Advancing Precision Radiation Oncology: Investigator Q&A

With $7 million in funding from the National Cancer Institute, researchers from Mass General Brigham and collaborators will form one of five centers that will be part of the newly established Radiation Oncology-Biology Integration Network (ROBIN)

Nearly half of all patients who have cancer are treated with radiation therapy, a treatment that uses high-energy beams to shrink tumors and destroy cancer cells. Many cancers can be cured with treatment plans that include radiotherapy. However, responses to radiation can vary, with some cancers responding poorly or not at all. To help determine why radiation therapy works well for some patients but not for others, and pave the way toward “precision radiation oncology,” the National Cancer Institute awarded over $7 million in funding across five years to researchers from Mass General Brigham, including founding members Brigham and Women’s Hospital and Massachusetts General Hospital, and collaborators at Boston Children’s Hospital, Dana-Farber Cancer Center and the University of California, San Francisco (UCSF). The Harvard-UCSF Radiation Oncology at the Interface of Pediatric Cancer Biology and Data Science team (KIDSROBIN) is one of just five centers across the country to be selected to form the network, and is the only center devoted to researching pediatric cancers. The researchers will study samples from a small number of patients, about 25 per cancer type, to learn about treating the biology of cancer.

This Q&A features three investigators who are working together across hospitals as part of the KIDSROBIN team:

• Co-principal investigator Daphne Haas-Kogan, MD, MBA, Chief of Enterprise Radiation Oncology at Mass General Brigham and Chair of the Departments of Radiation Oncology at Brigham and Women’s Hospital and Massachusetts General Hospital

• Principal investigator Franziska Michor, PhD, the Charles A. Dana Chair in Human Cancer Genetics of the Department of Biostatistics and Computational Biology at the Dana-Farber Cancer Institute

• Co-investigator David Kozono, MD, PhD, Director of Thoracic Radiation Oncology of the Department of Radiation Oncology at Brigham and Women’s Hospital

Q. What cancers and treatments are the focus of the KIDSROBIN center?

Kozono: We are studying two pediatric cancers. One, glioma, is the most common type of brain tumor in children. In particular, diffuse midline gliomas are aggressive tumors and, unfortunately, most children do not survive. The goal of this project is to better understand what causes some cancer cells to be more responsive to treatment than others, and why sometimes cells are resistant to radiation or become more resistant during treatment. Deep understandings of genetics and DNA repair biology may allow us to identify what contributes to resistance and ultimately deliver radiation that more completely destroys the tumor.

Second, we are studying neuroblastoma, the most common type of tumor that afflicts children outside the brain. We are studying a radiopharmaceutical, which has radioactive iodine coupled to a drug called MIBG, that is taken up by neuroblastoma cells so the cancer can be targeted with radiation at the cellular level. This treatment works well, but doesn’t cure all patients with high-risk disease, so we want to understand the genetic and molecular factors that correlate with drug uptake and response. Delivering radiation at the cellular level using a radiopharmaceutical is something that makes this study unique among other ROBIN projects.

Q. How might this research help improve treatment plans for patients with pediatric cancer?

Michor: Our work will bring together clinical data and biospecimens, including blood samples, tumor cells, genetic information and electronic health record information. One technique, pioneered in my lab over the last decade, is using predictive mathematic modeling platforms to study how cell populations change over time in response to treatment, given preclinical and clinical information. We demonstrated the feasibility of this model in patients with glioblastoma, which is the “adult version” of diffuse midline glioma. The promising results of these prior studies, where unique treatment schedules altered patterns of recurrence, suggest that we can build predictive mathematical modeling platforms to help us treat pediatric disease, too. In addition, we have an artificial intelligence aspect of the system that takes into account imaging and electronic health record datasets to understand these malignancies in even further depth.

Q. What makes the research team you have assesmbled unique?

Haas-Kogan: The importance of our collaborators cannot be understated. There are not many radiation oncology programs that engage so closely with data science experts like Dr. Michor, who is a rock star in her field. Likewise, Dr. Kozono is a mover and shaker in so many adult malignancies in terms of using science to better clinical care. Our other collaborators include principal investigators of transformative, large international clinical trials: Sabine Mueller, MD, PhD, MAS, from UCSF, is an expert in pediatric malignancies and is leading a definitive study of diffuse midline glioma through the Pediatric Neuro-Oncology Consortium; Steve DuBois, MD, MS, from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, is the principal investigator of an ongoing, definitive study of radiopharmaceuticals for treating high-risk neuroblastoma, and is also leading our study of neuroblastoma.

Building teams representing multiple forms of expertise is key to this endeavor. We have radiation oncology clinicians and experts in data science, including Danielle Bitterman, MD, Benjamin Kann, MD, Guergana Savova, PhD, and Hugo Aerts, PhD, and statisticians, including Annette Molinaro, MA, PhD. We have medical physicists, including Clemens Grassberger, PhD, who can help understand how radiation interacts with the tissues, and experts in cancer biology and DNA repair, including Dipanjan Chowdhury, PhD, and Mariella Filbin, MD, PhD, to help us understand response and resistance to radiation. Bringing such deep experts to the pediatric community has been inspring to me.

Q. How will this project promote and build on collaboration across Mass General Brigham and Harvard-affiliated institutions?

Haas-Kogan: Having spent eight years as the chair of the radiation oncology program at Brigham and Women’s Hospital, Boston Children’s Hospital, and Dana-Farber Cancer Institute, I’ve gotten to know the strengths of those institutions. Now, from my positions within the Mass General Brigham system, I have an even deeper understanding of the equally brilliant, successful, productive and collaborative individuals within this ecosystem, whether it’s at the academic medical centers, community hospitals or other entities. The fact that I spent 29 years at UCSF helps me bring in that group as well.

The ROBIN grant allows us to bring together so many individuals and communities with disparate but complementary expertise. Additionally, 15 percent of our funding each year is set aside to tackle interconnected problems via collaboration with the four other ROBIN centers. We also have a ROBIN Next generation Education and Scientific Training (NEST) Core, led by Ross Berbeco, PhD, and Jean Nakamura, MD. The ROBIN NEST promotes knowledge-sharing across the whole ROBIN, while also inspiring and training junior investigators to continue this research.

It means a lot that individuals who do basic science investigations, translational science, clinical trials, education, and, of course, clinical care all want to work together to cure children who, up until recently, could not be cured. The pediatric community deals with very rare tumors, and often gets the short end of the stick in terms of financial support and attention. Our collaborators bring things that are at the cutting edge of medicine into the pediatric realm, and that has been such a gift for me, our team, and for pediatric patients more generally.