Investigators at the University of Pennsylvania School of Medicine suspect that lab-grown brain organoids developed from a patient’s own glioblastoma may hold the answers on how best to treat this aggressive and very deadly form of brain cancer. These findings are based on a study with a keen interest in organoids—rapidly becoming an integral part of the drug discovery process.
The findings titled “A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter-and Intra-tumoral Heterogeneity” were recently published in Cell and reveal how glioblastoma organoids may serve as effective models to expeditiously test personalized treatment strategies.
A Difficult and Deadly form of Brain Cancer
Glioblastoma multiforme (GBM) are difficult to treat mostly due to tumor heterogeneity. Although recent breakthroughs in treatment—from surgery, radiation and chemotherapy to more advanced personalized cellular therapies—can slow tumor growth down and help patients live longer a cure doesn’t exist.
Currently investigators don’t have a way to recapitulate a tumor to probe for complex characteristics as well as rapidly and qualitatively assess which post-surgery therapies are optimal.
Organoids—grown in a lab—are derived from human pluripotent stem cells or patent tissues and grown to about the size of a pea—can recapitulate key genetic composition, brain cell type heterogeneity, and architecture as examples. With the availability of these models, researchers can recreate key features of patients’ diseased brains to support a more comprehensive and tailored analysis of their cancer and in the process imparting potentially additional ways to best attack the cancer.
The researchers sought a more rapid and reliable method to produce patient-derived glioblastoma organoids to capture the features and diversity of their respective parental tumors to support personalized testing therapies correlated to organoid profile as well as the establishment of a biobank for additional basic and translational glioblastoma research.
Why there have been Challenges?
The senior study lead Hongjun Song, reported, “While we’ve made important strides in glioblastoma research, preclinical and clinical challenges persist, keeping us from getting closer to more effective treatments. One hurdle is the ability to recapitulate the tumor to not only better understand its complex characteristics, but also to determine what therapies post-surgery can fight in a timelier manner.”
Organoids are beneficial for GBM research because 1) timing 2) ability to maintain cell type and 3) genetic heterogeneity. Brain tumor organoids developed this research group grow into use in a far more expeditious manner.
The researchers removed tumor specimens from 52 patients in order to grow corresponding tumor organoids in the lab reported Genetic Engineering and Biotechnology News. The team reports a successful 91.4% overall success rate for producing glioblastoma organoids (GBOs) with 66.7% of tumors expressing IDH1 mutation and 75% for recurrent tumors, within a couple weeks. Of great value, these glioblastoma organoids can be bio banked and recovered for ongoing analyses.
The team performed genetic, histological and molecular analyses in 12 patients in an attempt to establish that the newly generated GBOs had for the most part retained features and characteristics from the primary tumor in the patient. The team thereafter successfully transplanted 8 GBO samples into adult mouse brains. Importantly, the samples maintained key mutation expression up to three months thereafter. The research team, importantly, was able to observe in the mouse models, the infiltration of tumor cells into the surrounding brain tissue. This latter observation is a “major hallmark” of GMB.
Opening up New Models for Clinical Trials
The researchers subjected GBOs to standard-of-care and targeted therapies such as drugs from clinical trials and T (CAR-T) cell immunotherapy. The researchers demonstrated that for each treatment they evidenced how the organoid response differs and that any effectiveness was correlated to their genetic mutations in patient tumors.
These breakthroughs can open up new potential models for future clinical trials associated with personalized treatments based on individual patient tumor responses to various drugs.
A CAR-T Therapy Benefit
For example, the researchers observed some benefit in the organoids treated with CAR-T therapies, which have been employed in ongoing clinical trials to target EGFRvIII mutation, a driver of the disease. In six GBOs, the team evidenced the specific effect to patient GBOs with the EGFRvIII mutation with an expansion of CAR-T cells and reduction in EGFRvIII expressing cells.
Donald O’Rourke, MD and co-senior study investigator, concluded, “These results highlight the potential for testing and treating glioblastomas with a personalized approach. The ultimate goal is to work towards a future where we can study a patient’s organoid and test which CAR-T cell is going to be the best against their tumor, in real-time.” Moreover, shorter term goals are within reach: with the heterogeneity of glioblastomas, the ability for in vitro testing of various therapeutic options could aid in the refinement of patient enrollment in clinical trials because it is now potentially possible to more accurately define mutations and select the appropriate available targeted therapies for each one.
Hongjun Song, PhD, professor of neuroscience, Perelman School of Medicine, University of Pennsylvania
Donald O’Rourke, MD, professor in neurosurgery, director of the GBM Translational Center of Excellence, Penn’s Abramson Cancer Center