Basic Science Advances
Our brain tumor basic science research program is a world-class effort focused on delivering novel brain tumor therapies from the laboratory to the bedside. Areas of active investigation include immunotherapy, signal transduction pathways that contribute to the growth of tumor cells, oncolytic viruses, rare tumor exome sequencing, and the development of preclinical animal and brain organoid models for the treatment of brain tumors.
At the core of our program is a commitment to personalized medicine and the development of patient-specific therapies. This commitment begins in the operating room—where with patient consent—tumor samples are retrieved for laboratory investigation under controlled research tumor banking protocols. These specimens are critical to the development of translational targets for brain tumor therapy and brain organoid formation for the investigation of novel biological therapies. This initiative has led to the banking and study of thousands of unique tumor samples, facilitating personalization of brain tumor care for our patients.
Brain tumors are inherently immunosuppressive. Each tumor develops unique mechanisms to escape natural anti-tumor immune responses. We have recently discovered a unique immune escape mechanism that involves silencing of immune recognition genes. Importantly, we have discovered that a new class of tumor drugs, called ‘hypomethylating agents’, can awaken the expression of these genes and allow effective immune responses in IDH mutant gliomas. A Phase I clinical trial is currently being designed based on these findings and is currently being refined by the Alliance for Clinical Trials in Oncology consortium in preparation for a multicenter clinical trial.
Additionally, our program has a strong focus on developing personalized brain tumor therapy by studying humanoid brain organoid tumor models, a biologically more accurate model that simulates a patient’s condition in miniature in the laboratory by replicating the patient’s brain from induced pluripotent stem cells. These organoids are subsequently used to evaluate the biological and genetic evolution of individual brain tumors and, subsequently, to generate and test personalized therapies based on these findings. The desire to develop truly personalized medicine strategies is at the heart of these efforts.
Another exciting area of research in our department involves the development of genetically engineered oncolytic herpes-simplex viruses (oHSV) that can selectively kill proliferating glioma cells but not normal brain cells. Promising preclinical studies in mouse models indicate that this strategy is highly effective for the treatment of glioblastoma. Several patents have been generated and licensed based on this work, and studies are ongoing to evaluate safety testing in preclinical models in anticipation of oHSV clinical trials in the near future.
Previous work in our brain tumor program identified new vaccine strategies for the treatment of gliomas. Researchers in our group developed glioma-associated antigen peptide vaccines to boost tumor-specific immune responses. Phase I clinical trials of these vaccines demonstrate robust induction of antigen-specific immune responses and some clinical activity in both adult and pediatric patients with glioma. These trials are ongoing at the University of Pittsburgh Cancer Institute and Children’s Hospital of Pittsburgh. Recent studies have identified patterns of gene expression in peripheral blood mononuclear cells that are associated with response and resistance to peptide-based vaccination in pediatric low-grade gliomas. Future studies will evaluate whether these features are also seen in other subgroups of childhood brain tumors incorporated on our vaccine trials.
Another strategy in brain tumor research is to inhibit the pathways that promote tumor growth or to stimulate those that promote tumor cell killing. The poor response of malignant gliomas to conventional therapies, such as cytotoxic chemotherapy or radiotherapy, reflects resistance of these tumors to undergoing apoptosis in response to DNA damage or mitogen depletion. Through a large-scale screening study, we have identified several exploitable targets, which when inhibited induce tumor cytotoxicity. We have been examining pharmacological agents to inhibit these targets, alone and in combination with agents that induce apoptotic signaling in these tumors.
The clinical research branch of our Brain Tumor Program currently runs “personalized” clinical studies based on patients’ gene markers, such as human leukocyte antigen (HLA)-A2 (for immunotherapy studies), epidermal growth factor receptor (EGFR) variant III and chromosome 1p/19q co-deletion. In addition, the program offers a host of molecularly targeted treatment approaches for children whose brain tumors have genomic alterations that make them ideally suited for specific novel-agent trials. These include studies of MEK inhibitors (e.g. Selumetinib) for children with BRAF-altered low-grade gliomas, which are being conducted by the PBTC and more recently, the Children’s Oncology Group.
Similarly, members of our group are studying rare skull base tumors such as chordoma by performing whole exome sequencing to search for novel genetic alterations in these tumors that could lead to a better understanding of their oncogenesis as well as targets for treatment. These targets are then evaluated to see if current therapies can be applied to these rare tumors. The impact of methylation in skull base tumors is also being studied to understand if these genetic changes, which occur throughout life, play a role in tumor prognosis. In addition, our surgeons and pathologists have identified a molecular panel that can help predict chordoma clinical behavior and prognosis. This panel is now applied on a regular basis to our patients to provide a personalized approach for current and future treatment
Clinical Care Advances
Currently, clinical care of patients with skull base tumors, primary brain tumors and metastatic brain tumors related to systemic cancer represent a major focus for our department’s activities. During the last 38 years, the Center for Image Guided Neurosurgery has provided care to more than 20,000 patients with such tumors as an adjuvant or alternative minimally invasive treatment strategy. One of the most important adjuvant strategies to control brain tumor progression is optimization of radiation delivery techniques. Using technologies such as Gamma Knife® radiosurgery at UPMC Presbyterian (over 17,000 patients and more than 1,000 published articles, books or chapters) and linear accelerator radiation technologies at UPMC Shadyside, methods to enhance the efficacy and safety of radiation delivery have been pioneered. The International Radiosurgery Research Foundation and corporate entities have funded UPMC to perform radiosurgery for recurrent malignant gliomas coupled with bevacizumab as part of a phase 2 clinical trial. Long term outcome assessments have been completed for patients with metastatic brain cancer, a condition where radiosurgery often has replaced conventional surgery and radiation therapy as the initial management..
Working in concert with these advanced radiosurgery and radiation technologies, the UPMC Center for Cranial Base Surgery is the oldest skull base center in North America. They have been a source of innovation for decades, helping develop new and less invasive approaches, such as the endoscopic endonasal and transorbital approaches, to limit the impact of surgery for these challenging tumors.
Since 1975 the department has been noted as a source of innovation in brain tumor diagnosis and management. In 1981 the first dedicated CT scanner was installed in a unique operating room at UPMC Presbyterian to facilitate minimally invasive surgical techniques. Updated in 2009, this facility also serves as a site to explore less invasive strategies for tumor removals such as the endoscopic endonasal approach, endoport resection using guiding technologies coupled with endoscopic removal, and transorbital approaches. Working hand in hand with our skull base program innovative combined strategies for tumor biopsy or removal followed by adjuvant radiosurgery, chemotherapy, or immunotherapy has offered new advances in patient care resulting in ever longer high-quality outcomes. Our pediatric program has also been enhanced by the opening of an intraoperative MRI suite, which facilitates the goal of achieving safer and more extensive resections in challenging childhood brain tumors
Innovative imaging techniques are being developed and applied to better understand brain tumors and their structural relationship with surrounding white matter tracts. High-Definition Fiber Tractography (HDFT) provides a superior presurgical evaluation of the fiber tracts for patients with complex brain lesions, allowing us to reconstruct fiber tracts and design a less invasive trajectory into the target lesion. We are currently investigating its potential for not only presurgical planning and intraoperative navigation but also for neurostructural damage assessment, estimation of postsurgical neural pathway damage and recovery, and tracking of postsurgical changes, neuroplasticity, and responses to rehabilitation therapy. The ultimate goal is to facilitate brain function preservation and recovery in patients undergoing complex brain tumor surgery.
For more detailed information on brain tumor research at the University of Pittsburgh and UPMC, please visit the Hillman Cancer Center website.