Targeting SHP2-Dependent Adaptive Resistance to RAF Inhibition in BRAF-Mutated Glioma
Abstract
Scientific Objective and Rationale. Glioma is a brain cancer that affects more than 20,000 Americans each year, including military personnel and their families. While glioma is largely incurable, research into the specific genetic mutations that cause glioma has led to some discoveries. Targeted treatments against a mutation in the BRAF gene can cause profound and sometimes long-lasting remissions. These treatments, known as RAF and MEK inhibitors (RAFi and MEKi), have been remarkably successful for some patients with BRAF-mutant glioma, but they have no benefit for other patients. The reason why some patients benefit from RAFi and MEKi while others do not is poorly understood (this is known as treatment resistance). Resistance can occur because of other genomic mutations that make a glioma less sensitive to RAFi/MEKi. Resistance can also occur when a cancer cell changes the expression of different genes, known as adaptive resistance. Our lab studies the mechanism by which cancers become resistant to targeted therapy. Understanding resistance is critical for developing new glioma treatments. In this project, we are investigating whether a specific protein, SHP2, causes adaptive resistance to RAFi/MEKi in glioma. We will answer this question through a series of laboratory experiments using glioma cell lines derived from patients’ tumors. We will screen new combinations of targeted therapy against RAF, MEK, and SHP2 to see whether they are more effective against glioma cells and glioma growing in mice. We will also identify new resistance mechanisms using a big data approach to evaluate the RNA and protein signaling in glioma cell lines (RNA-sequencing and kinome analysis). Research Applicability. The results of this project will have important consequences for cancer research in several ways: (1) This proposal will generate pre-clinical data that allows us to take new combinations of RAFi, MEKi, and SHP2i into a clinical trial for people with BRAF-mutated glioma. Depending on the data, this could lead directly to a new treatment for children and adults with BRAF-mutated brain tumors. (2) Discoveries from this research proposal will help us understand the role of SHP2 in many types of cancer with BRAF mutations. These findings can be used by other researchers to help them make new discoveries in other cancers that might lead to new treatments. (3) SHP2 is important in glioma without BRAF-mutations, and this research will help us understand whether other drug combinations might be helpful for patients with glioma. Lastly, as Principal Investigator of this study, I am an early stage investigator who is passionately committed to discovering new cures for patients with glioma. This award would ensure I am able to stay focused on the science of discovery and able to establish leadership in the care and treatment discovery for patients with BRAF-mutated glioma. PI Career Goals. I devoted 15 years (following college) to obtaining the necessary education as a neuro-oncologist in order to care for patients with brain tumors and conduct research to discover new treatments for them. In my doctoral work I studied how gliomas, the most common brain cancer, develop resistance to targeted therapy by turning on other signaling pathways. I have continued this work as a first year Assistant Professor in Neurology, Oncology, and Neurosurgery at Johns Hopkins, where I care for adults with brain cancer, run clinical trials, and work in the laboratory to understand why some gliomas respond well to targeted therapy while others do not. My goal is to establish an independent research program that harnesses detailed molecular knowledge of glioma to develop and bring new targeted therapies to adults and children with glioma. Benefit for Military Personnel and Beneficiaries. Many Service members, Veterans, and their family members suffer from glioma. In fact, active Service members may be diagnosed with glioma more often than civilians in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110251
Entities
People
- Karisa C. Schreck
Organizations
- Johns Hopkins University
- United States Army