This proposal describes a 5-year career development plan with the goal of enabling Dr. Sriram Venneti to advance to the role of independent academic investigator and physician-scientist. Dr. Venneti has completed his clinical training in Anatomic Pathology and Neuropathology at the University of Pennsylvania and is currently engaged in a research fellowship at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Craig Thompson, an internationally recognized expert on cancer metabolism with a strong record of training clinician- scientists, will be the principle mentor. Dr. Eric Holland, renowned or his work in gliomas, and Dr. Jason Lewis, an expert in positron emission tomography (PET) imaging in cancer, will serve as co-mentors. Additionally, members of the advisory committee will provide scientific and career development guidance. This project builds on Dr. Venneti's previous research expertise and proposes further training in cancer metabolism, small animal PET imaging, brain tumor biology, research ethics, grant writing and biostatistics, by means of investigative research and formal course work. MSKCC has a rich and collaborative environment, and a strong institutional commitment to its trainees. At a minimum, Dr. Venneti will be provided with 75% protected research time. MSKCC thus provides the ideal setting for Dr. Venneti to carry out this program to transition to an independently funded academic scientist. The goal of this research is to unravel core metabolic pathways that gliomas use to survive and proliferate and to use this knowledge to develop more effective therapeutic strategies and diagnostic imaging modalities. Glutamine is the most abundant amino acid in the body and is an essential source of energy and macromolecules in many types of cancer;however, how glutamine is metabolized in gliomas driven by aberrant PI3K/AKT pathway activation (such as downstream of PDGFRA amplification and PTEN loss) or isocitrate dehydrogenase 1 (IDH1) mutations is not clearly understood. We address this significant gap in our knowledge by proposing the overall hypothesis that glutamine metabolism is central to the pathogenesis of gliomas and that 18fluorine-labeled glutamine (18F-FGln) can be used to image gliomas in vivo using PET.
Three specific aims will test this hypothesis. (1) Glutamine uptake will be evaluated in vivo using PET imaging with the glutamine analogue 18F-FGln in glioma animal models with PDGFRA amplification/PTEN loss or IDH1 mutations. (2) Glutamine metabolism will be determined in glioma cells lines bearing endogenous PDGFRA amplification/PTEN loss or IDH1 mutations. (3) Inhibition of glutamine metabolism by targeting the enzymes glutaminase and glutamate dehydrogenase will be evaluated as a viable therapeutic target for combatting gliomas with PDGFRA amplification/PTEN loss or IDH1 mutations in vitro and in vivo. These three aims together will enable development of a novel, non-invasive PET imaging modality to image glutamine metabolism in gliomas in vivo and to ascertain the role played by glutamine metabolism in the pathogenesis of gliomas, so as to create more effective ways to treat these deadly tumors.

Public Health Relevance

Glioblastomas, the most common malignant adult brain tumor, are highly aggressive and carry a dismal prognosis. Our goal is to assess nutrient metabolism in gliomas to understand the pathology of these tumors. This knowledge could be used to design newer and more effective therapies and diagnostic imaging tests.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Perkins, Susan N
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New York
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Giorgetti, Elisa; Yu, Zhigang; Chua, Jason P et al. (2016) Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing. Cell Rep 17:125-36
Kim, Michelle M; Parolia, Abhijit; Dunphy, Mark P et al. (2016) Non-invasive metabolic imaging of brain tumours in the era of precision medicine. Nat Rev Clin Oncol 13:725-739
Lu, Chao; Jain, Siddhant U; Hoelper, Dominik et al. (2016) Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352:844-9
Bayliss, Jill; Mukherjee, Piali; Lu, Chao et al. (2016) Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Sci Transl Med 8:366ra161
Wahl, Daniel R; Venneti, Sriram (2015) 2-Hydoxyglutarate: D/Riving Pathology in gLiomaS. Brain Pathol 25:760-8
Mucaj, V; Lee, S S; Skuli, N et al. (2015) MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma. Oncogene 34:2204-14
Venneti, Sriram; Huse, Jason T (2015) The evolving molecular genetics of low-grade glioma. Adv Anat Pathol 22:94-101
Ji, Minbiao; Lewis, Spencer; Camelo-Piragua, Sandra et al. (2015) Detection of human brain tumor infiltration with quantitative stimulated Raman scattering microscopy. Sci Transl Med 7:309ra163
Venneti, Sriram; Dunphy, Mark P; Zhang, Hanwen et al. (2015) Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci Transl Med 7:274ra17
Mathew, Lijoy K; Huangyang, Peiwei; Mucaj, Vera et al. (2015) Feedback circuitry between miR-218 repression and RTK activation in glioblastoma. Sci Signal 8:ra42

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