Advancements in Pediatric Brain Tumor Diagnosis and Understanding

Recent research from St. Jude Children's Research Hospital and its international collaborators has led to advancements in both the diagnosis and understanding of pediatric brain tumors. Developed by scientists, M-PACT, an AI-powered liquid biopsy tool, offers a new method for classifying pediatric brain tumors. Concurrently, separate studies have identified the cellular origin and a shared vulnerability in pineoblastoma and related tumors, and uncovered the mechanism by which ZFTA-RELA fusions drive pediatric ependymoma.

M-PACT: An AI-Powered Liquid Biopsy for Tumor Classification

St. Jude Children's Research Hospital scientists, in collaboration with institutions including the Hopp Children's Cancer Center Heidelberg (KiTZ) and the German Cancer Research Center (DKFZ), have developed M-PACT (Methylation-based Predictive Algorithm for CNS Tumors). This AI-driven tool utilizes liquid biopsies to classify pediatric brain tumors.

M-PACT analyzes circulating tumor DNA (ctDNA) found in cerebrospinal fluid, classifying tumors based on their DNA methylation patterns.

In a benchmarking test, M-PACT identified 92% of brain tumors, and in a validation cohort, it demonstrated an 88% accuracy in classifying embryonal CNS tumors. The tool is designed to differentiate between tumor relapse and secondary tumors, track changes in cancer aggression, and monitor treatment response.

Paul Northcott, PhD, a corresponding author and Director of the Center of Excellence in Neuro-Oncology Sciences (CENOS) at St. Jude, stated that M-PACT aims to advance liquid biopsy technology in pediatric neuro-oncology across various clinical scenarios. Co-first author Katie Han noted that M-PACT was specifically designed for ctDNA, rather than adapting existing tissue-based classifiers.

Co-first author Kyle Smith, PhD, from St. Jude, explained that M-PACT was trained using a deep neural network strategy, incorporating over 5,000 DNA methylation profiles from approximately 100 tumor types. This training involved computationally mixing large reference datasets with normal cell-free DNA datasets, allowing classification with minimal amounts of ctDNA.

Beyond tumor cells, M-PACT's sensitivity also allows it to identify non-cancerous cell types within the tumor microenvironment, which may offer insights into cancer interactions with normal cells. Dr. Northcott indicated that M-PACT's framework has potential applicability to other solid tumors and hematological malignancies, though informatics would need expansion for classification of the full spectrum of pediatric cancer types. These findings were detailed in Nature Cancer.

Shared Vulnerabilities Identified in Pineoblastoma and Related Brain Tumors

Researchers at St. Jude Children's Research Hospital, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and Uppsala University have identified the origin of pineoblastoma, a rare pediatric brain tumor, and discovered a shared dependency across multiple brain tumor types.

Through single-cell resolution profiling of the largest cohort of pineoblastoma tumors, scientists identified pinealocyte progenitors, an early cell population in the developing pineal gland, as most closely resembling these tumors. This suggests their role in pineoblastoma development. Mouse models were created to mimic human subtypes by perturbing pineoblastoma driver genes in these progenitors.

The study found that despite differing cancer drivers, all pineoblastoma subtypes shared a gene expression signature related to light sensitivity. Genes associated with photoreceptors and phototransduction, normally expressed in the pineal gland, were expressed at high levels in pineoblastoma.

This light-sensing signature was also observed in a subtype of Group 3 medulloblastoma and in retinoblastoma, highlighting a shared characteristic across anatomically distinct central nervous system tumor types.

Further investigation revealed that similar genes, transcription factors, and biomarkers of this program were shared among these tumor types. Using CRISPR technology to remove genes from this signature in pineoblastoma, medulloblastoma, and retinoblastoma cells, researchers observed that the tumors depended on these genes for survival. This discovery suggests a potential cross-tumor vulnerability and an avenue for exploring future therapeutic strategies. The results were published in Cancer Cell.

Mechanism Driving Pediatric Ependymoma Uncovered

Scientists at St. Jude Children's Research Hospital and Baylor College of Medicine have identified how ZFTA-RELA fusions, a common cause of pediatric ependymoma, contribute to the disease. The research, published in Nature, describes a mechanism by which fusion oncoproteins drive cancer.

The study found that the ZFTA-RELA fusion oncoprotein exploits open regions of the genome that regulate growth, thereby maintaining immature brain cells in an underdeveloped state. Stephen Mack, PhD, a co-corresponding author from St. Jude, noted that the gene programs are largely pre-set, and the fusion protein accesses and maintains these regulatory sites.

ZFTA-RELA mimics the activity of PLAG/L proteins, which typically activate cell development programs by binding specific DNA sequences.

While PLAG/L activity normally ceases upon development completion, ZFTA-RELA binds the same DNA sequence, keeping these developmental programs active and preventing cell maturation.

Alisha Kardian, a graduate student involved in the study, suggested that understanding how normal cells cease PLAG/L chromatin accessibility could offer strategies to counteract ZFTA-RELA oncogenic activity.

Researchers also observed that ZFTA/RELA ependymoma cells originate from a limited number of dominant ancestral cells. These cells' dominance was linked to an optimal ZFTA-RELA expression level, with both too little and too much expression being non-conducive to the observed effect. This finding may provide context for understanding tumor recurrence if even a few cells remain after therapy. Current treatments for pediatric ependymoma primarily involve surgery and radiation. Kelsey Bertrand, MD, a co-corresponding author from St. Jude, stated this research may contribute to understanding why ependymomas resist conventional chemotherapy and potentially lead to novel therapeutic approaches.