Biography:

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Dr. Byung-Gyu Kim obtained his PhD from Seoul National University in Seoul (the most fun city in the world!), South Korea with a project focusing on defining the role of cytokines in enhancing anti-tumor immune responses. Thereafter, he served as an Instructor at Yonsei University Medical School, investigating the role of Hox genes in liver regeneration and tumorigenesis, and mentoring graduate and medical students. He then moved to NCI/NIH in Washington DC (the second most fun city in the world!) to investigate TGF-beta signaling in the development and function of lymphocytes, and examined the importance of Smad4-dependent TGF-beta signaling in T cells as a requirement for suppression of spontaneous cancer in gastrointestinal tract. In 2006, he moved to Case Western Reserve University in Cleveland (yet another fun place!), Ohio to focus on the studies below.

 

My long-term research goals are to elucidate the cellular and molecular mechanisms of autoimmune diseases, inflammation and cancer. These efforts aim to provide greater understanding of the link between the disease pathogeneses and the immune system, and the development of therapeutically effective intervention strategies. In line with these long-term goals, three lines of research are being actively explored: 1) Mechanisms of Inflammation and Cancer, 2) Therapeutic Drugs for These Diseases, and 3) Cancer Immunotherapy by Inhibiting TGF-β Signaling. Modulation of inflammation and immune function is a common integrative theme among these three areas of research.

 

1. Mechanisms of Inflammation and Cancer

The mediators and cellular effectors of inflammation are important constituents of the local tumor environment. I have specific interests in the role of transforming growth factor-beta (TGF-β) in the regulation of immune cell development and function. Elucidation of these pathways will increase understanding of the pathogenesis of human/animal immune-associated diseases, enabling development of therapeutic practices in experimental and ultimately clinical settings. Our research is focused on the mechanisms of TGF-β signaling in mucosal immune function and the microenvironment that regulates epithelial transformation. To fully understand the mechanisms underlying the pathogenesis of inflammation-driven cancer, we are investigating: 1a) factors involving differentiation and function of immune cells; 1b) molecules affecting the transformation of epithelial cells; and 1c) host immune responses to microbial infections.

 

2. Therapeutic Drugs for These Diseases

The above studies of the molecular mechanisms in the pathogenesis of inflammation and colitis-associated colon cancer (CAC) will aid in the design of better therapeutic strategies for treatment of these diseases. To fully understand the mechanisms underlying the small molecule chemoprevention of CAC, we have forged strong collaborations with other investigators to conduct actively research in three areas: 2a) small molecule induction of tumor suppressor genes; 2b) mechanistic role of triterpenoids on immune cells; and 2c) development of other drugs.

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3. Cancer Immunotherapy by Inhibiting TGF-β Signaling

More recently, we have established preclinical syngeneic murine models and are actively establishing humanized murine models of osteosarcoma (OS) and multiple myeloma (MM), which we have employed to explore mechanisms of therapy resistance, collaborating with pediatric and medical oncologists who have translated these efforts into new investigator-initiated clinical trials. Our hypothesis is that inhibition of the TGF-β pathway represents a novel approach to ameliorate OS progression and to overcome resistance to proteasome inhibitors (PIs) in MM. To test this hypothesis, we actively collaborate with industry partner, MedPacto Inc. to investigate small molecule-mediated targeting of the TGF-β receptors to: 3a) increase anti-OS effect of chemotherapy; 3b) overcome therapy resistance in MM; and 3c) enhance natural killer (NK) cell activity stimulated with Elotuzumab and cytotoxic T cell (CTL) activity in combination with immune checkpoint inhibitors (e.g. anti-PD-1).

 

Current Funding:

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NCI Small Grants Program for Cancer Research (NCI Omnibus R03) (1R03CA259901-01A1)

12/1/2021-11/30/2023  Total Direct Costs: $100,000

Mechanisms of TGF-b-induced resistance to proteasome inhibitors in multiple myeloma

The aim of this project is to define the mechanisms through which TGF-b induces resistance to proteasome inhibitors and to demonstrate the potential utility of TGF-b inhibitor for treatment of patients with relapsed or refractory multiple myeloma..

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Bibliography (Selected publications from more than 30):

 

Kim, B.G., Malek, E., Choi, S.H., Ignatz-Hoover J.J. and Driscoll, J.J.: Novel Therapies Emerging in Oncology to Target the TGF-β Pathway. Journal of Hematology & Oncology 14(1):55, 2021.

 

Choi, S.H., Barker, E., Gerber, K., Letterio, J.J.¶ and Kim, B.G.¶^: Loss of p27Kip1 leads to expansion of mucosal CD4+ effector memory T cells and accelerates colitis-associated colon cancer in mice with a T cell lineage restricted deletion of Smad4. OncoImmunology 9(1):1847832, 2020 (¶corresponding author).

 

Barker, E.*, Kim, B.G.*, Yoon, J., Tochtrop, G., Letterio, J.J. and Choi, S.H.: Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation. Carcinogenesis 39:36-46, 2018 (*shared first authorship).

 

Li, Y., Kim, B.G., Qian, S., Letterio, J.J., Fung, J.J., Lu, L. and Lin, F.: Hepatic stellate cells inhibit T cells through active TGFβ1 from a cell surface-bound latent TGFβ1/GARP complex. J. Immunol. 195:2648-2656, 2015.

 

Lam, E., Choi, S.H., Pareek, T.K., Kim, B.G.¶ and Letterio, J.J.¶: Cyclin-dependent kinase 5 represses Foxp3 gene expression and Treg development through specific phosphorylation of Stat3 at Serine 727. Mol. Immunol. 67:317-324, 2015.

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Choi, S.H.*, Kim, B.G.*, Robinson, J., Fink, S., Yan, M., Sporn, M.B., Markowitz, S.D. and Letterio, J.J.: Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis. J. Clin. Invest. 124:2472-2482. doi: 10.1172/JCI69672, 2014.

 

Inoshita, H.*, Kim, B.G.*, Yamashita, M., Choi, S.H., Tomino, Y., Letterio, J.J. and Emancipator, S.N.: Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations. PLoS One 8(11): e78736-e78. doi:10.1371/journal.pone.0078736, 2013.

 

Ko, I.K.*, Kim, B.G.*, Awadallah, A., Mikulan, J., Lin, P., Letterio, J.J. and Dennis, J.E.: Targeting improves MSC treatment of inflammatory bowel disease. Mol. Ther. 18: 1365-1372, 2010.

 

Kim, B.G., Li, C., Qiao, W., Mamura, M., Kasprzak, B., Anver, M., Wolfraim, L., Hong, S., Mushinski, E., Potter, M., Kim, S.J., Fu, X.Y., Deng, C. and Letterio, J.J.: Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441: 1015-1019, 2006.

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For complete list of published work, please visit: https://www.ncbi.nlm.nih.gov/myncbi/1Pew8HFC10N5AW/bibliography/public/

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