Multipronged approach takes aim at malignant brain tumors
Researchers and clinicians at UCLA are making progress in their efforts to find effective treatments for malignant brain tumors — in part through a strategy that recognizes multiple options are needed coupled with the ability to predict which therapies will most benefit each specific patient.
“Thanks to our work in molecularly and genetically classifying these tumors, we have a better appreciation that there are different subtypes of the disease, and not all types can be treated equally,” explains Linda Liau, MD, PhD, director of the UCLA Brain Tumor Center.
Malignant gliomas, the most common of which is glioblastoma, are among the most lethal cancers and the second-leading cause of cancer death among young adults.
"The ability of glioblastoma to infiltrate and damage the surrounding brain makes it a particularly devastating tumor, in which complete surgical removal is impossible,” says Timothy Cloughesy, MD, director of the UCLA Neuro-Oncology Program at Ronald Reagan UCLA Medical Center. “It also is one of the most resistant tumors to radiation and chemotherapy. And because we don’t know how or what causes this tumor to develop, and it is detectable only when fully formed, we can’t prevent it or catch it early.”
Given the absence of a single effective therapy, UCLA’s efforts to change the outcomes of glioblastoma focus around evaluating and offering many promising therapies in clinical trials that approach killing or controlling the tumor from a variety of fundamental mechanisms. These include molecularly guided therapies — drugs that exploit information obtained by genetically profiling tumors then targeting specific molecular abnormalities found in a subgroup of patients; therapy that uses genes to deliver viruses to the tumor; and immune-based therapies, including tumor vaccines, to activate the patient’s native system against the cancer.
With next-generation sequencing techniques, it is now much easier to identify molecular targets than even a few years ago, Dr. Cloughesy notes. Nearly every patient’s tumor can be sent for sequencing, and then the patient can be assigned to a clinical trial based on the abnormalities found. “The drug companies are working with us to develop very focused agents,” Dr. Cloughesy says. “A drug might focus on a mutation found in only about 3 percent of glioblastomas, but if you can find something of great benefit for that small group of patients, that is significant. It’s a step toward personalized medicine.”
The UCLA Neuro-Oncology Program offers trials of drugs that target various mutations of the epidermal growth factor receptor (EGFR), the most common glioblastoma abnormality. The program also has trials of compounds targeting IDH-mutated tumors, as well as drugs taking aim at tumors with molecular pathways that, when activated, are known to contribute to tumor growth and progression.
When brain-tumor researchers are asked about the most promising areas for future study, both genetic profiling and immunotherapy consistently top the list, Dr. Liau says. UCLA is at the forefront of both fields. UCLA’s immune-based therapies currently in clinical trials use treatments that enable the immune system to kill tumor cells by targeting factors, known as immune checkpoint inhibitors, which impede the immune system from successful tumor control. In addition, Dr. Liau and her colleagues developed the first dendritic cell (DC)-based vaccine, known as DCVax, for brain-tumor patients to be used in humans. “The problem with brain tumors is that, despite treatment, they tend to come back,” Dr. Liau says. “The promise of immunotherapy and vaccines is that they can hopefully prevent the cancer from returning.”
Fifteen years ago, most experts believed it was not possible, because of the blood-brain barrier, for patients to mount an immune response to brain cancers. “We’ve found that these tumor vaccines can not only mount an immune response, but that a significant percentage of patients have had no recurrence for more than 10 years now, which for glioblastoma is very rare,” Dr. Liau says.
Currently, Dr. Liau and her colleagues at the UCLA Brain Tumor Center have begun to publish on genetic profiling and biomarkers to determine which patients are likely to fare well on immunotherapy. “Right now, we’re treating everyone the same way,” she says. “I am hopeful that in the next few years, we will have biomarkers that we can test either in the patient’s blood or via imaging. With these biomarkers, we will know in advance which patients will respond, and for those who won’t, we will work on other ways to treat the tumor.”
Many of the ongoing clinical trials for brain tumors grew out of studies that began at UCLA, which has a strong research base in each of the four major treatment targets: immunotherapy and tumor vaccines; alterations in cancer-cell metabolism; going after cancer stem cells to make them more sensitive to treatment; and taking aim at the IDH1 mutation, which is found in a subtype of glioblastomas and associated with significantly different tumor behavior.
“At UCLA, we are part of both a leading academic institution and a leading treatment center, and we have taken advantage of that by developing close working relationships along the continuum from the bench to the bedside,” Dr. Liau says. “Our basic scientists meet regularly to discuss what’s going on in the laboratories, and we share that information with the clinicians. This is particularly important in the brain tumor field, and it has been a key to our success in bringing new therapies to fruition.”