Interdisciplinary Initiatives Program Round 12 - 2024
Project Investigators:
Claudia K. Petritsch, Neurosurgery
Michael Lin, Neurobiology and Bioengineering
Abstract:
There is an urgent need for better treatments for brain cancers, especially for high-grade gliomas and metastases of other cancers to the brain. Gliomas have a 5-year survival rate of <50% in adults and cause more deaths in children than any other cancer, despite decades of research to improve surgery, chemotherapy, and radiation treatments. Recently, drugs targeting a biochemical pathway commonly hyperactive in brain cancer, the Ras/MAPK pathway, have proved helpful, but benefits are typically transient and resistance is common. Thus, there is intense interest in combining Ras/MAPK pathway inhibitors with other therapeutic agents to either overcome resistance or stimulate immunity against the tumor. However, systematic testing of the numerous possible combinations is severely limited by the expensive and time-consuming process of analyzing tissue samples and/or analyzing mouse survival to determine efficacy.
In this interdisciplinary project, we will break this logjam by synergistically combining the expertise of faculty members in Neurosurgery and Bioengineering. Specifically, this work will bring together, for the first time, the Petritsch lab, which has recently discovered that combination therapies can overcome Ras/MAPK inhibitor resistance and elicit anti-tumor immunity, with the Lin lab, which has recently developed technologies to non-invasively report Ras/MAPK activity and cell-cell interactions in living mice. In particular, the Petritsch lab has leading expertise in generating high-fidelity cellular and mouse models of brain cancers, while the Lin lab has been pioneering the improvement of light-emitting luciferase enzymes and their engineering to reveal biochemical or cellular events.
With the goal of developing more effective brain cancer treatments, our first aim is to test novel small-molecule drug combinations for durability in suppressing Ras/MAPK activity in the brain, using longitudinal non-invasive luciferase reporting of Ras/MAPK activity. Our second aim is to test combinations of Ras/MAPK inhibitors with antibodies that activate the immune system to kill cancer cells, using longitudinal non-invasive luciferase visualization of lymphocyte interactions with tumor cells. Optimization of combination therapies to extend Ras/MAPK suppression or enhance tumor immunity will identify specific combinations that can then be more extensively tested using traditional specimen sampling and survival analysis methods, and then introduced into clinical trials.
