Brain cancers have proved to be among the deadliest and most difficult malignancies to treat, with significant hurdles standing in the way of effective radiation and chemotherapy approaches. But the UCLA Brain Tumor Center — a National Cancer Institute-designated Specialized Program of Research Excellence (SPORE) — is making headway through a multidisciplinary approach to bringing basic discoveries to fruition for glioblastoma, the most aggressive and lethal brain tumor.
“The SPORE requires something few institutions have — the ability to take projects from bench to bedside within five years,” says Linda M. Liau, MD, PhD, chair of the UCLA Department of Neurosurgery and, with Professor of Neurology Timothy Cloughesy, MD, codirector of the UCLA Brain Tumor Center. “It builds a cadre of researchers working together on the same problem, with a focus on getting novel treatments to patients.”
“Every time we test a new treatment, we want to figure out why it’s not working for certain patients and how we can overcome that resistance,” adds P. Leia Nghiemphu, MD, professor of clinical neurology and a SPORE investigator. “The idea is to learn from the results, then go back to the lab and improve on them.”
The SPORE grant currently funds three projects that involve investigator-initiated clinical trials, each co-led by a clinician and a basic scientist. Dr. Liau and Robert Prins, PhD, a basic scientist and professor in the Department of Neurosurgery, are building on seminal work by Dr. Liau’s team that led to the development of a first-of-its-kind personalized cellular vaccine for glioblastoma, which has shown promising results in several earlier phase clinical trials.
Brain cancers were widely believed to be immune-privileged — incapable of being attacked by the immune system — until research in Dr. Liau’s lab demonstrated that when antigen-presenting cells were pulsed with tumor antigens and injected into mice, they could precipitate an immune response against tumors in the brain, extending survival.
From there, Dr. Liau’s team took the approach through phase one and phase two clinical trials with glioblastoma patients. Phase three, which began in 2007, administered the vaccine at 80 sites in North America and Europe. In interim findings reported in 2018, the median survival of all patients enrolled in the trial was 23.1 months — eight months longer than the median survival in previous studies using chemoradiation alone. The concept for the vaccine is simple: The tissue proteins removed during glioblastoma surgery are combined with antigen-presenting immune cells — aka, dendritic cells — generated from the patient’s blood. These cells are then activated in the lab to turn against the tumor cells before being injected back into the patient. Using the patient’s own tumor specimen avoids the need for HLA matching. More importantly, Dr. Liau says, glioblastomas are heterogeneous. “We now know it’s not one antigen that’s mutated; it’s hundreds, and they’re not the same in every patient,” she says. Using the patient’s own tumor tissue as the antigen source for the vaccine eliminates the need for us to second-guess which proteins to target for each individual patient.”
The next step involves applying lessons learned from the laboratory to improve the vaccine’s efficacy. To that end, the group led by Drs. Liau and Prins launched a trial in 2019 that uses the vaccine in combination with checkpoint inhibitors, based on their laboratory analysis of how tumors in animal models were able to overcome the immunotherapy.
In a second SPORE project, researchers are pursuing novel strategies to block the process, called phenotype conversion, that occurs when glioblastoma patients receive radiation therapy. “We think the reason tumors grow back and become resistant to radiation is that radiation treatment in itself induces cellular changes in tumor cells that make them stem-like and capable of regrowth,” says Dr. Nghiemphu, who is the clinical lead in this the project with the basic science lead, Frank Pajonk, MD, PhD, professor of radiation oncology.
The researchers found that in mouse models of glioblastoma, combining the dopamine receptor antagonist trifluoperazine with radiation delayed tumor recurrence, significantly extending survival. In a follow-up study, they added a statin used to lower cholesterol levels and found that, in combination with trifluoperazine and radiation, median survival in mice was extended fourfold compared with radiation alone. Based on those findings, the group is preparing to test these combination therapies in patients with recurrent glioblastoma after standard therapy to see if the strategy inhibits the development of the aberrant stem cells.
A third SPORE project is developing new strategies to deliver epidermal growth factor receptor (EGFR)-inhibiting drugs to the brain. EGFR is genetically altered in approximately 60% of glioblastoma tumors, making it a prime target for molecular therapies. Nonetheless, while EGFR antibodies have shown therapeutic success in treating certain breast and lung cancers, they have been ineffective in glioblastoma. “This is largely because these drugs haven’t had good blood-brain-barrier penetration, which has prevented them from getting to the brain at sufficient levels,” says Dr. Cloughesy, who also is director of the UCLA Neuro-Oncology Program.
Dr. Cloughesy is collaborating with David Nathanson, PhD, of UCLA’s Department of Molecular and Medical Pharmacology, and Michael Jung, PhD, the UCLA chemist whose laboratory laid the groundwork for the prostate-cancer drugs enzalutamide and apalutamide, on research aiming to develop more brain-penetrant EGFR inhibitors, with one novel drug that is on an IND-enabling path and should be available for use in patients in the near future. Meanwhile, Dr. Nathanson’s lab capitalized on the finding that EGFR regulates glucose metabolism to employ PET imaging as a tool to measure the metabolic vulnerabilities in glioblastoma that can potentially be exploited pharmacologically, improving how patients respond to targeted EGFR inhibitors. The researchers are using their newly developed biomarker to look for other potent brain-penetrant EGFR inhibitors.
In all of the UCLA SPORE projects, Dr. Cloughesy says, the common theme is developing ways to overcome resistance to current therapies. “There’s not going to be one cure for glioblastoma,” Dr. Liau adds. “It’s going to require a complex interplay of different treatments and stratification of different patients, as we learn which ones work for which type of tumor and which type of patient.”