Innovative and cutting-edge brain tumor research conducted at the University of Pittsburgh Department of Neurological Surgery occurs across multiple campuses at the University of Pittsburgh including the John Rangos Research Center at UPMC Children’s Hospital of Pittsburgh, the University of Pittsburgh School of Medicine, and the UPMC Hillman Cancer Center.
Brain tumor research at the University of Pittsburgh is one of the largest clinical and most productive basic/translational brain tumor programs in the country, encompassing research across the adult and pediatric brain tumor science spectrum and supported heavily in funding from the National Institutes of Health and other generous foundations. University brain tumor research is collaborative with researchers and clinicians from diverse fields, including neurosurgery, radiation oncology, neuro-oncology, neuropathology, and neuroradiology, working together to tackle the complex challenges associated with brain tumors. This multidisciplinary collaboration fosters a comprehensive understanding of brain tumor biology, enables faster translation of discoveries into clinical practice, and ultimately improves patient care with clinical trials.
The following laboratories are focused on brain tumor research:
• Brain Tumor Metabolism and Functional Cancer Genomics Laboratory
Explores the underlying disease mechanism of pediatric brain tumors, with a specific interest in pediatric cancer stem cells, brain tumor metabolism, epigenetics, and post transcriptional and translational regulation. Directed by Antony MichaelRaj, PhD.
• Brain Tumor Nanotechnology Laboratory
Involved in the testing of nanoparticle constructs for the targeted imaging and therapy of patient-based brain tumor models. Directed by Constantinos G. Hadjipanayis, MD, PhD, and lab manager Alexandros Bouras, MD.
• Fiber Tractography Laboratory
Focused on the application of High-Definition Fiber Tractography for presurgical planning and intraoperative navigation to facilitate brain function preservation. Directed by Fang-Cheng (Frank) Yeh, PhD.
• Rich Brain Tumor Laboratory
Focuses on identifying novel therapeutic paradigms in the treatment of advanced cancers, primarily malignant brain tumors, through the prism of stem cell biology to identify core regulatory pathways amenable to pharmacologic targeting. Directed by Jeremy Rich, MD, deputy director of the UPMC Hillman Cancer Center.
• Translational Neuro-Oncology Laboratory
Develops novel preclinical models of glioma and identifies drug targets for early-phase clinical trials in patients with malignant brain tumors. Directed by Kalil Abdullah, MD.
Brain Tumor Research Advances
Significant contributions to brain tumor research have occurred at the University of Pittsburgh, with numerous groundbreaking discoveries and innovations. Researchers have pioneered novel techniques for intraoperative brain tumor visualization for fluorescence-guided surgery (FGS). In addition, brain tumor imaging has been developed at the University of Pittsburgh, such as advanced MRI and PET imaging, which allow for better visualization and characterization of tumors. These imaging tools aid in precise tumor diagnosis, treatment planning, and monitoring of treatment response.
Brain tumors are inherently immunosuppressive. 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. 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.
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 Brain Tumor Biology and Therapy Laboratory, led by Dr. Agnihotri, has recently identified novel and clinically actionable pathways in diffuse midline gliomas (DMG), pediatric gliomas, and glioblastoma multiforme (GBM) with publications in JCI Insight, Molecular Oncology, and Developmental Cell. Dr. Agnihotri was one of a handful of international researchers awarded a 2022 Distinguished Scientist Award and Grant from the Sontag Foundation for study of pediatric brain tumors. He also received an Idea Development Award from the Department of Defense and a V-Foundation grant to support his brain tumor research.
The Brain Tumor Evolution Therapy Lab, led by Dr. Hu, has focused on developing a new class of drugs for targeting the immune-suppressive microenvironment in glioblastoma and understanding molecular mechanisms of medulloblastoma metastatic dissemination. An important publication in Nature Cell Biology was published this year. This work in the lab has been supported by NIH/National Cancer Institute (NCI) R01 and NINDS R21 grants.
The Brain Tumor Metabolism and Functional Genomics lab, led by Dr. MichaelRaj, were involved in multiple high impact journal publications in Science and Nature Communications. Dr. MichaelRaj was the recipient of a new research grant by the Matthew Larson Foundation studying pediatric ependymomas.
The Pediatric Neurosurgery ImmunoOncology lab, led by Dr. Kohanbash, advanced research across multiple focus areas including preclinical testing of immunotherapies, big data generation and analysis, and radiochemistry. The lab published two primary research articles including a manuscript in Cancer Research Communications demonstrating the potential for a new PET imaging agent to be used for monitoring immunotherapy responses. The lab obtained new NIH R01 and R21 grant funding from the NCI and NINDS, respectively and received a grant from the Ian’s Friends Foundation to develop a novel swine model of DIPG.
Brain Tumor Translational Advances
The Department of Neurological Surgery brain research efforts have been at the forefront of developing innovative treatment strategies for brain tumors. Researchers have conducted extensive investigations into targeted therapies, immunotherapies, and gene therapies that hold great promise for improving patient outcomes. Their work has led to the development of clinical trials testing novel treatments, providing hope for patients who have limited options.
An important new clinical trial, which will be the first in the U.S. for newly diagnosed GBM patients, will be intraoperative photodynamic therapy (PDT). Patients will initially undergo a maximal resection of their GBM tumor with the use of 5-ALA fluorescence-guided surgery (FGS). After completion of tumor removal during surgery, intraoperative 5-ALA PDT will then be performed. Patients will then go onto their standard of care treatment options after their tumor removal and PDT. Enrollment of the first GBM patients will occur in late 2023, with Jan Drappatz, MD, associate director of neuro-oncology at UPMC, serving as the principal investigator.
