Optimization of Autophagy Inhibition as a Clinical Target for Brain Tumors
Abstract
The Peer Reviewed Cancer Research Program (PRCRP) Topic Areas focus on tumors and medical conditions with an especially strong negative impact on patients. This is certainly true for patients with brain tumors and their families. The proposed research addresses the critical need for the development of new therapy options for pediatric brain tumor patients. In addition, this project can also be widely applied to cancer in children, adolescents, and young adults, as well as adult brain cancer. Scientific Objective: The primary objective of this study is to better understand how to combine a treatment that blocks a survival mechanism in brain tumors with other cancer therapies to improve survival of patients. The survival mechanism, autophagy, is a way for cells to recycle proteins and other things inside the cell and use them for energy when the cell is under stress. Cancer cells use this not only to survive the harsh environments they grow in, but also to find ways to survive treatments we use to try and kill them. We have shown in previous research that a specific mutation found in some tumor cells (BRAFV600E) can make them addicted to this survival pathway and more sensitive to drugs that block autophagy. Brain and spine tumors are the most common solid tumor in children and are the leading cause of death in pediatric cancer patients. They are difficult to treat, not only because of their aggressive nature, but also due to the short- and long-term side effects associated with current therapies such as radiation and chemotherapy. It is clear that novel therapies, such as autophagy drugs, are needed to treat these challenging cancers. 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. The proposed project builds on exciting recent data to identify more brain tumors that are dependent on this survival pathway, identifying those patients as ideal candidates for future clinical trials with autophagy inhibition drugs. It will also give us the information we need to choose the right autophagy-inhibiting drugs. With the development of new drugs that block this process, we have to be sure we are using the most effective and least harmful drug for our patients. Finally, by identifying how blocking autophagy is helping to kill tumor cells, we will be able to design new drug combinations to further enhance the benefit of inhibiting autophagy. Using novel laboratory techniques including direct patient tumor samples and new models of low-grade brain tumors (that are traditionally hard to grow), this project is the first step in the development of future clinical trials. Ultimate Applications of the Research: Based on my previous research supported by the PRCRP, a clinical trial is already in the planning process to block autophagy in brain tumor patients with the BRAFV600E mutation. While this is exciting, we feel this approach could benefit a wider patient population including patients with other mutations that activate the same growth signals as BRAFV600E. By using Food and Drug Administration-approved drugs currently available for use in patients, my studies allow me to collect the preclinical information that can be used to rapidly move from my lab to human clinical trials. The ultimate goal of these studies is to design a trial for pediatric brain tumor patients that will incorporate autophagy inhibition with targeted therapies in patients with brain tumors that are dependent on autophagy for survival. The broad range of patients this may help includes children, young adults, and the older adult brain tumor population. How will this research help Service members and their families? This research has the potential to help a broad r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810386
Entities
People
- Jean Mulcahy Levy
Organizations
- United States Army
- University of Colorado Denver