One of the barriers to creating new therapies for pediatric low grade gliomas is the lack of models for finding new drugs.
A “mouse model” does not exist.
The various genetic mutations are not represented in the models that do exist.
Medical researchers do not understand why some low grade gliomas recur, causing the patient to suffer through multiple lines of therapy, while a lucky few patients’ tumors stop growing after one line of treatment.
Why low grade gliomas occur is unknown.
Imagine An Answer’s research will address these questions and speed the development of new drugs for patients with low grade glioma.
Prior to 2017, there were no genetically accurate cancer cells that could be replicated and grown in the lab.
Creating a model to find new therapies:
With funding provided by IAA, Dr. Raabe and his team at Johns Hopkins University have successfully created a cell line from a patient with a particularly aggressive low grade glioma, caused by neurofibromatosis (NF1). This is valuable because patients with NFI represent a significant portion of those with low grade gliomas. These patients often lose sight in one or both eyes, because these tumors grow in the nerves that connect the eye to the brain.
Scientists are currently testing new drugs against this cell line and are also testing if the cell line will make tumors in mice.
Figure 1: [JHH CRC1-NF1] Microscopic picture of human cancer cells derived from a patient with a low grade glioma. These cells are grown in a dish in special conditions similar to those used to grow neural stem cells.
Testing new drugs in current and new models
Imagine An Answer-funded scientists have found that two drugs which are known to work individually in low grade glioma work much better when combined. This is true both in a lab dish as well as in a mouse model. The two drugs have been combined in other cancer types, but have never been used together in pediatric low grade glioma.
Figure 2: Graph showing combination therapy with carboplatin and everolimus suppresses the growth of the BT40 tumor, which models pediatric low grade glioma harboring a BRAFV600E mutation.
They have also found that new drugs that are in early phase clinical trials have excellent activity against low grade glioma models. In particular, a drug that blocks a key metabolic pathway can suppress the growth of tumor cells in mice.
Figure 3: Pictures of immunodeficient mice (called nude mice) into which human BT40 cancer cells have been implanted under the skin. The mouse on the left is treated with saline, while the mouse on the right is treated with a drug blocking a key metabolic pathway. Tumors on the right are much smaller than those in the mouse on the left.
Further experiments are under way to determine if this drug will work with other therapies for low grade glioma.
In September 2017, the IAA-funded team at Johns Hopkins submitted for publication the first of three scientific manuscripts on low grade glioma. As of now, Dr. Raabe and his colleagues have found that the most aggressive types of pediatric low grade glioma express a protein called mTOR, and that inhibitors of mTOR decrease the growth of some pLGG cells. They are studying the metabolism of the pLGG cells to find and validate new combinations of drugs that work with mTOR inhibitors to kill pLGG cells. Two scientific manuscripts in the final stages of preparation. These IAA-funded scientific studies will provide the justification for new clinical trials going forward for pLGG.