Autophagy and mTOR Inhibition in Pediatric Gliomas with BRAF Mutations
The primary objective of this study is to better understand how to combine a treatment that blocks a survival mechanism in pediatric brain tumors with other cancer therapies to improve survival. The survival mechanism, autophagy, is a way for cells to recycle things inside the cell and use them for energy when under stress. Cancer cells also use this to find ways to survive treatments we use to try and kill them. Brain and spine tumors are the most common solid tumors in children and are difficult to treat because they are aggressive and there are many side effects associated with our current therapies. I have been able to show that brain tumors with a specific genetic mutation, called BRAFV600E, are more sensitive to blocking the autophagy survival pathway than cells without the mutation. Understanding the mechanisms behind why this happens, we can use the effect it to its full advantage.
Moving beyond treating cancer cells in a plastic dish, I will generate brain tumors in a mouse model, allowing me to mimic how tumors would respond in a pediatric patient, and treat them in mini-clinical mouse trials. Using FDA-approved drugs allows me to collect the information that can be used to rapidly move from my mouse models to future human clinical trials. The second goal of my project is to expand in using this treatment to design better combination therapies with other new drugs that block additional cell pathways, further improving treatment for pediatric brain tumor patients.
"An ALSF Young Investigator Award is the type of support early investigators need to get a solid start in the research field and build the base they need for a long and successful career in advancing pediatric cancer research. With this grant, I look forward to rapidly moving my own research from the lab to new treatment options for children with brain tumors." ~Jean Levy, MD
Project Update (7/2016)
Researchers have discovered that altering the process of autophagy can change the way tumor cells respond to therapy, but as my own research has found not all cancer cells respond the same way to blocking this survival pathway. Therefore, a one-size-fits-all approach to altering autophagy is not appropriate for cancer treatment, particularly in kids. It is a complex process, which makes studying its role in tumor cell death challenging. This project built on exciting data I uncovered that showed I am able to identify specific pediatric tumors that are dependent this survival pathway, making those patients potentially ideal candidate for future clinical trials incorporating autophagy inhibition drugs.
Using novel laboratory techniques in addition to using patient tumor samples and a mouse model of pediatric brain tumors, the combination of these research approaches is the first step in the development of future clinical trials. I have been able to show that cancer cells with specific genetic mutations in the BRAF pathway are more sensitive to autophagy inhibition than cells without the mutation, and that blocking autophagy in combination with other drugs improves tumor cell killing. Moving beyond treating cancer cells in a plastic dish, I generated brain tumors in a mouse model which allowing me to mimic as near as possible how tumors would responds in a pediatric patient, and treat them in mini-clinical mouse trials. I have also been able to test primary patient tumor samples to show effectiveness directly on fresh human tumors. Early results from the mini-clinical mouse trials and testing of primary patient tumors are encouraging that the combination therapies improve tumor cell kill in our mouse patients.