Page 19 - Hormel Report 2021

Project 2: Colon cancer is the third most common cancer diagnosed in men and women in the US. Beta-catenin is a central component of the Wnt sig- naling pathway, and its overexpression is associated with colon cancer. The importance of this pathway in cancer makes it a target for drug development; but despite efforts, the effectiveness of Wnt/beta- catenin inhibitors in clinical trials is to be determined; and strategies to identify patients who respond to the inhibitors are elusive. Cyclin-dependent kinase
2 (CDK2) plays a pivotal part in cell cycle regulation and is involved in several biological processes. Evidence suggests CDK2 inhibition elicits antitumor activity. We found at least one small molecular inhibitor of beta-catenin and CDK2 effective in suppressing colon cancer growth and continue to identify additional novel, nontoxic small molecule inhibitors. We also intend to complete the pharma- cokinetic, dose ranging and toxicology studies necessary to collect the preclinical data to support an Investigational New Drug application.
Project 3: Esophageal cancer is a major health issue worldwide with high mortality because of
its diagnosis at advanced stages. Chronic gastro- esophageal reflux disease (GERD) causes injury to the esophagus resulting in Barrett’s esophagus (BE). BE is the pre-neoplastic lesion preceding esophageal adenocarcinoma (EAC). Despite surgery, chemo- therapy, and radiotherapy, the 5-year survival of
EAC patients is less than 40%. Even after radical esophagectomy, only 10-20% of patients survive 5 years and those with inoperable cancer only anoth- er 13-29 months. In contrast, over 90% of patients with early stage disease after surgery or treatment survive 5 years or more. Thus early detection is critical for successful treatment. Preliminary analy- sis suggests that thromboxane A2 (TXA2) specific synthase (TBXAS) and TXA2 receptor (TBXA2R) are
highly expressed in BE and EAC patients accompa- nied by elevation of circulating TXA2. This pathway is constitutively activated during GERD-BE-EAC pro- gression. Notably, seratrodast, a TBXA2R antagonist, suppresses BE and EAC cell growth, suggesting a TXA2-targeting strategy for management of BE
and EAC.
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Publications:
• Cao, Y., Xie, L., Shi, F., Tang, M., Li, Y., Hu, J., Zhao, L., Zhao, L., Yu, X., Luo, X., Liao, W., and Bode, A. M. (2021) Targeting the signaling in Epstein-Barr virus-associated diseases: mechanism, regulation, and clinical study. Signal Transduct Target Ther 6, 15
• Li, Y., Shi, F., Hu, J., Xie, L., Zhao, L., Tang, M., Luo, X., Ye, M., Zheng, H., Zhou, M., Liu, N., Bode, A. M., Fan, J., Zhou, J., Gao, Q., Qiu, S., Wu, W., Zhang, X., Liao, W., and Cao, Y. (2021) Stabilization of p18 by deubiquitylase CYLD is pivotal for cell cycle progression and viral replication. NPJ Precis Oncol 5, 14
• Calderon-Aparicio, A., and Bode, A. M. (2021) Roles of regulator of chromosome condensa- tion 2 in cancer: Beyond its regulatory function in cell cycle. Oncol Rev 15, 525
• Hu, J., Li, Y., Li, H., Shi, F., Xie, L., Zhao, L., Tang, M., Luo, X., Jia, W., Fan, J., Zhou, J., Gao, Q., Qiu, S., Wu, W., Zhang, X., Liao, W., Bode, A. M., and Cao, Y. (2020) Targeting Epstein-Barr virus oncoprotein LMP1-mediated high oxidative stress suppresses EBV lytic reactivation
and sensitizes tumors to radiation therapy.
Theranostics 10, 11921-11937
• Bode, A. M., and Roh, E. (2020) Are FDA-
Approved Sunscreen Components Effective in Preventing Solar UV-Induced Skin Cancer? Cells 9
Figure 1: Sunlight-induced signaling in skin carcinogenesis