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.
Tumor-stromal interactions affect tumor progression
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.
Role of connective tissue growth factor (CTGF) in cancer
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 connective tissue growth factor (CTGF). The most extensive literature to date defines a role for CTGF in wound healing and fibrotic disease. A picture is also emerging of CTGF as a key factor in many types of cancer, playing a prominent role in mediation of tumor-stromal communication. CTGF is highly over-expressed in a wide variety of tumors, including those with extensive connective tissue stroma, such as pancreatic cancer, osteolytic breast cancer, and glioblastoma. In these cancers, levels of CTGF correlate with tumor severity and disease progression.
The role of CTGF in cancer is related to its observed actions in binding to other pathogenic factors and modulating their signals. For example, research shows that CTGF is induced by, and works in concert with, other growth factors (e.g., VEGF, TGF-beta) to recruit and activate tissue-remodeling cells, including fibroblasts, endothelial cells, and smooth muscle cells, involved in angiogenesis (the formation of new blood vessels). Certain tumor types are highly dependent on angiogenesis to maintain a supply of oxygen and nutrients essential to tumor survival and growth. CTGF is also implicated in other stages of tumor progression. CTGF has been identified as an invasion-specific gene in pancreatic cancer and as causal for bone metastasis of breast cancer cells in vivo.
Blocking CTGF: new approach to treating cancer
Due to its apparent role as a central mediator of tumor-stromal signaling, blocking the activity of CTGF is expected to have therapeutic benefit in treating certain cancers. As such, FibroGen is developing fully human monoclonal antibodies against CTGF for treating cancer. Because high circulating levels of CTGF are found only under pathological conditions, targeting CTGF for therapeutic intervention in cancer is expected to be more precise in affecting tumor cells and pathological processes while leaving healthy cells and normal physiological processes intact.
Additionally, blocking the activity of angiogenic factors is a promising new approach to treating cancer and was recently validated by the approval of Genentech's Avastin®, an anti-VEGF humanized monoclonal antibody for treating metastatic cancer of the colon or rectum. Because CTGF acts proximally to known pro-angiogenic factors, such as VEGF, and because CTGF has shown the capacity to induce angiogenesis in vivo that correlates with tumor vascularization and progression, inhibition of CTGF function may provide an additional and more selective approach to inhibit tumorigenesis in humans.
Development of anti-CTGF fully human monoclonal antibodies
FibroGen is developing anti-CTGF fully human monoclonal antibodies for the treatment of certain cancers characterized by cell adhesion, invasiveness, and metastasis. Research funding has been provided in part by the National Cancer Institute as a Phase I Small Business Innovation Research grant. Testing of lead therapeutic candidates in several models of tumor progression and metastasis is underway.
Market opportunity
FibroGen believes that anti-CTGF therapy is a promising new approach to treating multiple CTGF-driven cancers for which there are no good treatment alternatives today. These tumors have extensive connective tissue stroma and include such cancers as pancreatic cancer, osteolytic breast cancer, and glioblastoma. FibroGen is initially focusing on pancreatic cancer for which the American Cancer Society estimates 31,860 new cases in the U.S. in 2004. An estimated 31,270 deaths will be caused by the disease, making pancreatic cancer the fourth leading cause of cancer death overall. At present, there are no well-established screening programs for pancreatic cancer. Because pancreatic cancer generally develops without early signs or symptoms, the disease is usually detected at advanced stages, and only biopsy yields a confirmed diagnosis. After diagnosis, the one-year relative survival rate of patients with cancer of the pancreas is about 24%, and the 5-year rate is about 4%. For those diagnosed with local disease (i.e., cancer has not metastasized, or spread, to other organs), the 5-year relative survival rate is still only 17%. Currently available treatments for pancreatic cancer are mainly surgery, chemotherapy, and radiation. Due to the limited effectiveness of these approaches to treating this extremely aggressive cancer, there is an urgent need for novel therapies that are safe and effective.
