CBTTC Guest Blogger:
Pablo G. Cámara, PhD.
Assistant Professor of Genetics
University of Pennsylvania, Perlman School of Medicine
It is hard to conceive an event in life causing greater suffering and distress than learning one’s child has been diagnosed with cancer. Even more distressing to families and clinicians alike are the limited treatment options available to address and cure these diseases in children. Because childhood cancer is generally rare, there are multiple impediments associated with pediatric cancer research. Chiefly, making scientific inferences and extracting robust conclusions usually requires studies involving a large number of specimens. Doing so with a rare disease necessitates large multi-institutional efforts sustained over long periods of time. The logistics associated with these efforts are complicated and have direct and profound implications on the type of research studies that can be performed. Additionally, the amount of resources that pediatric cancer research receives from public funding agencies is limited and the field only attracts a small number of investigators. All of these challenges and limitations are remarkably represented in the case of childhood ependymoma.
Childhood ependymoma is a devastating type of brain cancer marked by its chronic and relapsing pattern. Pediatric ependymal tumors are circumscribed anaplastic gliomas that typically arise from the ventricular system or the cerebral hemispheres. They constitute nearly one third of the central nervous system neoplasms among children aged less than 3 years. The disease remains a significant therapeutic challenge, with a 5-year overall survival rate smaller than 55% among this age group. No chemotherapy has proven effective, so the standard treatment of the primary neoplasm consists of maximal safe resection and radiotherapy. However, nearly half of cases recur one or multiple times and survival after recurrence is low. Furthermore, this treatment often leads to long-lasting effects on the growth and development of the child.
When I started my laboratory at the University of Pennsylvania nearly two years ago, I realized it was a great opportunity to initiate a line of research in pediatric ependymoma. I am a young investigator interested in basic research, and driven by the curiosity and beauty of understanding living organisms, and Nature in general, at the microscopic scale. Why would a basic scientist find pediatric ependymoma to be a fascinating subject of research, aside from the obvious human reasons for wanting to cure childhood cancer? Let me explain my reasons for studying ependymoma and why I believe we are entering an exciting time where many of the above difficulties and limitations in the study of childhood ependymoma are being overcome in new and unique ways.
I find fair to say that the current knowledge about the mechanisms of development, progression, and relapse of pediatric ependymal tumors is comparable to that of adult brain tumors fifteen years ago. Childhood ependymomas can be classified into four molecular groups with distinct transcriptomic, genetic, epigenetic, and clinical features. However, the factors that underlie development and growth of these tumors remain largely unidentified. Although supratentorial tumors have been associated with RELA and YAP1 gene fusions (ST-RELA and ST-YAP1 molecular groups), no recurrent driver mutations have been identified in posterior fossa tumors (PF-A and PF-B molecular groups), which constitute 80% of childhood ependymomas. This lack of recurrent genetic alterations in ependymal tumors is often interpreted as a potential indication for other types of alterations, such as aberrant methylation events and other epigenetic modifications.
However, the specific alterations and molecular pathways in ependymoma are yet to be discovered. As a researcher in basic science, I find this current lack of understanding of the biology underlying these tumors particularly attracting, since it has the potential to lead to numerous discoveries. Additionally, I find particularly fascinating the relation of childhood ependymoma to human development. Childhood ependymoma can be thought of as a failure in the molecular processes that occur during the early stages in the development of the central nervous system. Being grade II or III tumors, these tumors preserve much of the morphology and characteristics of the healthy tissue. As such, it is possible to study ependymal tumors through the lens of developmental biology, and this is precisely the angle we are taking in my laboratory.
We are entering into an exciting era for the study of childhood ependymoma. The emergence of large multi-institutional tissue banks for pediatric brain tumors, and in particular the Children’s Brain Tumor Tissue Consortium (CBTTC), has given researchers the necessary resources to perform large-scale multi-omics studies of childhood ependymoma. Through its participating institutions, the CBTTC has stored flash-frozen tissue samples from 265 children with ependymoma, sequenced 397 whole genomes, and profiled the transcriptome of 197 ependymal tumors. These unique resources are available for investigators to begin uncovering the molecular mechanisms that underlie childhood ependymoma. Furthermore, the recent development of highly-parallelizable microfluidic devices for single-cell and single-nuclei transcriptomic and epigenomic profiling has enabled new ways of looking at these tumors, allowing for systematic characterizations of their cellular ecosystem. All these approaches and resources are being accompanied by numerous advances in the fast-moving field of computational biology. Critically, these efforts are being complemented by the development of mouse models for childhood ependymoma, which will set a new arena for testing and validating hypotheses.
With all these tools at hand, I find we are now poised to explore the heterogeneity, evolution, dynamics, and molecular pathways of childhood ependymoma in powerful and unique ways. Thus, we expect much progress during the next five years in understanding the biology of pediatric ependymal tumors, which we hope will translate into better and more efficient therapies for children with ependymoma.