Cancer
CTGF mediates tumor/stromal signaling
Healthy cells become cancerous when normally tightly controlled processes for growth and survival become deregulated. Cancer cells no longer respond to chemical signals that inhibit growth or that cause abnormal cells to self-destruct. Rather, they divide, proliferate, and may progress to more advanced disease stages in which different chemical signals cause the tumor to lose anchoring to its supportive extracellular matrix and metastasize, or spread, to other parts of the body.
The microenvironment between solid tumors and their surrounding stroma (supportive extracellular matrix of connective tissue comprised of proteins and various cells types) is a dynamic one of chemical signaling that affects the various stages of tumor progression, including tumor growth, proliferation, and metastasis.
This dialogue between tumor cells and the surrounding stroma is mediated by growth factors, chemokines, and extracellular matrix components. Often these factors are produced by the tumor cells themselves, and they act in concert to coordinate cellular functions that ultimately lead to development of characteristic tumor traits, including cell migration, growth, survival, and metastasis.
The "communication factors", as described above, provide valuable targets for therapeutic intervention in cancer. FibroGen is focused on understanding how aberrant signaling pathways contributing to tumor cell migration, growth, survival, and metastasis are mediated by CTGF, which is highly over-expressed in a wide variety of tumors including pancreatic cancer, glioblastoma, and B-cell acute lymphoblastic lymphoma (ALL).
Anti-CTGF therapy may enbale a multi-pronged attack on tumor growth and metastasis through inhibition of CTGF-mediated activities including angiogenesis, cell migration, and epithelial to mesenchymal transition (EMT). EMT occurs during late stage tumorigenesis and leads to the generation of invasive tumor cells, which migrate into the surrounding tissue, penetrate the endothelial layer of the blood vessels and travel to secondary organ sites to form metastases.
Anti-CTGF therapy for pancreatic cancer
Several lines of research implicate CTGF in pancreatic cancer. Studies have shown that the gene for CTGF is overexpressed in human pancreatic cancer. One study found that among pancreatic cancer tissue samples taken from 19 patients, 15 exhibited an average 59-fold enhancement of CTGF gene expression over normal pancreatic tissue compared to an average 4.5-fold increase above normal in chronic pancreatitis, a disease where CTGF over-expression is associated with pancreatic fibrosis.1
CTGF was identified as an invasion-specific gene in pancreatic ductal adenocarcinoma (PDAC)2 and is highly expressed within the neoplastic epithelium.3 The CTGF polypeptide is expressed and secreted by PDAC tumor cells and stromal cells, including stellate cells, and may have both autocrine and paracrine effects on these cell types.
CTGF has been shown to be involved in tumor growth and metastasis.4,5,6 In a recent study, pancreatic tumor growth in mice could be completely prevented by blocking the expression of CTGF in tumor cells, and animals implanted with tumor cells expressing lower levels of CTGF survived longer than those implanted with tumor cells expressing high levels of CTGF.6 The same report also revealed that survival of tumor cells is affected by CTGF levels; tumor cells with comparatively low levels of CTGF gene expression were more prone to self-destruct under experimentally-induced conditions of hypoxic stress compared to tumor cells with higher levels of CTGF gene expression.
In addition, PDAC tumors often exhibit a high degree of desmoplasia, characterized by a fibrotic connective tissue stroma, the extent of which has been found to correlate with CTGF levels.1 CTGF has been shown to promote epithelial to mesenchymal transition (EMT),7 a process whereby normal epithelial cells become migratory, matrix-producing fibroblasts, which has been shown to be important during invasion and metastasis.8
FibroGen believes that FG-3019, the company’s fully human monoclonal antibody that selectively binds to and blocks the action of CTGF, represents a unique approach to the treatment of pancreatic cancer by preventing the metastatic spread of tumor cells through the disruption of multiple pro-tumor pathways. Results from nonclinical models of pancreatic cancer have shown that treatment with FG-3019 reduces tumor growth and metastasis.4, 5 A phase I trial of FG-3019 in pancreatic cancer is ongoing.
References
- Wenger, C, et al. Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells. Oncogene 1999; 18:1073-1080.
- Ryu, B., et al. Invasion-specific genes in malignancy: serial analysis of gene expression comparisons of primary and passaged cancers. Cancer Res. 2001; 61:1833-1838.
- Iacobuzio-Donahue C.A., et al. Exploring the host desmoplastic response to pancreatic carcinoma: gene expression of stromal and neoplastic cells at the site of primary invasion. Am J Pathol. 2002 Jan;160(1):91-9.
- Dornhöfer N, et al. Connective tissue growth factor specific mAb therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 2006; 66:5817-27.
- Aikawa T, et al. Connective tissue growth factor specific antibody attenuates tumor growth, metastasis and angiogenesis in an orthotopic mouse model of pancreatic cancer. Mol. Cancer Ther. 2006 May;5(5):1108-16.
- Bennewith K, et al. The role of tumor-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Res. 2009; 69:775-784.
- Burns WC, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol. 2006 Sep;17(9):2484-94.
- Yang J and Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008 Jun;14(6):818-29.
