Dr. Fridley’s research aims to comprehensively examine the tumor microenvironment (TME) in Ewing sarcoma (EWS) tumors, focusing on how immune cell abundance, location and proximity to other cells may affect clinical outcomes. This study is positioned to be the first and largest spatially focused analysis of the EWS TME to date.

EWS is a rare bone and soft tissue cancer, primarily diagnosed in children and young adults. While most patients experience favorable long-term survival with standard chemotherapy, those with advanced or recurrent cancer following initial treatment face significantly lower survival rates. Hence, there is an urgent need for innovative therapies and reliable biomarkers to inform treatment strategies for this patient subgroup.

EWS tumors exhibit a complex TME that can influence clinical outcomes. Dr. Fridley’s team will analyze tumor tissue samples from 50 patients with EWS to assess features such as the abundance and spatial interactions of perinucleolar compartments (PNCs), tumor-infiltrating lymphocytes (TILs) and immunosuppressive cells. This work aims to clarify the connection between the TME and clinical outcomes, facilitate the development of new biomarkers for personalized therapy and inform novel therapeutic approaches targeting PNCs or harnessing TIL populations through immunotherapy.

“No study of this magnitude has been conducted to elucidate the tumor immune microenvironment of EWS and the potential role of PNCs in determining clinical outcomes,” said Dr. Fridley. “This research is critical to the advancement of new biomarkers to guide treatment decisions for patients with EWS.”

Co-investigators on this study include Terrie Flatt, DO, MA, Hematology/Oncology/BMT; John David Nolen, MD, PhD, Pathology and Laboratory Medicine; Melissa Gener, MD, Pathology and Laboratory Medicine; and Anders Meyer, MD, University of Kansas Medical Center.

Dr. Iwakuma and Dr. Godwin’s study will build on previous preclinical findings by developing antibody conjugated nanoparticles (ACNPs) that will help medications target Ewing sarcoma (EWS) cells and improve drug efficiency.

EWS is a rare pediatric cancer with an identifiable gene fusion that causes an abnormal transcription factor which is impenetrable by current therapies. Children’s Mercy and the University of Kansas Medical Center created the Ewing Sarcoma Consortium where researchers study pediatric cancer treatments and strive to develop advanced therapies. Dr. Iwakuma and Dr. Godwin’s study will focus on factors that affect cancer treatments like drug toxicity.

A previous study published by Godwin’s team showed two drug combinations that shrunk tumors in preclinical models. However, the side effects could be dangerous for pediatric patients. To reduce the risk, Drs. Iwakuma and Godwin are looking at creating a barrier out of ACNPs designed to attack EWS cells. They hypothesize that encapsulating medications in nanoparticles with biomarker antibodies will reduce drug toxicity.

This study bridges the gap in knowledge on treatment options for EWS, delivery options for cancer drugs and aids in the development of a Phase I therapeutic clinical trial for pediatric EWS patients.

“The proposed preclinical studies establish a novel drug delivery system of a highly effective synergistic drug combination of mitotic inhibitors that can be leveraged towards a future early phase clinical trial for EWS,” said Dr. Iwakuma. “The impact of this research will be highly significant as it addresses the need for novel therapies with safe and effective drug delivery approaches through ACNPs.” 

University of Kansas Medical Center researchers — Stefan Bossmann, PhD, and Leonidas Bantas, PhD — are co-investigators on this study.

Dr. Parrales Briones’ study plans to investigate whether clinically available drugs kill osteosarcoma cells that have mutated or lack p53, a process referred to as “p53 synthetic lethality.”

The tumor suppressor protein, p53, is mutated or absent in nearly half of diagnosed cancers. Preclinical findings showed that a combination of reactive oxygen species (ROS) inducers and DNA-damage repair inhibitors can kill cancer cells deficient in p53.

Dr. Parrales Briones’ team hypothesizes that a combination of an FDA-approved ROS inducer and a DNA-damage repair inhibitor will work together to kill osteosarcoma cells lacking p53 and cause minimal side effects. This study will analyze what is the best combination, potential side effects and whether different amounts of p53 affect drug efficiency.

The study intends to help expedite the development of advanced treatment options for pediatric cancer and a new clinical trial to test these findings.

“Development of efficient and safe treatments for osteosarcoma and other cancers require the precise identification of cancer-specific targets and vulnerabilities. Our study will contribute to identifying such vulnerabilities and help in developing cancer-specific treatments with less side effects, which is particularly important in pediatric cancers,” said Dr. Parrales Briones.

Michael Hageman, PhD, University of Kansas, serves as a co-investigator.

Dr. Ranjan’s study plans to test how the gene MDM4 affects the production of the essential molecule NAD⁺, and how it interacts with medications blocking the enzyme nicotinamide phosphoribosyltransferase (NAMPT).

Many pediatric cancers — like Ewing sarcoma, osteosarcoma and acute myeloid leukemia — overexpress the MDM4 gene. MDM4 blocks the tumor suppressor protein, p53, but recent studies have found that MDM4 could also negatively affect cancer growth in tumors lacking p53. However, there are no treatments that target tumors with high levels of MDM4 missing p53.

Preclinical findings show that tumors with high levels of MDM4 without p53 are sensitive to NAMPT inhibitors which suppresses the ability to produce NAD⁺. Dr. Ranjan’s team will analyze why MDM4 causes sensitivity to medications blocking NAMPT and how MDM4 affects NAD⁺ production. Dr. Ranjan hypothesizes that tumors with overexpressed MDM4 suppress NAD⁺ which causes a sensitivity to NAMPT-blocking medications.

This study aims to support the advancement of biomarker-guided treatments for children with high-risk cancers overexpressing MDM4.

“Understanding why MDM4‑overexpressed tumors are vulnerable to NAMPT inhibitors may allow us to match the right therapy to the right patient, helping us move toward more precise, biology‑informed treatment strategies in pediatric oncology,” said Dr. Ranjan.

Co‑investigator on this study is Anita Saraf, PhD, University of Kansas.