Angiogenesis, the process of forming new blood vessels, is central to wound healing and reproduction in the body. Tumor cells and stroma, the connective tissue around the tumor can also stimulate angiogenesis, by secreting angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Without the blood and nutrients supplied by newly-generated blood vessels, it is thought that no tumor would grow to be more than a few millimeters in size. Lymphangiogenesis, a related process, is the formation of new lymphatic vessels. The blood and lymphatic vessels are thought to provide two of the principle routes by which cancer metastasizes (spreads) from the original tumor site.
For over seven years, LICR has coordinated and supported a global Program to research angiogenesis and lymphangiogenesis with the aim of developing therapies that could target both processes. The efforts of the Program investigators, drawn from the Melbourne, Stockholm and Uppsala Branches as well as Affiliates in Helsinki and Kuopio (Finland), have identified four of the five known vascular endothelial growth factors (VEGF-B, VEGF-C, VEGF-D and VEGF-E) and two of the four known platelet-derived growth factors (PDGF-C and PDGF-D) as well as a novel receptor, VEGF receptor-3 (VEGFR-3).
Following secretion by tumor cells, VEGF-C and VEGF-D promote lymphatic metastasis by binding to VEGFR-3 on endothelial cells and initiating the processes of lymphangiogenesis and tumor cell invasion into those new lymphatic vessels. Research conducted by LICR Angiogenesis Program Affiliates in Helsinki and Kuopio (Finland) showed that inhibition of VEGFR-3 can block both lymphangiogenesis and tumor cell invasion in a mouse tumor model when VEGFR-3 inhibition is commenced soon after the tumor is transplanted. Although inhibition of VEGFR-3 at a later stage significantly reduced lymphangiogenesis, it could not block tumor cell invasion and spread. These data suggest that VEGF-based adjuvant therapies intended to prevent lymphatic metastasis following surgery may need to target both blood vessel angiogenesis as well as lymphangiogenesis.(1)
Vascular endothelial growth factor-D (VEGF-D) is a secreted lymphangiogenic protein known to play an important role in tumor-induced lymphangiogenesis and lymphatic metastasis. In order to elucidate the growth factor’s role(s) in embryogenesis and normal adult tissues, investigators from the Melbourne Branch generated and analyzed a mouse model with an inactive VEGF-D gene. While the abundance of lymphatic vessels in the lung was reduced, suggesting VEGF-D has a role in the pulmonary lymphatic system, overall the mouse model’s lymphatic vasculature was relatively normal. This indicates that VEGF-D appears to be dispensable for formation of the lymphatic vasculature during embryogenesis or that another VEGF can compensate for VEGF-D during development.(2,3)
LICR has a singular focus on cancer but recognizes that some of its medical research findings may have therapeutic value for other human diseases. Thus LICR places great importance on supporting and facilitating, principally through the licensing of its intellectual property, the research and development of non-oncology therapies for human benefit. Several of these licensing relationships involve discoveries from the LICR’s Angiogenesis Program.
A new spin-off company, Lymphatix Ltd, was launched in November 2005 with Helsinki University Funds providing €1 million to initiate operations. Lymphatix Ltd plans to develop and commercialize products based on VEGF-C and VEGF-D (licensed from LICR) as pro-angiogenic/lymphangiogenic factors in the treatment of human conditions with impaired blood supply (e.g. heart ischemia) or lymphoid drainage (e.g. edema).
In 2005, Ark Therapeutics Group plc announced the first results from a Phase II clinical trial of a pro-angiogenic therapy, Trinam®, which utilizes VEGF-D licensed from LICR. Trinam® appears to prevent blood vessel blockage following vascular graft access surgery (insertion of an artificial blood vessel) required for patients with kidney failure to undergo dialysis.