Monoclonal Antibody Blocks Pro-Life Molecular Signaling in Pancreatic Tumors

A monoclonal antibody that selectively binds to connective tissue growth factor (CTGF) slows the progress of pancreatic tumors by decreasing the activity of XIAP (X-linked inhibitor of apoptosis), a protein that promotes cancer cell survival.

CTGF causes a variety of cellular responses including reduced cell adhesion and enhanced cell migration and proliferation. CTGF has also been shown to be essential for epithelial to mesenchymal transition (EMT), a process whereby normal functioning cells morph into ones that produce mainly scar tissue (of which collagen in the major protein component). Cellular responses to CTGF also have effects at the tissue level including remodeling, formation of new blood vessels (angiogenesis), changes in blood vessel architecture (permeability and stiffness), and replacement of normal tissue with scar tissue.

Treatment of pancreatic ductal adenocarcinoma (PDA) is hampered by poor tissue perfusion that restricts the amount of drug able to reach the tumor. Furthermore, cells in the tumor microenvironment produce molecules, such as CTGF, that provide "pro-life" cues that promote drug resistance in the cancer cells.

Investigators at Cold Spring Harbor Laboratory (NY, USA) used a mouse pancreatic cancer model to study the impact on tumor growth caused by the interaction between CTGF and Fibrogen Inc.'s (San Francisco, CA, USA) CTGF-specific monoclonal antibody, FG-3019.

They reported in the July 8, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that pancreatic tumors in mice treated with FG-3019 in combination with the chemotherapeutic drug gemcitabine stopped growing. The response to FG-3019 correlated with the decreased expression of a previously described promoter of chemotherapy resistance, the X-linked inhibitor of apoptosis protein.

"In addition to drug delivery being a problem, there is also this nurturing aspect that prevents cancer cells responding to the drugs," said senior author Dr. David A. Tuveson, professor of medical oncology at Cold Spring Harbor Laboratory. "Both CTGF and XIAP have been shown to be present in human pancreatic cancer tumors so combination therapy using antagonists of either molecule could be a feasible approach."

Related Links:
Cold Spring Harbor Laboratory
Fibrogen Inc.