Exploring Pediatric Neuro-Oncology

By Benjamin Traubici

Cancer is the second leading cause of death in children under the age of 15.1 The most common childhood cancer in this age group is leukemia, accounting for 28% of childhood cancers, followed by brain cancer and lymphoma, which account for 26% and 19% respectively.1 However, brain cancer is currently the leading cause of death and morbidity among all childhood cancers.2 The large-scale impact of childhood cancer means that improving clinical outcomes remains an important focus for many researchers and institutions, including Dr. Uri Tabori, a clinician-scientist focused on children with brain tumours.

Dr. Tabori completed his medical degree at the Hadassah School of Medicine in Jerusalem, Israel. He completed his pediatric residency in Israel at the Sorasky Medical Center (SMC), followed by his pediatric hematology and oncology fellowship at the Chaim Sheba Medical Center (CSMC). After working as a staff physician at the CSMC and the SMC, he completed his research and clinical fellowship at the Hospital for Sick Children (SickKids). Now, as a professor at University of Toronto’s Institute of Medical Science (IMS) and an oncologist at SickKids, he treats children with brain cancer and conducts cancer research, concentrating on neuro-oncology.

Dr. Tabori chose to pursue a specialty in pediatric oncology because at the time, he felt that this field was on the cusp of incredible advancements. He believed that progress in molecular biology and genomic research would help provide important strides to improve clinical care for children with cancer. And he was right. What Dr. Tabori finds important about his work is that it begins from a clinical perspective, finds its way into molecular research, and then translates back to new therapies for children.

A major focus of Dr. Tabori’s research is on pediatric cancer predisposition, which refers to conditions in which there is an increased risk of developing cancer at a young age. His research found that many patients with childhood cancer have mutations in the mismatch repair and polymerase genes. These mutations cause dysfunctional DNA proofreading, or simply, the inability to repair mistakes in the DNA code, which lead to hypermutation in every cell in the body, significantly increasing the risk of developing cancers. After exploring the implications of these mutations, Dr. Tabori contemplated on how to help these patients. Since it is a rare condition, he and many other researchers formed an international consortium, called The International Replication Repair Deficiency Consortium (IRRDC),3 which now includes institutions in more than 50 countries. The IRRDC provides free molecular testing and counselling for patients around the world, including in low- and middle-income countries. The IRRDC also collects data in order to learn more about these mutations and create animal models to test new drugs and treatments for patients.3 The IRRDC has already produced significant findings on the impact of these mutations, such as the fact that the mutational burden of cancers arising from these mismatch repair and polymerase deficiencies is 1000 times more than other childhood tumours.4 Even more importantly, they also discovered that these cancers with hypermutations are highly immunogenic, so they are responsive to immunotherapy.4 Thanks to his research as part of the IRRDC, physicians can find these deadly tumours early and offer innovative treatments beyond the standard cytotoxic chemotherapy and radiation therapy.

Dr. Tabori believes that translational research like this is an essential part of healthcare and a pivotal reason why he entered the field: “You take a condition, you think, you work in parallel, you do clinical, molecular, and animal models, and you find therapy for these children.” This is the path he tries to take in his research, to identify clinical problems and use research to find treatments for patients.

Currently, the standard practice for treating children with brain cancer is surgery followed by radiation, and then chemotherapy. This course of action can be risky to the patient since radiation is damaging to the developing brain, so an important aspect of Dr. Tabori’s research is to analyze the effectiveness of immunotherapy, which uses the immune system to attack cancers. Dr. Tabori focuses on a specific type

Dr. Uri Tabori

MD, Professor in the Institute of Medical Science, and Medical Biophysics and Paediatrics Department at University of Toronto; Section head of Neurooncology in the Division of Haematology/ Oncology at The Hospital for Sick Children; Garron Family Chair in Childhood Cancer Research; Lead of International Replication Repair Deficiency Consortium (IRRDC)

Photo provided by Dr. Uri Tabori of immunotherapy called immune checkpoint inhibition. An immune checkpoint is active when proteins on the surface of immune cells called T cells form a connection with partner proteins on tumour cells.5 This checkpoint sends a signal to the T cell that prevents it from attacking the cell; this is usually used in our bodies as a way for our immune systems to recognize our own healthy tissues and prevent it from attacking them, but cancer cells have learned to express these proteins as well to mask as normal tissues and “evade” destruction by T cells.

Immune checkpoint inhibitors block checkpoint proteins from binding with partner proteins, thus allowing T cells to attack tumour cells. Some checkpoint proteins that these inhibitors act against include CTLA-4, PD-1, and PD-L1.5 Dr. Tabori helps to conduct clinical trials utilizing immunotherapy, sometimes in conjunction with colleagues around the world, to understand its effects and hopefully utilize it more in clinical practice, preventing the deleterious side effects of radiation and chemotherapy.

Translational researchers like Dr. Tabori are always looking for ways to improve clinical practices, and in his case part of his work has focused on improving diagnostic procedures for brain tumours. Today, to reach a definitive diagnosis for a brain tumour you must perform surgery and do a biopsy to analyze tissue. However, Dr. Tabori is developing non-invasive “liquidbiopsy” diagnostic techniques that detect mutations in the cerebrospinal fluid (CSF) or blood of patients with brain tumours. Not only can these techniques detect brain tumours without invasive procedures, but they can also detect tumours when they recur before they can be detected on medical images.

As Dr. Tabori states, “The best way to treat cancer is to prevent it,” which has led to a highly interesting project that his lab is embarking on. He and the members of his lab are working with key scientists involved in mRNA vaccine formulations, including some at the biotechnology company Moderna, to develop cancer vaccines. These would enable doctors to prevent cancers from forming in some children. Therefore, the challenge for his lab in the future is to create cancer preventative methods through conducting cutting edge research on both vaccine and immune-related interventions to improve upon cancer interception techniques.

The translational process of using research to find new therapies to treat disease and solve clinical problems is an essential part of healthcare advancement. Clinician scientists like Dr. Tabori work every day to bring the innovations of research into clinical practice. The products of Dr. Tabori’s research on childhood cancers will provide us a greater understanding of these conditions and open doors to new treatments that improve patient health and wellbeing. As he continues to push the boundaries of research and innovate for the benefit of his patients and patients all over the world, Dr. Tabori emphasizes that, “for us here at SickKids, the future is now.”

References

1. Seigel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2022. CA: A Cancer Journal for Clinicians. 2022 Jan; 72(1):7–33.

2. Cancer.gov. Cancer in Children and Adolescents [Internet]. NIH: National Cancer Institute. 2019 [updated 2021 November 4; cited 2023 Mar 7]. Available from https://www.cancer.gov/types/childhood-cancers/child-adolescent-cancers-fact-sheet

3. Replicationrepair.ca. Research. [Internet]. IRRDC. [cited 2023 Feb 16]. Available from https://replicationrepair.ca/team/.

4. Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nature Genetics. 2015;47(3):257–62.

5. Cancer.gov. Immunotherapy to Treat Cancer [Internet]. NIH: National Cancer Institute. 2019 [updated 2019 September 24; cited 2023 Feb 16]. Available from https://www.cancer.gov/about-cancer/ treatment/types/immunotherapy.