In 2022, the University of Pittsburgh Department of Neurological Surgery became an integral part of the Glioblastoma Therapeutics Network, a collaborative effort by the National Cancer Institute (NCI). This program, led at UPMC by Kalil Abdullah, MD, and his Translational NeuroOncology Lab is designed to stimulate scientific and clinical teams from select institutions across the country to develop promising drugs in the laboratory and then design clinical trials that can be performed at multiple sites. As a component of this NIH-funded effort, researchers are currently evaluating new drugs that may be used to treat the most difficult brain cancer, glioblastoma. One of these drugs targets IDH-mutant gliomas, which are more common in younger adults. In addition to laboratory work, clinical trials are being planned for both new drugs.
A new form of treatment—magnetic hyperthermia therapy (MHT)—for GBM is now under development at the UPMC Hillman Cancer Center in the Brain Tumor Nanotechnology Laboratory, directed by Dr. Hadjipanayis. MHT relies on the intratumoral delivery of magnetic iron-oxide nanoparticles (MIONPs) for the generation of local hyperthermia after application of an alternating magnetic field (AMF). MHT is currently being studied in preclinical brain tumor models in combination with adjuvant therapies (chemoradiation). A trial has been launched for studying MHT for treatment of canines with spontaneous gliomas with Johns Hopkins University. Treatment planning is also under development with Penn State University. A new collaboration with Blue Pearl Pet Hospital in Pittsburgh is being established for further study of MHT in canine brain tumor patients prior to launching a clinical trial for human brain tumor patients.
Clinical Care Advances
As one of the highest volume tumor centers in the country, care of our neurooncology patients is facilitated by an emphasis on cutting-edge technology and clinical 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 41 years, the UPMC Center for Image-Guided Neurosurgery has provided care to more than 20,000 patients using minimally invasive options to biopsy, resect, or provide adjuvant therapies. 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 18,000 patients have been treated and over 1,400 articles, books, or chapters have been published) and linear accelerator radiation technologies at UPMC Shadyside, methods to enhance the efficacy and safety of radiation delivery have been pioneered.
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. Now updated this facility also serves as a site to explore less invasive strategies for tumor removal such as the endoscopic endonasal approaches, 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. This year, the UPMC Hillman Cancer Center obtained the AIRO/BrainLab system, allowing for intraoperative CT scanning to allow navigated instrumentation during oncologic spinal reconstruction, and high-fidelity intraoperative frameless registration for patients with brain tumors. This substantial investment is a foundational commitment to advancing state-of-the-art brain neurosurgical oncology care.
In 2023, Laser Interstitial Thermal Therapy (LITT) has been an area of emphasis at UPMC. Both the UPMC Hillman Cancer Center and UPMC Presbyterian utilize this technology for patients with brain tumors and radiation necrosis across our region and worldwide. One of the primary advantages of LITT is its minimally invasive nature, as it involves the use of a thin laser probe inserted directly into the target tissue. This allows for precise and localized treatment, reducing the risk of damage to surrounding healthy tissues. LITT is particularly beneficial for brain tumors and lesions, as it provides an alternative to open surgery, thereby minimizing the risk of complications, reducing hospital stays, and promoting quicker recovery times. Moreover, LITT is performed under real-time MRI guidance, enabling the neurosurgical team to monitor and adjust the treatment as necessary, ensuring optimal outcomes. Additionally, LITT is associated with lower morbidity rates and improved quality of life for patients, as it preserves neurological function and avoids the need for traditional open craniotomy procedures.
In 2023, a new academic-industrial partnership is being launched by the UPMC Department of Neurological Surgery, the University of Pennsylvania and Synaptive Medical. This new initiative entitled “Diffusion MRI-Guided Pre-Operative Planning for Supra-Total Resection of High-Grade Gliomas” will be led by Ragini Varma, PhD, professor of radiology at the University of Pennsylvania, and Constantinos Hadjipanayis, MD, PhD, in partnership with Wes Hodges, founder of Synaptive Medical, to provide an enhanced preoperative planning tool for brain tumor surgery that will facilitate extended safe resection of glioblastoma tumors that are not evident with conventional imaging. The tool will be created by integrating diffusion MRI based methods to visualize white matter pathways in edematous and infiltrated regions of the brain, into a commercial neuro planning and navigational software with Synaptive Medical Inc. that will be used by clinical partners at UPMC, the University of Pennsylvania, the University of Nebraska, and the Ochsner Clinic Foundation for evaluation of clinical utility and patient safety. The extended resection facilitated by the enhanced tool is expected to lead to better patient outcomes.
Focused ultrasound will now be available at UPMC for treatment of patients in 2024. Research efforts are underway to establish important clinical trials utilizing focused ultrasound for treatment of brain tumors by opening of the blood brain barrier and sonodynamic therapy in combination with 5-ALA administration.
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 ability to obtain fiber-tracking preoperatively has now been expanded to the UPMC Hillman Cancer Center at UPMC Shadyside, allowing a multimodal approach to tumor resection. The goal is to facilitate brain function preservation and recovery in patients undergoing complex brain tumor surgery.
For brain tumor patients, presurgical brain mapping is performed using magnetoencephalography (MEG), a cutting-edge technology and the most advanced method of functional brain imaging. MEG recordings provide a direct measurement of brain functions allowing brain surgeons to view critical functional areas of brain to determine the best way for removing brain tumors, while preserving brain function and improving recovery.