Dr. Venneti’s lab studies the biology of pediatric and adult brain tumors (such as gliomas thought to be of glial origin) with a specific focus on understanding the regulation of cancer metabolism and epigenetics as drivers of pathology. Cancer cells including brain tumor cells reprogram their metabolism by altering nutrient uptake and metabolism to support their aberrant proliferation and survival. The two principle nutrients that cancer cells use are the sugar glucose and the amino acid glutamine. These two nutrients are central to many anabolic processes including the biosynthesis of ATP, nucleotides, proteins and lipids. Recent years have seen the emergence of the concept that metabolic reprogramming in cancer cells is not a passive process. Rather, oncogenes and inactivated tumor suppressors in cancer cells directly reprogram the metabolism of cancer cells. These metabolic pathways can directly rewire the epigenome and provide novel avenues to develop newer diagnostic and therapeutic targets.
Adult gliomas: A classic example of how metabolism is reprogramed in brain tumors and regulates epigenetic changes is isocitrate dehydrogenase (IDH) mutations in gliomas. Wild type IDH proteins form core components of the TCA cycle, where they catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). IDH mutations catalyze the generation of the oncometabolite D-2HG from α-KG. IDH-mutant tumors occur in younger adults and confer favorable prognosis relative to wild type gliomas. D2-HG generated in IDH-mutant tumors inhibits a variety of α-KG -dependent enzymes involved in DNA methylation and histone methylation. IDH 1/2 mutant gliomas show both DNA and histone hypermethylation, occurring as a consequence of elevated D2-HG, resulting in impaired cellular differentiation.
Pediatric gliomas: The Venneti lab studies how metabolism is reprogramed in pediatric gliomas including diffuse intrinsic pontine gliomas (DIPG) with histone mutations and ependymomas bearing C11orfRELA fusions. These studies are focused towards understanding cancer metabolism in these poorly studied tumors to enable the development of novel therapies. The overlap between brain development and brain tumors with respect to metabolic and epigenetic changes during brain development are also studied.
Imaging cancer metabolism: One of the focuses of the lab is to image cancer metabolism in patients. This is achieved by positron emission tomography (PET) imaging. PET imaging is a valuable non-invasive diagnostic tool that allows assessment of metabolism in vivo. This technique takes advantage on increased nutrient uptake by cancer cells and is based on injection of the nutrients glucose or glutamine labeled with radionuclides such as 18F or 11C into animal models or patients. The radionuclide undergoes decay emitting positrons that are localized by a PET scanner. We have successfully translated glutamine-based PET imaging to glioma patients and future projects are based on evaluating metabolic imaging as a biomarker for tumor progression and therapeutic response.
