CREATING A STANDARD OF CARE FOR PEDIATRIC BRAIN TUMORS – FOR THE FIRST TIME
Defeat Pediatric Brain Tumors (DPBT) is a powerful, unique global research and drug discovery program which aims to improve clinical outcomes for pediatric brain tumor patients and enable the development of the first-ever standard of care for treating pediatric high-grade gliomas (pHGG) – the most lethal of pediatric cancers.
Pediatric brain tumors are the leading cause of cancer-related deaths among children and young adults ages 19 and younger, surpassing leukemia. Over the past decades, little progress has been made in the treatment of pediatric brain tumors, while tremendous advances have been made across the rest of the pediatric cancer spectrum, as new discoveries in the lab have led to new treatments in the field that have significantly improved survival.
For example, the most common form of childhood cancer, acute lymphoblastic leukemia, was generally diagnosed as fatal 50 years ago; today, cure rates for the disease reach close to 90%.
However, for the 4,600 children diagnosed annually with a brain tumor, the scientific needle has barely moved, with only 25% of children suffering from a malignant brain tumor surviving five years – rates that trend on par with where they were nearly 40 years ago.
But, never before in the history of mankind’s battle with cancer has so much progress been made. Critical findings in recent years – including many funded by the National Brain Tumor Society – have positioned the field of pediatric brain tumors to enter a new era in treatment and survival. Among the most transformational of these findings was clear evidence that pediatric high-grade gliomas are biologically and molecularly distinct and separate from their adult counterparts. These findings allow scientists to break from the norm of the past decades, and catalyze them to develop pediatric-specific treatments that finally move us away from using adult therapies on children, a strategy that simply has not worked.
NBTS has built a track-record of success, playing a critical role in funding many of the field’s crucial findings that have brought us to the threshold of a new era in 2016. From that strong foundation, we have launched the Defeat Pediatric Brain Tumors Research Collaborative program.
Key findings from the Defeat Pediatric Brain Tumors program:
- The tools for translational research. DPBT researchers successfully created over 30 new model systems that can be used to study the role of various cell mutations and test the efficacy of new drugs on pHGG tumor cells. Model systems (cells from patient tumor samples that can be grown in a laboratory dish or in a mouse) are important tools for cancer research. Models that represent the variety of different changes seen in these tumors can be used to both study the functional role of different mutations within the cell, as well as test potential new drugs to see if they can kill the pHGG tumor cells.
- Techniques for detection of tumor mutations to enable more personalized treatments. The underlying mutations in pHGGs can change over time, including after initial treatment, with some mutations vanishing and new ones appearing. Finding simple ways to detect and track these mutations in patients could unveil new targets for drugs as well as inform ongoing treatment plans and strategies. To do this type of tracking and analysis, researchers and doctors need to perform tests on samples of a tumor taken by biopsy. However, for pHGG patients, the prospect of repeated surgical biopsies is often not only extremely risky, but simply out of the question. Addressing this challenge, DPBT researchers focused on the possibility of using a “liquid biopsy” to collect DNA fragments shed from the main tumor in bodily fluids like blood, urine, or cerebrospinal fluid (CSF). They found that detecting and analyzing circulating tumor DNA from CSF is the most reliable and promising method to refine moving forward.
- Leveraging Research to Predict Response to Treatment. Researchers in the DPBT Collaborative analyzed 130 tumor tissue samples from patients participating in a pHGG clinical trial along with these patients’ treatment response history to learn how specific mutations in the tumor correlate with treatment response. This will help stratify patients for future clinical trials evaluating potential new treatments, as well as in regular clinical practice for determining optimal drug regimens for patients.
- Searching for More Effective Drugs. Researchers within the DPBT Research Collaborative evaluated over 1,300 approved and experimental drugs in the pHGG cell culture models they developed, using both individual drugs and drug combinations. They were able to identify encouraging new drug combinations, such as a combination of GDC0084 (a PI3K inhibitor) and PD0325901 (a MEK inhibitor) that most potently kill pHGG cells in vitro.
Many chemotherapy drugs, and ionizing radiation work by damaging tumor DNA. However, tumors have an ability to escape treatment and survive by fixing its broken DNA. Preventing tumor cells from repairing their DNA can make therapy more effective. DPBT-funded researchers profiled a number of inhibitors of the DNA damage repair for their ability to sensitize tumor cells to chemotherapy or ionizing radiation. PARP inhibitors and ATR inhibitors, which prevent the repair of DNA damage, showed promise when given in combination with chemotherapy drugs like topotecan and etoposide. Another drug of this class, AZD1390, a CNS penetrant ATM inhibitor, emerged as the best in vitro sensitizer of ionizing radiation. More importantly, when researchers started to look deeper at molecular profiles of the tumors in their models, they found strong potentiation of radiation in most pHGG models with defective p53 pathway activation, whereas tumors with wild-type p53 were significantly less responsive. These findings will help select the best treatments for the right patients.