Researchers Building Childhood Cancer Isoform Atlas to Find Immunotherapy Targets

CHOP and Penn researchers will use Childhood Cancer Data Initiative Data to identify isoforms for immununotherapy targets.

By Lauren Ingeno

Although cancer is the leading cause of death by disease among children in the United States, the diagnosis is still rare, making it difficult for researchers to gather enough data to answer important scientific questions.

To address this challenge, Congress approved funding for the National Cancer Institute's Childhood Cancer Data Initiative (CCDI) in 2019. The goal of the CCDI is for medical institutions to collect and share data from every child, adolescent, and young adult diagnosed with cancer, to speed up diagnosis and inform treatment for all types of childhood cancers.

With new funding from the initiative, researchers at Children's Hospital of Philadelphia and the University of Pennsylvania will use CCDI data to develop, apply, and disseminate informatics tools that will help to identify new pediatric cancer immunotherapy targets by building a Childhood Cancer Isoform Atlas.

"Our lab has a long-standing interest in developing and applying technologies for studying RNA and protein isoform diversity," said Yi Xing, PhD, director of CHOP's Center for Computational and Genomic Medicine, who is leading the NCI project with Richard Aplenc, MD, PhD, CHOP Research Institute's assistant vice president and chief clinical research officer. "One of the key aims of this project is to identify isoforms that could be targeted by immunotherapy and lead to the development of novel therapies for hard-to-treat pediatric cancers."

Messenger RNA, or mRNA, is the genetic material that tells the body how to make proteins. In a process called splicing, nascent precursor mRNA can be cut and joined, or spliced, into mature mRNA prior to serving as instructions for protein synthesis. During splicing, certain regions of precursor mRNA (exons) remain, while other regions (introns) are removed.

Sometimes, the spliceosome (a cellular machine that catalyzes splicing) creates variability by skipping or including exons in alternative ways. This "alternative splicing" process allows a single gene to generate multiple proteins, or isoforms, which have different amino acid sequences with similar or distinct functions. However, the operation can easily go awry, leading to malfunction, and ultimately, disease.

Prior research suggests that these protein isoforms could potentially be targets for immunotherapy, the treatment that harnesses a patient's immune system to fight cancer.

"Protein isoforms formed from abnormal alternative RNA splicing are compelling yet understudied tumor antigens," Dr. Xing said.

To discover these potential targets, Dr. Xing and his research team previously created a computational platform, called IRIS (Isoform peptides from RNA splicing for Immunotherapy target Screening), which incorporates multiple informatics approaches and integrates large-scale RNA and protein data to uncover tumor antigens that arise due to alternative splicing. The Proceedings of the National Academy of Sciences published the CHOP research team's work in May 2023.

For their CCDI project, Dr. Xing and colleagues will expand upon their work with IRIS, applying and enhancing their tools to the field of pediatric cancer to aggregate and analyze the CCDI datasets. They plan to leverage novel sequencing technologies and informatics tools for RNA and protein isoform analysis as well as multi-omic "big data" integration.

"To develop and apply our tools in the context of a unique NCI initiative, I think that provides some exciting opportunities to eventually develop novel therapies for pediatric cancers," Dr. Xing said.

All software developed in this project will be made open source, readily usable on NCI-supported cloud computing systems, and freely available to the research community.