Nearly 2,500 children in the United States are diagnosed with brain tumors each year, making these malignancies among the most common solid tumors in children and adolescents. Despite advances over the past few decades, the treatment of brain tumors remains one of the most challenging clinical areas in oncology. To shed light on this issue, The ASCO Post recently spoke with internationally regarded pediatric brain tumor expert, Mark W. Kieran, MD, PhD, Director of Pediatric Medical Neuro-Oncology at Dana-Farber Cancer Institute and Associate Professor of Pediatrics at Harvard Medical School and Boston Children’s Hospital, Boston.
Please tell the readers a bit about your background and current position.
I trained in Canada, where I received a PhD (in immunology) from the University of Alberta, Edmonton, and an MD from the University of Calgary. I then completed a postdoctoral fellowship in molecular biology at the Pasteur Institute in Paris and a pediatric residency at McGill University in Montreal, before moving to Boston and the Dana-Farber Cancer Institute/Boston Children’s Hospital for a fellowship in pediatric hematology-oncology.
After additional postdoctoral training, I became the first Director of Pediatric Medical Neuro-Oncology at Dana-Farber, and I continue in that position to this day. In addition to my clinical responsibilities, I have maintained a laboratory-based program focused on attacking novel pathways in cancer.
As Director of Pediatric Medical Neuro-Oncology, my first task was to develop three strong areas of focus: (1) an outstanding clinical program offering state-of-the-art therapy for all patients with tumors of the brain and spine; (2) a comprehensive brain tumor survivors program for patients after therapy; and (3) a translational research program to rapidly move ideas from the laboratory into the clinic.
A Challenging Field
Please give the readers some insight into the different challenges faced in pediatric brain tumors.
Although pediatric brain tumors are not the most common cancers, they are the number one cause of cancer-related death in children. Nevertheless, compared to similar-appearing adult cancers, they are rare, and so for decades, treatment followed standards that were developed in adult brain tumors.
Our understanding of the mutations that drive brain tumors, the development of targeted drugs that inhibit them, and the harnessing of the immune system to find and kill tumors are all rapidly progressing.— Mark W. Kieran, MD, PhD
Over the past decade, we have focused our efforts on the molecular signature of pediatric brain tumors rather than their appearance under the microscope. What we discovered was the majority of pediatric tumors have different molecular features from adult tumors. This has completely altered our approach to treatment, with an emphasis on developing therapies aimed at the targets found in -pediatric tumors.
Developing specific targeted therapies should not just improve cure rates for these tumors but should also reduce the toxic effect of chemotherapy and irradiation on the developing brain. This research started with the development of a major sequencing project for all pediatric brain tumors and the creation of cell lines on which drugs could be tested. A second critical effort has been the establishment of a methodology to determine how well a drug can penetrate the brain.
Unlike the rest of the body, the brain is surrounded by the blood-brain barrier, which prevents many drugs from entering into the central nervous system. Many clinical trials in both adult and pediatric patients have used drugs now known not to penetrate the brain, which may account for the particularly poor outcome of these patients. By developing a standardized method for determining which drugs can enter the brain, we can now select only agents with that ability for clinical testing.
You worked in the lab of Dr. Judah Folkman, best known for his research on tumor angiogenesis, which was once considered to be among the most promising areas of investigation. Where are we in that field?
Dr. Folkman’s recognition that tumor cells need to regulate the microenvironment in order to survive provided an opportunity to attack them not just head-on, but by removing the supporting structures that they depend on. Although the scientific and medical communities hoped that this would be the Achilles heel of cancer, the complexity of the mechanism that regulates the microenvironment and blood supply to the tumor—angiogenesis—was underestimated.
While the initial enthusiasm of the antiangiogenic approach has waned, surgery alone, chemotherapy alone, and radiation alone have also not been effective for the majority of cancers. But antiangiogenic and metronomic approaches have been incorporated into a number of combination treatments and have added to the growing array of effective treatments for cancer.
Do you have any closing thoughts about the future of neuro-oncology?
Although brain tumors continue to be a major cause of cancer-related morbidity and mortality, I believe there is real reason for optimism. Our understanding of the mutations that drive brain tumors, the development of targeted drugs that inhibit them, and the harnessing of the immune system to find and kill tumors are all rapidly progressing. Within the foreseeable future, these advances should significantly improve the outcomes of both adult and pediatric patients with brain tumors. ■
Disclosure: Dr. Kieran has consulting and advisory board agreements with Novartis, Boehringer, Lilly, Sanofi, Bristol-Myers Squibb, Sigma Tau, Merck, Bayer, and Takeda Pharmaceuticals.