A Message from the CBTTC’s Scientific Co-Chair
Dr. Michael Prados, MD
Neuro-Oncologist, UCSF Benioff Children’s Hospital
Professor and Charles B. Wilson Endowed Chair of Neurological Surgery; UCSF Weill Institute for Neurosciences
Co-Project Leader; Pacific Pediatric Neuro-Oncology Consortium (PNOC)
Scientific Co-Chair; Children’s Brain Tumor Tissue Consortium (CBTTC)
I first became interested in neuro-oncology in the early 1980s, when I was faculty at a small teaching hospital; part of the Louisiana State University School of Medicine in Baton Rouge, Louisiana. Adult medical oncology was clearly an exciting and emerging clinical specialty, and my academic appointment was to help manage all of the adult cancer patients at the hospital, including participation in early phase clinical trials. During my time, I rarely saw patients with brain tumors, but one case in particular was the reason I ultimately embarked on a career in this field. The patient was a young physician in family practice who presented with a seizure and acute vision loss. She had a large malignant glioma seen on a CT scan (we didn’t have MR imaging at that time at my hospital). Surgery was incomplete, the pathology was glioblastoma, and there were essentially no clinical trials available to her. After whole brain radiotherapy and BCNU chemotherapy, she never really improved, but was cognitively intact until late in the course of her illness. After several months of home visits, I was able to be with her husband and young children at the time of death. It was the first time I pronounced a patient, at home, with children around. I’ve never forgotten that experience.
The experience was frustrating to me as a young physician, and the lack of knowledge and research was notable, compared to so many other cancers. A few years later, in 1985, I entered into a Neuro-Oncology fellowship at the University of California San Francisco. The fellowship included training in both adult and pediatric brain tumors, and while the adult cases far outnumbered the children I saw, and every patient mattered deeply, the impact the children had on my thinking about these diseases was truly life changing in many ways. I was fortunate being in an academic center where translational research was the primary focus, linked to clinical trial development. I’ve remained at UCSF since that time because of that fact, and have tried to keep this vision as part of the mission of our clinical research group.
Over the years, having run the North American Brain Tumor Consortium (later to become the Adult Brain Tumor Consortium), and as UCSF site Principal Investigator of the Pediatric Brain Tumor Consortium (both NCI/CTEP funded), it became clear to me that funding was insufficient, and there were really few opportunities to take reasonable risks, preventing us to really move the field forward quickly enough in ways that would be significant. We were doing trials based upon findings from other cancers; rarely ever using human tumor tissue as a prime source for discovery, using drugs/strategies that were of lower priority from pharmaceutical partners, and lacking resources to implement a forward-thinking national strategy. This was particularly and uniquely true, unfortunately, for pediatric neuro-oncology.
Reflecting on this lack of success/strategy, we started the Pacific Pediatric Neuro-Oncology Consortium (PNOC) in 2013 and began a journey that sought to change the way we do research. We recognized that we needed multiple institutions and investigators working collectively to conduct clinical trials quickly and to answer why some therapies worked, and just as importantly, why most did not. While focused on the children with the highest unmet needs, within the context of early phase clinical trials, we felt every child had a unique tumor biology and deserved a more “precision/personalized” treatment strategy. Indeed, our first trials mandated tumor tissue as a requirement for enrollment. “Biomarker-driven” clinical research made sense to us, given the impressive gains in pre-clinical discovery over the last decade. Even within DIPG, we felt we must obtain tumor tissue prior to any treatment. This was a strategy we tried to implement within the CTEP portfolio, within the PBTC, but were not allowed to pursue at that time. Outside of those constraints, but still within what we considered reasonable risk for a potential reward (e.g. improved outcomes, and less likelihood of futile treatment), we were able to accomplish what was then considered a paradigm shift in clinical trial design. The approach is now so much more common, but there is much work yet to be done. With truly dedicated and engaged investigators (and now 19 centers in the US and more globally), we continue to learn and to discover, and hopefully will continue to focus on biologically driven, patient-centered research.
At about the same time as PNOC was started, the Children’s Brain Tumor Tissue Consortium (CBTTC) embarked on a similar “disruptive” strategy to collect and freely share the molecular features of children and young adults with brain tumors from multiple sites across the United States, and globally. The idea of a biorepository, without academic halls or research silo’s was (and still is) innovative, and would allow more discovery than any single scientist or academic center could possibly imagine, that could inform translational research, particularly if rapid, easy dissemination were possible. The CBTTC has made this possible, via critical online, cloud-based platforms with support from a team of biologists and staff making it all happen, in real time, freely. But the CBTTC has more than a biorepository as its purpose, with the goal, like the PNOC, to improve the lives of children with brain tumors and other rare diseases. Linking biology with clinical data allows the repository to be a “living” entity; always growing and always learning. Linking the repository to all interested scientists makes it grow even faster.
CBTTC and PNOC have a similar vision and mission, and aligning those visions allows even greater progress to be made. Discovery, to translation, to therapy, and back again will ultimately be the reason children and young adults will see improvement in both quality of life and overall survival. Now having disease-specific working groups, strategically thinking, over time, about these tumors, supported by PNOC and CBTTC “cores”, is an example of integrative, comprehensive, translational research. The working groups are composed of scientists and clinicians, partnering with advocates and philanthropy, all working together across platforms and independent of academic or other boundaries. This will, in my mind, truly make a difference.
Having the opportunity and privilege of being a part of these organizations has been the highlight of my medical career. Within an academic setting, one can be successful by grant funding, publications in peer review journals, named professorships, recognition. But, if any of those metrics don’t translate to a child having a longer and better life, or at least the promise of that, then the “success” doesn’t really mean much. What really is meaningful, and significant, is how we work together, freely, towards that common goal of improved outcomes in the lives of these children and their families. Success without significance makes no sense anymore. Success with significance does make sense.