and cancer progression.

According to Dr. Nemechek, preliminary data indicates that ZMYND8 increases leukemia cell sensitivity to doxorubicin while its loss drives therapy resistance. She and her team will further investigate the role of ZMYND8 in response to stimulating the immune system vs. exposures to the cytotoxic drug doxorubicin as well a its role mediating increased drug sensitivity.

“Ultimately, our goal is to discover and develop new or synergistic targeted therapies that will target the leukemia cells that resist current treatments and drive disease recurrence,” said Dr. Nemechek.

Multi-principal investigators on the study include Scott Younger, PhD, Genomic Medicine Center, John Perry, PhD, Hematology/Oncology/BMT, Children’s Mercy. Soumen Paul, PhD, University of Kansas Medical Center, acts as a co-investigator.

Dr. Park’s study looks at peptides on glioblastoma invasion and their connection to CRK and CRKL adaptor proteins.

Glioblastoma is the most common and most aggressive primary malignant brain tumor and currently, the only successful treatment of it is to be surgically removed. Glioblastoma cells easily spread to neighboring healthy brain tissues, which makes it hard to completely remove it surgically and thus means the cancer is likely to come back.

Dr. Park and his team are studying how to block the ability of glioblastoma cells from spreading to neighboring tissues. They’re doing this by looking specifically at the adaptor proteins known as CRK and CRKL, which are often found in elevated levels within glioblastoma cells. CRK and CRKL play a significant role in the tumor’s aggressive behavior.

Dr. Park and his team have developed peptides that bind to CRK/CRKL and prevent them from having interactions. They are studying if restricting or wearing down the CRK and CRKL proteins using these peptides will keep glioblastoma from spreading.

“The proposed approach is innovative because it designs antagonist peptides and develops delivery methods for designer peptides to target protein-protein interactions and block glioblastoma cell motility,” said Dr. Park. “The research is significant because it establishes critical knowledge, strategy, and tools for developing CRK and CRKL inhibitors for blocking glioblastoma invasion.”

Co-investigators include Hung-Wen (Henry) Yeh, PhD, Children’s Mercy Kansas City, Stefan Bossmann, PhD, University of Kansas Medical Center, Anuradha Roy, PhD, Justin Douglas, PhD, and David Johnson, all of the University of Kansas.

Dr. Prosser-Dombrowski’s study looks to better understand the underlying drivers of leukemia in infants. As she explains, infants with leukemia have a higher risk of dying from their cancer than older children and need more effective, less toxic treatment. Older children have benefited from new therapies that can precisely target their cancer, but these targets have been missing in infants. Further studies are needed to understand the underlying drivers of leukemia in infants so that targeted treatments can be developed.

She and her team plan to apply new studies, supported with recent technological advances, to understand changes in the genetic code, gene expression and its regulation, and the specific proteins present in infant leukemia cells.

“With our interdisciplinary team and resources, including our experimental model of developing infant leukemia and available patient samples, we will establish a comprehensive signature of infant leukemia biology that will provide a foundation for therapy development,” said Dr. Prosser-Dombrowski.

Team members include: Midhat Farooqi, MD, PhD, Clinical Genetics, Genomic Medicine Center, Co-PI; John Perry, PhD, Hematology/Oncology/BMT, Co-I; Jay Vivian, PhD, Clinical Genetics, Co-I; Irina Pushel, PhD, Genomic Medicine Center, Co-I; Michael Washburn, PhD, University of Kansas Medical Center, Co-I; Jacqelyn Nemechek, PhD, Hematology/Oncology/BM, collaborator; and Priyanka Prem Kumar, BS, Clinical Genetics, collaborator.

Dr. Ramsey and Dr. Flatt’s study looks at the metabolism of mercaptopurine (6MP) in children with acute lymphoblastic leukemia to understand why some patients experience more toxicity than others.

