Translational Neuro-Oncology Laboratory

The Laboratory for Translational Neuro-Oncology at the UPMC Hillman Cancer Center, under the direction of Kalil Abdullah, MD, MSc, is focused on developing novel clinical models of glioma and identifying druggable targets to facilitate early phase clinical trials. 

Gliomas are intensely heterogenous tumors that not only contain numerous cell types, but also demonstrate the ability to transition between different phenotypic states. This complexity has made developing model systems that recapitulate human tumor biology both difficult and essential. Traditionally, models of gliomas are 2-dimensional cell lines and only represent certain subtypes of the highest-grade glioma, glioblastoma. This is because the unique biology of lower grade gliomas has prevented them from being studied either outside of the lab or in animals. Ex-vivo culture systems have been created allowing researchers to investigate critical aspects of the tumor microenvironment, immune response, and discover targets for therapy. The laboratory has previously shown the ability to establish lower grade glioma organoids in vitro, maintain those cultures for extended periods of time, hibernate, and then reanimate tumor tissue without loss of either genetic or phenotypic fidelity. This work also includes extensive and sophisticated live-cell imaging analysis that allows for longitudinal, non-invasive assessment of organoid response to treatment.

The organoid model systems, in addition to glioma stem cell and mouse models, allows researchers to perform highly sophisticated assessments of drug response across platforms, and identify rare but critical druggable targets in gliomas. These analyses include complex metabolic tracing and immune cell response assessment. Despite the fundamental principles of genomics, immunology, and cellular cancer biology that underlie this work, the Translational Neuro-Oncology Lab group focuses on projects that have high potential for immediate clinical translation.  

A major area of focus in our lab is exploiting metabolic vulnerabilities in glioma. We have identified a series of critical metabolic targets through large-scale multi-omic screens that are promising drug targets. Our work in this area represents a synergy between comprehensive molecular and mechanistic approaches and cancer neuroscience. 

Studying metabolic vulnerabilities in glioma, a type of brain tumor, has the potential to yield significant advances in our understanding of tumor biology and the development of novel therapeutic strategies. Gliomas exhibit distinct metabolic alterations compared to normal brain tissue, which can be exploited to target and treat these tumors more effectively. Here are key advances that can be made from studying metabolic vulnerabilities in glioma:

  1. Identification of metabolic alterations: Investigating the metabolic profile of glioma cells can reveal specific alterations in metabolic pathways compared to normal brain cells. This includes changes in glucose metabolism, amino acid metabolism, lipid metabolism, and mitochondrial function. Understanding these alterations provides valuable insights into the tumor’s unique metabolic requirements and vulnerabilities.
  2. Targeting altered glucose metabolism: Glioma cells often exhibit increased glucose uptake and utilization, known as the Warburg effect. Exploiting this metabolic dependency, researchers can develop targeted therapies that interfere with glucose metabolism. For example, inhibiting key enzymes involved in glucose metabolism or employing drugs that selectively target glucose transporters on tumor cells can impair their energy production and growth.
  3. Exploiting amino acid metabolism: Glioma cells have distinct amino acid requirements for survival and growth. Studying the altered amino acid metabolism in gliomas can lead to the identification of vulnerabilities that can be targeted therapeutically. For instance, specific amino acid transporters or enzymes involved in amino acid metabolism can be targeted to disrupt the tumor’s nutrient supply and inhibit its proliferation.
  4. Targeting lipid metabolism: Altered lipid metabolism is another characteristic feature of gliomas. Tumor cells may rely on increased lipid synthesis to meet their energy and membrane synthesis needs. Understanding the specific alterations in lipid metabolism pathways within glioma cells can open avenues for developing therapies that disrupt lipid synthesis or utilization, effectively targeting tumor growth.
  5. Expanding therapeutic options: The study of metabolic vulnerabilities in glioma can provide new avenues for developing targeted therapies beyond traditional approaches like surgery, radiation, and chemotherapy. By exploiting the unique metabolic features of glioma cells, researchers can identify and develop drugs or combination therapies that specifically target these vulnerabilities, potentially leading to more effective and less toxic treatment options.
  6. Personalized medicine approaches: Metabolic profiling of glioma tumors can provide valuable information for personalized medicine approaches. Analyzing the metabolic characteristics of individual tumors can help identify patient-specific vulnerabilities and guide the selection of targeted therapies. This approach allows for tailored treatment strategies that consider the unique metabolic profile of each patient’s tumor, potentially improving treatment outcomes.
  7. Overcoming therapeutic resistance: Gliomas often develop resistance to conventional therapies, posing a significant challenge for successful treatment. Investigating metabolic vulnerabilities can offer insights into the mechanisms underlying treatment resistance and help develop strategies to overcome it. By targeting the metabolic alterations that drive therapy resistance, researchers can enhance the effectiveness of existing treatments or develop new therapeutic approaches to combat resistant gliomas.

By targeting the altered metabolic pathways and vulnerabilities specific to glioma cells, researchers can potentially improve treatment outcomes, overcome therapeutic resistance, and pave the way for more personalized and effective approaches to managing this challenging form of brain tumor. To that end, the TNO maintains active collaboration with other laboratories and pharmaceutical companies worldwide. Because of the nature of their research, a close interplay between the neurosurgical operating room and the laboratory is paramount. As such, they have an expansive team of highly motivated scientists and clinical research coordinators that facilitate tissue acquisition, processing, and analysis.