Brain Tumor Research
Our brain tumor 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, and the development of preclinical animal 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 targeted therapies. This commitment begins in the operating room, where a portion of most tumor samples is retrieved for laboratory investigation. These specimen are critical to the development of translational targets for brain tumor therapy. This initiative has led to the banking and study of hundreds of unique tumor samples, facilitating personalization of brain tumor care for future generations of 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 gliomas. Phase I clinical trial is currently being designed based on these findings.
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.
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. These preclinical studies are coupled with a robust clinical trials effort in association with the Adult Brain Tumor Consortium and the Pediatric Brain Tumor Consortium (PBTC), which are examining novel molecularly agents in the treatment of 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. AZD6244) for children with BRAF-altered low-grade gliomas, which are being conducted by the PBTC.
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. In addition, our surgeons and pathologists have identified a molecular panel that can help predict chordoma clinical behavior and prognosis.
Currently, management of 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 28 years, the Center for Image Guided Neurosurgery has provided care to more than 10,000 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 and Cyberknife and True beam technologies at UPMC Shadyside, methods to enhance the efficacy and safety of radiation delivery have been pioneered. The International Gamma Knife 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 is rapidly replacing conventional radiation therapy as the initial procedure.
Another exciting area of research in our department involves the development of genetically engineered oncolytic herpes-simplex viruses 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. Further safety testing in preclinical models is warranted to move this strategy into clinical trials. Other elements of this work involve studying improvements to virus delivery and intratumoral viral spread.
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 surgery.
For more detailed information on brain tumor research at the University of Pittsburgh and UPMC, please visit the University of Pittsburgh Cancer Institute website.