Like kisMET: targeted therapy and radiation synergize in pediatric high-grade glioma

An abnormal gene which causes cancer becomes something else when scientists learn how to control it. It becomes a target. Identifying good targets is a tremendous milestone for cancer researchers. However, it is only the start of a long journey from lab to clinic — a journey that most drugs don’t ever complete.

An all-too-common story in cancer research tells of treatments that look promising in the lab but don’t work in patients. The reasons for this are as varied and complex as the different molecules in the body. For example, discovering a new target does not mean it will become a treatment. Some targets are not druggable, meaning either they are too biologically important to be altered with a drug, existing chemistry approaches aren’t up to the task of locking onto or modifying them, or the drug has off-target effects. It may also be that the drug does not translate to actual human patients, due to the differences between patients and laboratory models. Successful drugs overcome these obstacles but finding them takes time and resources.

By studying targets and potential drugs for them, translational researchers provide valuable insights and guidance to clinicians about which drugs are most likely to succeed. Bridging the expanse between target discovery and clinical trials means that translational researchers can help get promising treatments to patients faster.

A promising target in pediatric high-grade glioma

At St. Jude, translational research is a multidisciplinary endeavor. For Suzanne Baker, PhD, St. Jude Comprehensive Cancer Center Neurobiology & Brain Tumor Program co-leader and Department of Developmental Neurobiology member, her work on childhood brain tumors couldn’t succeed without this approach. “Each different specialty is a key piece that makes the entire study possible,” says Baker, co-corresponding and co-senior author on a new collaborative research paper. “To do this work, we must coordinate and work together to answer these questions.”

Baker runs a translational laboratory studying pediatric high-grade gliomas (pHGG), a group of brain tumors with very poor outcomes.

Patients are affected by these tumors at different ages, in different areas of the brain, and with different mutations that drive them. The Baker Lab tries to understand how disruptions of normal regulatory mechanisms contribute to these cancers and how we can counteract these effects therapeutically.

In a recent study published in Molecular Cancer, Baker and her colleagues, including co-first and co-corresponding author Marc Zuckermann, PhD, a visiting scientist from the German Cancer Research Center and co-first author Chen He, PhD, a scientist in the Baker lab, identified a drug called capmatinib as effective for pHGG driven by a genetic mutation called a MET-fusion, which results in a fusion oncoprotein.

Fusion oncoproteins occur when genetic rearrangement brings together parts of two different genes resulting in a hybrid gene. In doing so, this hybrid gene now contains incorrect instructions for making a protein. The resulting abnormal fusion protein can contribute to cancer development. The MET gene is a well-known target in many types of cancers because it normally creates a protein involved in cell growth and survival signaling. When these processes go awry, cancer can easily occur. In pHGG, MET-fusions are found in infants and older children. The mutations also occur in adults.

“We have known about aggressive tumors with a MET-fusion for a long time, and we have developed fast and straightforward methods to find out if a tumor has a MET-fusion in the pathology laboratory,” said Jason Chiang, MD, PhD, St. Jude Department of Pathology and an author on the study. “Now, it is really exciting that with a team of scientists at St. Jude and across the Atlantic Ocean, we have identified a promising treatment for these tumors.”

The right model to answer the right question

Knowing that MET-fusions were involved in about 12% of pHGG gave the Baker lab a place to start. Several different drugs target MET, but which one is most likely to succeed? To find out, the researchers had to use the right models. The team established and characterized two orthotopic mouse models (models created using implanted tumor cells), each with distinct MET-fusions.

These models included an immunocompetent murine allograft model in which the tumor tissue came from the same genetic background as the mouse, and a patient‐derived orthotopic xenograft created from tissue samples from a MET‐fusion infant hemispheric glioma patient for whom conventional therapy and targeted therapy with the MET inhibitor cabozantinib had not worked.

Armed with the models, the researchers studied the efficacy and pharmacokinetic properties (how the drugs behave in the body) of three MET inhibitors: capmatinib, crizotinib, and cabozantinib. The drugs were studied alone and in combination with radiotherapy, a standard treatment for pHGG in older children.

All inhibitors are not created equal

The results showed capmatinib worked better than the other MET inhibitors. Notably, capmatinib could better cross the blood-brain barrier, the physical separation between the brain and the rest of the body. The blood-brain barrier exists to protect us, but also prevents many drugs from getting across it and hindering drug development for brain tumors. Since capmatinib could get across, it reached the tumor and had the desired effect on the diseased cells.

“The brain is such an important organ that we have a blood-brain barrier to protect it from any toxins that we might encounter in the environment – and that’s what drugs look like to the barrier,” explained Baker. “It can really limit access of a drug to get into the tumor, and that’s a major challenge for brain tumors that is different than for solid tumors or leukemia.”

In the models, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy, suggesting that the treatments synergize, improving each other’s effect. Radiotherapy works by using radiation to damage DNA and kill disease cells. The researchers found that capmatinib increased radiation-induced DNA double-strand breaks and delayed the natural repair mechanisms that might fix such breaks. This increased the effect of radiotherapy.

“Inhibition of receptor tyrosine kinases is not generally thought of as a mechanism of radiosensitization, although there is preclinical and clinical data to support this,” explained Christopher Tinkle, MD, PhD, St. Jude Department of Radiation Oncology and co-senior author on the study. “Based on this and the fact that MET alterations have been observed across the age range of pediatric high-grade glioma, we were excited to evaluate the effect of capmatinib on radiotherapy. We were impressed with the synergistic interaction we observed, which suggests that this combination therapy may merit clinical evaluation in appropriately selected patients.”

Closing the gap between the lab and clinic

The case for capamatinib is compelling, and with the evidence provided by Baker and her colleagues, it is a logical next step to test how the drug performs in patients. Even though other MET inhibitors weren’t as effective in pHGG as investigators had hoped, MET remains a promising target. Baker and her colleagues are closing the gap between the lab and clinic, by doing the laboratory work to determine which of the MET inhibitors is most likely to work well in the brain.

“Once you know what mutations exist, it opens up many possibilities,” said Baker. “When another patient comes into the clinic with that mutation, we want to be able to offer something that we’ve tested in the lab, and that we can say with high confidence, we think it’s going to work better for that patient.”