FibroGen, Inc., a biotechnology-based drug discovery company, announced the publication of two studies demonstrating that connective tissue growth factor (CTGF) plays a causative role in pancreatic cancer and that FG-3019, the company's fully human monoclonal antibody against CTGF, blocks tumour growth and metastases in preclinical models of pancreatic cancer. The studies were published in the May 22 issue of Molecular Cancer Therapeutics and the June 1 issue of Cancer Research.
The role of CTGF as the central mediator of tissue remodelling and fibrosis (persistent and excessive scarring) is well established in the scientific literature. Several recent studies also implicate CTGF in tumour progression, including tumour cell survival and metastasis, in which CTGF is a key link in the communication between tumour cells and their stroma (the area surrounding the tumour) during the desmoplastic reaction. Desmoplasia involves the formation and proliferation of fibroblasts (cells that produce fibers and structural elements found in the extracellular matrix) and of fibrous connective tissue around the growing cancer. Elevated CTGF levels have been detected in a number of late-stage cancers besides pancreatic, including breast, glioblastoma, and sarcomas.
In a study led by Amato Giaccia, Ph.D., Professor of Radiation Oncology and Radiation Biology at Stanford, researchers found that CTGF expression levels were elevated in tissue sections of pancreatic tumours. The scientists also examined human pancreatic cancer cells that were engineered to express high levels of CTGF and found this modification led to increased tumour growth in mice as a result of elevated levels of cell proliferation and decreased levels of apoptosis ("programmed" cell death, which is normally observed in diseased cells). The scientists also reported that tumour growth by the engineered cancer cells could be inhibited by blocking CTGF with FG-3019.
"These data provide the first direct evidence implicating CTGF as a causative factor in promoting the progression of pancreatic tumours and suggest that CTGF is a viable therapeutic target," said Dr. Giaccia.
In a separate study examining the effects of blocking CTGF activity with FG-3019, researchers at Dartmouth led by Murray Korc, M.D., Professor of Pharmacology and Toxicology and Chair of Medicine, implanted human pancreatic cancer cells into the pancreas of mice and treated them with FG-3019 two weeks after implantation. At the end of the six-week study, mice treated with FG-3019 exhibited decreased tumour growth and metastasis compared to control mice. The results also demonstrated that treatment with FG-3019 attenuated tumour angiogenesis (the formation of new blood vessels necessary for tumour cell survival and growth). There were no detectable drug-related side effects, and FG-3019 was not observed to interfere with the efficacy of gemcitabine, the current standard of clinical care, in this study.
"Our findings not only provide insight into the role of CTGF in tumour growth, progression and metastasis, but also suggest that FG-3019 warrants further study as a therapy for patients with pancreatic cancer," said Dr. Korc.
"These studies shed light on the potentially pivotal role of CTGF in mediating the aggressive behaviour of pancreatic cancer by controlling the stromal tissue remodelling process that allows tumour cells to grow and spread," said David Y. Liu, Ph.D., Vice President of Research at FibroGen. "While other growth factors have been targeted by experimental treatments for pancreatic cancer, these new findings suggest that blocking the activity of CTGF with FG-3019 provides a unique way to target the disease at a crucial point. With FG-3019, we see a unique potential for preventing the metastatic spread of tumour cells by disrupting multiple pro-tumour pathways. We are therefore planning to initiate clinical studies in 2007 in patients with pancreatic cancer."
Pancreatic cancer is the fourth leading cause of cancer death in the United States with over 30,000 new cases diagnosed each year. The median survival is approximately six months, and the mortality rate is nearly one hundred percent within five years after diagnosis. Pancreatic cancer is a particularly dangerous cancer because of its high rate of metastasis. The current standard of care for metastatic pancreatic cancer is gemcitabine.
FG-3019 is an investigational fully human monoclonal antibody against CTGF. In a phase 1 study of FG-3019 in patients with idiopathic pulmonary fibrosis, FG-3019 was found safe and well tolerated. Currently, FG-3019 is the subject of a phase 1b study in diabetic patients with incipient nephropathy. In preclinical models, FG-3019 has been shown to block fibrosis in the lung, kidney, heart, liver, and intestines; reverse arterial stiffness and improve cardiac function; and decrease proteinuria while improving renal function.