Brian Barth, Ph.D.

Brian Barth, Ph.D.

Assistant Professor of Pharmacology

Educational Background:

Post Dococtoral Fellow, Pharmacology, Penn State College of Medicine 2012
Ph.D. Biochemistry and Molecular Biology, Neuroscience Option, University of Alaska Fairbanks, 2009
M.S. Cell and Molecular Biology, Colorado State University, 2005
B.S. Biochemistry and Molecular Biology, Colorado State University, 2004

Training:

Postdoctoral Fellowship, Pharmacology, Penn State College of Medicine
Instructorship, Hematology and Oncology, Penn State Hershey Cancer Institute (2012-2015)

General Area of Interest and/or Specialty:

Cancer, leukemia, experimental therapeutics, sphingolipid biology, NADPH oxidase, nanomedicine, natural products, drug discovery

Research Statement

My overarching research goal is to understand how dysfunctional sphingolipid metabolism contributes to the development and progression of diseases such as acute myeloid leukemia (AML). I am particularly interested in utilizing this knowledge to discover and develop experimental therapeutic modalities that manipulate these biologically relevant pathways. In order to facilitate my goals as a researcher, I have divided my research into two categories: 1) sphingolipid and NADPH oxidase biology in leukemia, and 2) experimental therapeutics and nanomedicine. In order to address these areas I have developed a translational research program that utilizes state-of-the-art animal models to characterize the pathobiology of disease as well to engage in effective preclinical experimental therapeutic testing. By understanding how sphingolipid biology varies in the pathobiology of leukemia, we can initiate drug discovery processes, including from natural products, to identify and optimize new therapeutically active molecules.

Sphingolipid and NADPH Oxidase Biology in Leukemia

Ceramide is a sphingolipid noteworthy for its roles in regulating cellular stress responses and apoptosis. It has been postulated that cellular ceramide levels are diminished in malignant conditions while pro-oncogenic metabolites increase. My research has focused on evaluating sphingolipid metabolism in AML, as well as specific metabolism of drug-like ceramide analogs. We have learned that flux through sphingolipid metabolic pathways varies considerably in AML yet specific differences persist that seem to be unique to disease progression and status. Therefore, it is hypothesized that changes in sphingolipid metabolism reflect progression of AML, and related hematological disorders, to a phenotype where ceramide-based therapeutics are only effective in combination with inhibitors of ceramide metabolism. In addition, ceramide and metabolites such as ceramide-1-phosphate are important regulators of NADPH oxidases. These enzymes can augment proliferation and promote survival by redox signaling mechanisms that enhance leukemogenic signaling networks, and not surprisingly are upregulated in AML. Hence, it is further hypothesized that AML with augmented NADPH oxidase activity has the ability to survive and proliferate in spite of elevations in otherwise pro-apoptotic ceramide. Therefore, the development of strategies to block NADPH oxidases may be useful to direct ceramide-based therapeutic effects towards apoptosis. My research program evaluates differences in sphingolipid metabolism in AML and other hematological disorders, and manipulate s sphingolipid metabolism in order to gain further knowledge of its relevance to disease progression as well as to develop better therapeutic modalities. Additionally, my lab’s research uses approaches, including transgenic animal models, to identify links between ceramide accumulation and the reinforcement of leukemogenic signaling pathways through the NADPH oxidase. Altogether, a better understanding of the links between sphingolipid biology and NADPH oxidases can help to improve sphingolipid-based therapeutic strategies for AML. 

