Dr. Zhiqiang An

Regular Member

The University of Texas Health Science Center at Houston
Medical School
Institute of Molecular Medicine

Research Interests:

• Antibody therapeutics
• Drug resistance mechanisms
• HER/ErbB signaling pathways
• Cancer targets
• Antibody response to experimental vaccines

We are studying the cancer drug resistance mechanisms in the human epidermal growth factor receptor (HER/ErbB) signaling pathways using monoclonal antibodies as platform technology. Drug resistance is often a limiting factor for clinical efficacy of existing cancer therapies. Growing evidence indicates that HER3/ErbB3 plays an important role in the overall HER signaling pathway and in drug resistance. Currently, there are no HER3-targeting therapies and clinical development of HER3 therapeutics is limited. By employing in vitro, in vivo, and clinical approaches, we are studying the molecular basis of physiological and pathophysiological states of the HER3 mediated signaling cascade. The proteolytic process mediated by proteases including matrix metalloproteinases (MMPs) in the tumor microenvironment plays a critical role in tumor growth, invasion, metastasis, and cancer drug resistance. The molecular mechanisms underlining the complex roles of proteases in cancer biology are currently poorly understood. Recent studies suggest that proteases in tumor microenvironment may invade host immunosurveillance by cleavage of antibodies or shedding cell surface receptors to allow cancer cells to escape immune response. We are studying the interactions between proteases and anti-tumor antibodies in the tumor microenvironment to delineate the roles of proteases play in tumor resistance to antibody immune therapies.

Projects/Techniques:

• Detection of phosphorylation states of signaling molecules in the HER/ErbB pathway in cancer cell lines, xenograft tissues, and in breast cancer clinical samples by Nanopro and Western blotting
• Visualization of protein-protein interactions on cell surface using Proximity Ligation Assay
• Testing therapeutic antibody drug efficacy in cancer xenograft models
• Generation of antibodies against cancer target via immunization and hybridoma methods
• Cloning of antibody encoding gene from antibody producing B cells and hybridoma cells
• Affinity maturation of antibody via phage display
• Humanization of antibodies for drug development
• Protein and antibody purification
• Development of stable cell line expressing cancer targets

Selected Publications:

Fan X, Brezski RJ, Fa M, Deng H, Oberholtzer A, Gonzalez A, Dubinsky WP, Strohl WR, Jordan RE, Zhang N, An Z. A 2012. single proteolytic cleavage within the lower hinge of trastuzumab reduces immune effector function and in vivo efficacy. Breast Cancer Res. 14(4):R116.

Byung-Kwon Choi, Xuejun Fan, Hui Deng, Ningyan Zhang, Zhiqiang An. 2012. ERBB3 (HER3) is a key sensor in the regulation of ERBB-mediated signaling in both low and high ERBB2 (HER2) expressing cancer cells. Cancer Medicine 1(1):28-38.

Choi B-K, Cai X, Yuan Y, Huang Z, Fan X, Deng H, Zhang N, An Z. (2012). HER3 intracellular domains play a crucial role in HER3/HER2 dimerization and activation of downstream signaling pathways. Protein & Cell 3(10):781-789.

Glantschnig H, Scott K, Hampton R, Wei N, McCracken P, Nantermet P, Zhao J, Vitelli S, Huang L, Haytko P, Lu P, Fisher J, Sandhu P, Cook J, Williams D, Strohl W, Flores O, Kimmel D, Wang F, Z. An. 2011. A rate-limiting role for DKK1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody. J Pharmacol Exp Ther. 338(2):568-578.

Glantschnig H, Hampton R, Lu P, Zhao J, Vitelli S, Huang L, Haytko P, Cusick T, Ireland C, Jarantow S, Ernst R, Wei N, Nantermet P, Scott K, Fisher J, Talamo F, Orsatti L, Reszka A, Sandhu P, Kimmel D, Flores O, Strohl W, An Z, and Wang F. 2010. Generation and Selection of Novel Fully Human Monoclonal Antibodies that Neutralize Dickkopf-1 (DKK1) Inhibitory Function in vitro and Increase Bone Mass in vivo. Journal of Biological Chemistry 17;285(51):40135-47.

Program Affiliation:

Program in Experimental Therapeutics