Wei Chen

Overview:

My general area of interest relates to how cancer develops and how to identify cancer therapeutic agents. In particular I hope to identify molecular signals that underlie the changes necessary for directing normal tissue to a malignant state in cancer. Therefore, I have been studying how extracellular signals are deciphered by seven trans-membrane receptors and their regulatory proteins to control cell proliferation and differentiation. My major research focuses on studying GPCR, Smoothened, TGF-beta and Frizzled receptor trafficking and signaling as well as their roles in tumor biology. Abnormalities in the receptors or other proteins they interact with either directly or indirectly result in malignancies. Moreover, as a result of our research, we have established a state-of-the-art high throughput, high content screening platform in my laboratory to identify novel small molecules that modulate the activity of these receptors. We have found many new small molecules that block Hedgehog pathway. These chemical compounds may have the potential to become new therapeutic agents to treat many refractory cancers of the pancreas, liver, breast, prostate, and skin.

Positions:

Associate Professor in Medicine

Medicine, Gastroenterology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1999

University of Toledo

Grants:

Targeting the WNT/beta-catenin pathway in triple negative breast cancer

Administered By
Medicine, Gastroenterology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Publications:

β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion.

Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic beta-cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating beta-cell function and whole body glucose homeostasis. Initially, we inactivated the Barr1 gene in beta-cells of adult mice (beta-barr1-KO mice). Beta-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, two widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in perifused KO islets in vitro. Additional in vivo and in vitro studies demonstrated that Barr1 enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. Pull-down and co-immunoprecipitation experiments showed that Barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote Barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These findings suggest that strategies aimed at promoting Barr1 signaling in beta-cells may prove useful for the development of efficacious antidiabetic drugs.
Authors
Barella, LF; Rossi, M; Zhu, L; Cui, Y; Mei, FC; Cheng, X; Chen, W; Gurevich, VV; Wess, J
MLA Citation
Barella, Luiz F., et al. “β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion.J Clin Invest, vol. 130, June 2019, pp. 3732–37. Pubmed, doi:10.1172/JCI126309.
URI
https://scholars.duke.edu/individual/pub1402624
PMID
31184597
Source
pubmed
Published In
J Clin Invest
Volume
130
Published Date
Start Page
3732
End Page
3737
DOI
10.1172/JCI126309

Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth.

The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.
Authors
Wang, J; Mook, RA; Ren, X-R; Zhang, Q; Jing, G; Lu, M; Spasojevic, I; Lyerly, HK; Hsu, D; Chen, W
MLA Citation
Wang, Jiangbo, et al. “Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth.Bioorg Med Chem, vol. 26, no. 20, Nov. 2018, pp. 5435–42. Pubmed, doi:10.1016/j.bmc.2018.09.016.
URI
https://scholars.duke.edu/individual/pub1353138
PMID
30274939
Source
pubmed
Published In
Bioorg Med Chem
Volume
26
Published Date
Start Page
5435
End Page
5442
DOI
10.1016/j.bmc.2018.09.016

Correction: phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion.

Authors
Hamilton, E; Blackwell, K; Hobeika, AC; Clay, TM; Broadwater, G; Ren, XR; Chen, W; Castro, H; Lehmann, F; Spector, N; Wei, J; Osada, T; Lyerly, HK; Morse, MA
MLA Citation
Hamilton, E., et al. “Correction: phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion.J Transl Med, vol. 11, 2013, p. 82. Pubmed, doi:10.1186/1479-5876-11-82.
URI
https://scholars.duke.edu/individual/pub932870
PMID
23536971
Source
pubmed
Published In
Journal of Translational Medicine
Volume
11
Published Date
Start Page
82
DOI
10.1186/1479-5876-11-82

Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.

The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress, suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab- and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific antiserum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine-induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific antiserum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted.
Authors
Morse, MA; Wei, J; Hartman, Z; Xia, W; Ren, X-R; Lei, G; Barry, WT; Osada, T; Hobeika, AC; Peplinski, S; Jiang, H; Devi, GR; Chen, W; Spector, N; Amalfitano, A; Lyerly, HK; Clay, TM
MLA Citation
Morse, Michael A., et al. “Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.Int J Cancer, vol. 126, no. 12, June 2010, pp. 2893–903. Pubmed, doi:10.1002/ijc.24995.
URI
https://scholars.duke.edu/individual/pub726619
PMID
19856307
Source
pubmed
Published In
Int J Cancer
Volume
126
Published Date
Start Page
2893
End Page
2903
DOI
10.1002/ijc.24995

Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling.

beta-Arrestins bind to activated seven transmembrane-spanning (7TMS) receptors (G protein-coupled receptors) after the receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of beta-arrestin 2 (betaarr2) for the single transmembrane-spanning type III transforming growth factor-beta (TGF-beta) receptor (TbetaRIII, also referred to as betaglycan). Binding of betaarr2 to TbetaRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-beta receptor (TbetaRII), which is itself a kinase, rather than by a GRK. Association with betaarr2 led to internalization of both receptors and down-regulation of TGF-beta signaling. Thus, the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.
Authors
Chen, W; Kirkbride, KC; How, T; Nelson, CD; Mo, J; Frederick, JP; Wang, X-F; Lefkowitz, RJ; Blobe, GC
MLA Citation
Chen, Wei, et al. “Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling.Science, vol. 301, no. 5638, Sept. 2003, pp. 1394–97. Pubmed, doi:10.1126/science.1083195.
URI
https://scholars.duke.edu/individual/pub691852
PMID
12958365
Source
pubmed
Published In
Science
Volume
301
Published Date
Start Page
1394
End Page
1397
DOI
10.1126/science.1083195