Diffuse intrinsic pontine glioma (DIPG) is a complex and challenging tumor. Its location in the brain stem, combined with its diffuse nature, makes it inoperable. No chemotherapy drug has yet been effective against it. Radiation provides only temporary relief before the malignancy returns. And the scarcity of both tumor tissue and research funding has made it difficult for scientists to study it. Recent advances in the OR and in the lab, however, are starting to change the tumor’s grim profile.
For decades, neurosurgeons were reluctant to biopsy pontine gliomas for fear of inflicting devastating neurological harm on their young patients. Stereotactic needle biopsy now makes it possible to biopsy these tumors, not only confirming the diagnosis but also securing tissue samples for research.
At the Children’s Brain Tumor Project laboratory, we now have several distinct patient-derived DIPG cell lines growing in vitro. Using these cell lines, we can study the molecular alterations present in these tumors and select effective molecular targeted therapies to test. We are learning more every day about the genetic mutations, epigenetic alterations, and the activation of stem cell pathways that might be causing these malignancies. (We also have gliomatosis cerebri cell lines growing, but GC cells grow more slowly than DIPG cells do, so it will take a bit longer for them to be ready for testing.)
As we learn more about DIPG’s molecular characteristics, we can apply newly developed high-throughput screening (HTS) techniques to try to match those characteristics with existing FDA-approved drugs. Using HTS, we can examine millions of variables in already-approved oncology drugs in search of promising candidates to test against DIPG. These drugs are in clinical use today for other cancers, and we are testing them on our collection of DIPG cell lines. The goal of the initiative is to identify the most potentially effective drugs for DIPG, and then rapidly transition them to clinical trials.
Perhaps even more significantly, HTS allows us to predict which combinations of oncology drugs would make good candidates to use in synergy against DIPG based on the molecular profile of the tumor cells. (In other cancers, synergistic drug combinations have succeeded when single drugs have failed.) Synergistic drug pairs have special potential for success against chemo-resistant cancer cells. Drugs can be specifically paired to attack the cancer cells on parallel paths, so that when the first encounters drug resistance from the tumor, the second is able to continue on its mission. The combinations can also achieve a desired effect at a lower total dosage, usually with fewer side effects.
The next step is to inject our DIPG cells into animal models, then use convection-enhanced delivery (CED, the technique being used in Dr. Souweidane’s clinical trial) to deliver specially selected drug pairs into the tumor. Since we’ll have very detailed information about the tumor cells, we’ll be able to choose drugs that have the best chance of success against those particular cells. It’s a tremendous first step toward developing personalized treatments that will someday allow us to select the most promising drugs to use in children with DIPG.