Pediatric high-grade glioma continues to have dismal survival despite relentless efforts to develop effective treatments. For patients with diffuse midline glioma (DMG) – sometimes called diffuse intrinsic pontine glioma (DIPG) – the  development of resistance to radiotherapy, the current standard of care, as well as to experimental chemotherapies and molecularly targeted therapies, continues to thwart efforts to meaningfully extend survival beyond a year following diagnosis.

New therapies that target the underlying causes of resistance are desperately needed to improve outcomes for patients with DMG/DIPG. In our lab, we are investigating how treatment resistance in DMG/DIPG develops, with the goal of informing drug development research. We work with pharmacologists and pediatric oncologists to develop both preclinical models of DMG/DIPG and molecularly targeted therapies that effectively pass through the blood-brain barrier, a layer of cells that protects the brain from harmful agents, but may also block certain treatments. Our ongoing studies are shedding light on the role cancer stem cells play in driving resistance in DMG/DIPG and demonstrating how targeting the repair mechanisms of DNA may prompt both stronger responses to radiotherapy and anti-cancer immune activity in DMG/DIPG tumors.

Mutations in the KRAS gene are common in non-small cell lung cancer (NSCLC), but until recently, KRAS was considered ‘undruggable.’ Now, KRAS inhibitors are being tested in the clinic for various malignancies, and some are controlling tumor growth. In 2021, sotorasib, an inhibitor of KRAS bearing the G12C mutation, received FDA approval.

But resistance to targeted therapies – and therefore, relapse – is common. Resistance to sotorasib has been linked to changes in the tumor microenvironment. Understanding the processes driving these changes is essential for developing treatments that provide long-term responses in patients, especially as other Kras inhibitors enter clinics and come to the market. We have developed a preclinical model of KrasG12D-mutant NSCLC in which expression of KrasG12D can be induced and reversed - essentially, turned on or off - to give us insight into how KrasG12D contributes to remodeling the tumor microenvironment in NSCLC during treatment and relapse. Our major goal is to understand mechanisms underlying this remodeling process that will inform future treatment approaches that prompt long-term responses.