Experimental Therapeutics and Nanomedicine

It is a primary goal of my lab's research to apply the knowledge gained from mechanistic biological studies to the development and testing of translational experimental therapeutics. There is a particular interest in chemical library and natural product screening, as well as in the development of nanodelivery systems for drug delivery. Our research team has adapted bioassays for screening approaches which target different aspects of AML pathobiology. In this way, chemical libraries have been screened for compounds that enhance nanoliposomal ceramide (e.g. 7,8-benzoflavone), and which have subsequently been formulated into nanoliposomes to enhance in vivo therapeutic efficacy. Likewise, our research team has employed these assays in coordination with chemist colleagues through a natural products fractionation process with the goal of identifying novel therapeutics. One example has been the evaluation of Oplopanax horridus (Devil’s club), which is a plant native to Alaska and the Pacific Northwest that is used in traditional indigenous medicine. Using bioassay-directed approaches, extracts and refined fractions have been identified with potent anti-AML activity. In vivo efficacy of extracts has been further evaluated using immunodeficient mice engrafted with human AML. Improvements to the therapeutics identified through these natural products and chemical library screening efforts occurs primarily by formulating them into nanodelivery systems. Fundamentally, our research with nanotechnologies seeks to improve the ability to deliver therapeutic molecules to target cells while simultaneously decreasing systemic toxicity. As an example of this utility, our previous research developed CD117 (c-kit)-targeted nanoparticles to preferentially target blast-crisis chronic myeloid leukemia cells in an in vivo murine model. Overall, my research program embraces nanotechnology platforms as a means to enhance therapeutics identified through mechanistic laboratory science and screening processes. The ability to validate experimental therapeutics in robust animal models is a hallmark of my lab’s endeavors.​

Publications

Morad SA, Tan SF, Feith DJ, Kester M, Claxton DF, Loughran TP Jr., Barth, BM, Fox TE, Cabot MC  (2015). Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia--Impact on enzyme activity and response to cytotoxics. Biochimica et biophysica acta. 2015; 1851(7):919-28.

Barth BM, Brown TJ, Adams MT, Garcia AM, Fisher LN, et al. (2015) Combinatorial Efficacy of Nanoliposomal Ceramide and the Antioxidant 7,8- Benzoflavone for Acute Myeloid Leukemia.  Journal of Leukemia.; 2:152.

McGill CM, Alba-Rodriguez EJ, Li S, Benson CJ, Ondrasik RM, Fisher LN, Claxton DF, Barth BM (2014). Extracts of Devil's club (Oplopanax horridus) exert therapeutic efficacy in experimental models of acute myeloid leukemia. Phytotherapy research : PTR. 2014; 28(9):1308-14.

Doi K, Liu Q, Gowda K, Barth BM, Claxton D, et al. (2014). Maritoclax induces apoptosis in acute myeloid leukemia cells with elevated Mcl-1 expression. Cancer biology & therapy. 2014; 15(8):1077-86.

Matters GL, Cooper TK, McGovern CO, Gilius EL, Liao J, Barth BM, Kester M, Smith JP. (2014). Cholecystokinin mediates progression and metastasis of pancreatic cancer associated with dietary fat.  Digestive diseases and sciences. 2014; 59(6):1180-91.

Barth BM, Keasey NR, Wang X, Shanmugavelandy SS, Rampal R, et al. (2014). Engraftment of Human Primary Acute Myeloid Leukemia Defined by Integrated Genetic Profiling in NOD/SCID/IL2rγnull Mice for Preclinical Ceramide-Based Therapeutic Evaluation. Journal of Leukemia. 2014; 2:146.

Hankins JL, Ward KE, Linton SS, Barth BM, Stahelin RV, et al. (2013). Ceramide 1-phosphate mediates endothelial cell invasion via the annexin a2-p11 heterotetrameric protein complex. The Journal of biological chemistry. 2013; 288(27):19726-38.

Barth BM, Shanmugavelandy SS, Kaiser JM, McGovern C, Altınoğlu Eİ, et al. (2013). PhotoImmunoNanoTherapy reveals an anticancer role for sphingosine kinase 2 and dihydrosphingosine-1-phosphate. ACS nano. 2013; 7(3):2132-44.

Brown TJ, Garcia AM, Kissinger LN, Shanmugavelandy SS, Wang X, et al. (2013). Therapeutic Combination of Nanoliposomal Safingol and Nanoliposomal Ceramide for Acute Myeloid Leukemia. Journal of Leukemia. 2013; 1:110.

Barth BM, Shanmugavelandy SS, Tacelosky DM, Kester M, Morad SA, et al. (2013). Gaucher's disease and cancer: a sphingolipid perspective. Critical reviews in oncogenesis. 2013; 18(3):221-34.

Hankins JL, Doshi UA, Haakenson JK, Young MM, Barth BM, et al. (2013). The therapeutic potential of nanoscale sphingolipid technologies. Handbook of experimental pharmacology. 2013; (215):197-210.