Some pediatric patients with leukemia are more prone to toxic side effects than others, limiting the doses administered and treatment options available. Mercaptopurine (6MP) is a chemotherapy drug. It interferes with the growth of cancer cells and can reduce immune system activity.

Variants in two genes have already been identified in the metabolism pathway that increase risk for toxicity. These two genes, TPMT and NUDT15, are tested in routine clinical care before administering 6MP so the dose can be adjusted if necessary. The team explains that there are many other enzymes that likely contribute to variability in 6MP metabolism and associated toxicities.

The study team will recruit pediatric patients for an observational study of the metabolites found in the blood and urine that have been associated with toxicity.

“We will look for genetic reasons for differences in metabolism and toxicity, with the goal of using genetics to optimize dosing and improve clinical outcomes for Hispanic patients treated with 6MP,” said Drs. Ramsey and Flatt. “Our long-term goal is to understand what contributes to this variability in toxicity, specifically for mercaptopurine (6MP), and how we may be able to adjust treatment to avoid toxicity.”

Co-investigators include Midhat Farooqi, PhD, MD, Paul Toren, PhD, Robert Tessman, PhD, Erin Boone, PhD, and Brooke Fridley, PhD, all of Children’s Mercy Kansas City.

Dr. Vivian’s study looks at targeting the autophagy pathway as a possible strategy for treatment of leukemia.

Infants with acute lymphoblastic leukemia face a terrible prognosis - only about one out of three survive because the leukemia becomes resistant to all available treatments. Most of these cancers involve rearrangement of the KMT2A (KMT2A-r) gene on chromosome 11.

Autophagy is a normal cellular process where a cell "eats" its own components, in essence recycling old and damaged proteins and organelles within a cell. Recent studies have suggested that autophagy becomes highly activated in cancer cells in response to many therapies, and this activation may play a role in the cancer resistance to these treatments.

This study will focus on the potential for using compounds that target and change autophagy as a new technique to treat early onset childhood leukemia. It includes the discovery of new treatments that alter autophagy activity as well as how these new drugs may enhance current and new therapies for childhood leukemia.

“It is of critical importance to improve the extremely poor prognosis of pediatric leukemias, and to determine additional molecular pathways in leukemia that influence both existing chemotherapeutic and investigational drug response,” said Dr. Vivian. “These studies will lay the groundwork for new therapies to improve the prognosis of many difficult to treat childhood cancers.”

Co investigators include John Perry, PhD, Children’s Mercy Kansas City, and Scott Weir, PharmD, PhD, University of Kansas Medical Center.

Dr. Yadav’s study looks at developing precision medicine strategies to treat diffuse intrinsic pontine gliomas (DIPGs). DIPGs are the most aggressive pediatric brain tumors. There are no treatment options beyond conventional ones, such as radiotherapy, and that isn’t normally successful.

His study focuses on the primary mutation associated with these tumors: H3K27M, a genetic alteration that affects histone H3, a protein involved in epigenetic regulation and leading to oncogene activation.

The long-term goal is to enhance treatment options for H3K27M-mutant DIPGs by identifying and validating new therapeutic agents and combinations that specifically target the unique vulnerabilities associated with this mutation. The team performed high-throughput drug screening, which identified six drugs more effective against H3K27M-mutant cells. From there, they selected the top five - Gemcitabine, Cytarabine, Cladribine, Floxuridine, and Pyrimethamine - based on their potent activity and ability to cross the blood-brain barrier.

The team will explore the effectiveness of these drugs, understand how the compounds restore epigenetic regulation that was disrupted by the H3K27M mutation, and explore therapeutic combinations.

“By identifying and validating new therapies for DIPG, this project has the potential to significantly impact treatment strategies and patient survival, contributing to broader efforts in cancer research and therapy development across the Midwest and beyond,” said Dr. Yadav.

Co-investigators include Kevin Ginn, MD, Children’s Mercy, and Anuradha Roy, PhD, The University of Kansas.