Brian Van Tine, M.D., Ph.D.

Associate Professor
Internal Medicine
Oncology

Cancer Biology Program
Molecular Cell Biology Program
Molecular Genetics and Genomics Program

  • 314-747-3096

  • 314-362-7942

  • 314-362-7086

  • 731 South West Tower

  • bvantine@WUSTL.EDU

  • https://sites.wustl.edu/vantinelab/

  • Cancer, Metabolism, Human in mouse Cancer Models, New Therapies, Tumor Models, Metobolomics, Mouse Genetics

  • Understanding the metabolism of sarcomas for therapeutic development

Research Abstract:

We focus on many areas of therapeutic tumor metabolism:

ASS1 (Argininosuccinate Synthase 1)<span style="font-size: 19.2px;"> – The goal of this project is to characterize the metabolic response to arginine deprivation in sarcomas that lack argininosuccinate synthase 1 (ASS1), an enzyme that aids in endogenous arginine production, thus making these tumors arginine auxotrophic. We are trying to identify additional points of therapeutic intervention that induce a synthetic lethal response when targeting sarcoma tumors, in combination with arginine depletion using pegylated arginine deiminase (ADI-PEG20).

ME1 (Malic Enzyme 1) – Synovial Sarcoma (SS) is an aggressive malignancy with a bimodal age distribution and a high metastatic potential. SS accounts for approximately 10% of all soft tissue sarcomas. Currently, there are no FDA approved targeted therapies for SS. The primary focus of my research is identification and functional evaluation of metabolic dependencies in Synovial Sarcoma. We have identified aberrations in malic enzyme 1 (ME-1) expression in synovial sarcoma and other soft tissue sarcomas.  ME1 catalyzes the oxidative decarboxylation of malate to generate pyruvate and CO2, producing NADPH from NADP+ in the process. NADPH is an essential reducing equivalent within the cell, providing electrons for reductive biosynthesis and recycling of cellular antioxidant systems. I am currently studying the metabolic consequences of variable ME1 expression in SS, specifically the effect on glutamine utilization and redox homeostasis. Understanding the cellular mechanisms that compensate for variable ME1 expression in SS and other cancers may identify metabolic dependencies that are therapeutically actionable.

PHGDH – Osteosarcoma is the most common type of primary malignant bone tumor. Current treatment regimens use high-dose methotrexate, which targets the folate pathway by inhibiting dihydrofolate reductase, as part of a pathway that converts serine to purines. We hypothesized that inhibition of PHGDH, the rate-limiting step in serine biosynthesis, would be active for the treatment of osteosarcoma, and are exploring methods of inhibiting the resulting survival pathways to develop novel therapies for osteosarcoma.

Lipids – Our lab has shown that many sarcomas deficient in ASS1 are able to evade cell death over time, even when treated with ADI-PEG20. This project focuses on understanding fatty acid metabolism by identifying lipid localization, recycling, and response of cells to inhibition of beta oxidation.

Selected Publications:

1.Bean GR, Kremer JC, Prudner BC, Schenone AD, Yoa, J,
Schultze, MB, Chen, DY, Tanas, MR, Adkins, DR, Bomalaski, J, Rubin, BP, Michel,
L, Van Tine BA. A Metabolic Synthetic Lethal
Strategy with Arginine Deprivation and Chloroquine Leads to Cell Death in ASS1
Deficient Sarcomas. Cell Death and Disease. 2016

2.Kremer JC, Prudner BC, Lange SE, Bean GR, Schultze MB,
Brashears CB, Radyk MD, Redlich N, Tzeng SC, Kami K, Shelton L, Li A, Morgan Z,
Bomalaski JS, Tsukamoto T, McConathy J, Michel LS, Held JM, Van Tine BA.
Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine
Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers. Cell reports
2017, 18(4):991-1004.

3.Kremer JC, Van Tine BA. Therapeutic
arginine starvation in ASS1-deficient cancers inhibits the Warburg effect. Mol
Cell Oncol. 2017 Mar 1;4.

4. Prudner BC, Sun F, Kremer JC, Xu J, Huang C, Sai KKS,
Morgan Z, Leeds H, McConathy J, Van Tine BA. Amino Acid Uptake
Measured by AFETP Increases in Response to Arginine Starvation in ASS1-Deficient
Sarcomas. Theranostics. 2018 Mar 7:8(8):2107-2116.

5. Prudner BC, Rathore R, Robinson AM, Godec A, Chang SF,
Hawkins WG, Hirbe AC, Van Tine BA. Arginine Starvation and
Docetaxel Induce c-Myc-Driven hENT1 Surface Expression to Overcome Gemcitabine
Resistance in ASS1-Negative Tumors. Clin Cancer Res. 2019 Aug 15. Doi: 10.
1158/1078-0432.CCR-19-0206. Epub 2019 May 21.

6. Rathore R, Schutt CR, Van Tine BA. PHGDH
as a mechanism for resistance in metabolically-driven cancers. Cancer Drug
Resist. 2020;3:762-774. doi: 10.20517/cdr.2020.46. Epub 2020 Sep 17

7. Rogers LC, Zhou J, Baker A, Schutt CR, Panda PK, Van
Tine BA
. Intracellular arginine-dependent translation sensor reveals the
dynamics of arginine starvation response and resistance in ASS1-negative cells.
Cancer Metab. 2021 Jan 21;9(1):4. doi: 10.1186/s40170-021-00238-9.

8. Rathore R, Caldwell KE, Schutt C, Brashears CB,
Prudner BC, Ehrhardt WR, Leung CH, Lin H, Daw NC, Beird HC, Giles A, Wang WL,
Lazar AJ, Chrisinger JSA, Livingston JA, Van Tine BA. Metabolic
compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate
dehydrogenase inhibition in osteosarcoma. Cell Rep. 2021 Jan 26;34(4):108678.
doi: 10.1016/j.celrep.2020.

Last Updated: 3/23/2021 2:53:29 PM

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