Barth BM, Gustafson SJ, Hankins JL, Kaiser JM, Haakenson JK, et al. (2012). Ceramide kinase regulates TNFα-stimulated NADPH oxidase activity and eicosanoid biosynthesis in neuroblastoma cells. Cellular signalling. 2012; 24(6):1126-33.

Tacelosky DM, Creecy AE, Shanmugavelandy SS, Smith JP, Claxton DF, Adair JH, Kester M, Barth BM. (2012). Calcium phosphosilicate nanoparticles for imaging and photodynamic therapy of cancer. Discovery medicine. 2012; 13(71):275-85.

Barth BM, Gustafson SJ, Kuhn TB. (2012). Neutral sphingomyelinase activation precedes NADPH oxidase-dependent damage in neurons exposed to the proinflammatory cytokine tumor necrosis factor-α. Journal of neuroscience research. 2012; 90(1):229-42.

Hankins JL, Fox TE, Barth BM, Unrath KA, Kester M. (2011). Exogenous ceramide-1-phosphate reduces lipopolysaccharide (LPS)-mediated cytokine expression. The Journal of biological chemistry. 2011; 286(52):44357-66.

Barth BM, Cabot MC, Kester M. (2011). Ceramide-based therapeutics for the treatment of cancer. Anti-cancer agents in medicinal chemistry. 2011; 11(9):911-9.

Jiang Y, DiVittore NA, Kaiser JM, Shanmugavelandy SS, Fritz JL, Heakal Y, Tagaram HR, Cheng H, Cabot MC, Staveley-O'Carroll KF, Tran MA, Fox TE, Barth BM, Kester M. (2011). Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer biology & therapy. 2011; 12(7):574-85.

Barth BM, I Altinoğlu E, Shanmugavelandy SS, Kaiser JM, Crespo-Gonzalez D, et al. (2011).  Targeted indocyanine-green-loaded calcium phosphosilicate nanoparticles for in vivo photodynamic therapy of leukemia. ACS nano. 2011; 5(7):5325-37.

Tagaram HR, Divittore NA, Barth BM, Kaiser JM, Avella D, et al. (2011). Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut. 2011; 60(5):695-701.

Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, et al. (2011). Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nature medicine. 2011; 17(1):55-63.

Barth BM, Gustafson SJ, Young MM, Fox TE, Shanmugavelandy SS, et al. (2010). Inhibition of NADPH oxidase by glucosylceramide confers chemoresistance. Cancer biology & therapy. 2010; 10(11):1126-36.

Chapman JV, Gouazé-Andersson V, Messner MC, Flowers M, Karimi R, Kester M, Barth BM, Liu X, Liu YY, Giuliano AE, Cabot MC. (2010). Metabolism of short-chain ceramide by human cancer cells--implications for therapeutic approaches. Biochemical pharmacology. 2010; 80(3):308-15.

Barth BM, Sharma R, Altinoğlu EI, Morgan TT, Shanmugavelandy SS, et al. (2010). Bioconjugation of calcium phosphosilicate composite nanoparticles for selective targeting of human breast and pancreatic cancers in vivo. ACS nano. 2010; 4(3):1279-87.

Barth BM, Stewart-Smeets S, Kuhn TB. (2009). Proinflammatory cytokines provoke oxidative damage to actin in neuronal cells mediated by Rac1 and NADPH oxidase. Molecular and cellular neurosciences. 2009; 41(2):274-85.

Altinoğlu EI, Russin TJ, Kaiser JM, Barth BM, Eklund PC, et al. (2008). Near-infrared emitting fluorophore-doped calcium phosphate nanoparticles for in vivo imaging of human breast cancer. ACS nano. 2008; 2(10):2075-84.

Gustafson SJ, Barth BM, McGill CM, Clausen TP, Kuhn TB. (2007). Wild Alaskan blueberry extracts inhibit a magnesium-dependent neutral sphingomyelinase activity in neurons exposed to TNFa. Current Topics in Nutraceutical Research. 2007; 5(4):183-188.

 

 

Rudman Hall, Room 383
Durham, NH 03824
Phone: 
(603) 862-3422