Julia Draznin Maltzman, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 10, 2003
Angiogenesis literally means the birth of new blood vessels. (In Greek, "angio" means blood vessel and "genesis" means birth or beginning). Under controlled physiologic conditions it is a normal and essential process. For example, angiogenesis is a necessary part of fetal development, wound healing, and recovery from a heart attack. However, during the process of cancer growth and spread, angiogenesis allows the tumor to make its own blood supply in order to obtain the nutrients and oxygen it needs for survival. The result is a web of vessels that allows the tumor to grow even more and spread (metastasize) to other far away organs.
Vascular Endothelial Growth Factor (VEGF) is a protein that is secreted by the tumor and acts on the VEGF receptors found on the endothelial cells. Blood vessels are lined with endothelial cells. For the most part, these cells serve to maintain the integrity of the blood vessels. However, various hormones and proteins can direct these cells. Cancer cells, for example, secrete proteins that command endothelial cells to grow and extend into the tumor mass itself. This helps to establish a blood supply so the cancer can grow and thrive. Once the VEGF protein binds to its complementary receptor on the endothelial cell, a number of signals or messages are initiated within the cell. These signals include cell activation and proliferation, cell survival and an increase in endothelial cell migration.
As the tumor grows and recruits more and more blood supply, a network of small capillaries forms and becomes very disorganized. There is lack of direction to the flow of blood and empty vessels may form. The chaotic vascular system that forms eventually results in increased pressure. As the pressure builds these vessels become "leaky". To use an analogy, when more and more pressure builds with in a pipe due to increased or turbulent water flow, weak joints in the pipes may begin to leak out water. Similarly, as pressure increases within the blood vessels, smaller proteins and plasma can ooze out. These proteins will have nowhere to go and will squeeze their way in between the tumor cells themselves. The build up of proteins and plasma in the tumor mass itself is called edema. As the edema builds, tumor cells will become more starved for oxygen and other nutrients. Lack of oxygen, in turn, causes the cancer cells to secrete even more VEGF and propagate this vicious cycle.
The simple presence of proteins such as VEGF is not sufficient to ensure angiogenesis. For blood vessels to form, these proteins must defeat a range of angiogenesis inhibitors that hold back blood vessel growth. Researchers have found several naturally occurring proteins that can inhibit angiogenesis. Two such inhibitory proteins called angiostatin and endostatin seem to be particularly important. A balance, between angiogenesis inhibitors (angiostatin and endostatin) and activators (VEGF) determines whether a tumor can trigger the growth of new blood vessels. Researchers who study angiogenesis are investigating both the proteins secreted by the tumor and the cells that they command. They hope that by affecting the tumor's blood supply, the cancer growth may be stopped and the tumor may be eradicated. This has lead them to work on a class of drugs called "angiogenesis inhibitors".
Most angiogenesis inhibitors (anti-angiogenic drugs) work by either binding to the signaling protein (VEGF) and thereby not allowing it to interact with its complementary receptor on the endothelial cell, or, by binding to the receptor and blocking any interactions with its respective protein. One such drug that has received much attention in the press recently is called bevacizumab (Avastin, Genentech). Bevacizumab is a humanized monoclonal antibody that binds directly to VEGF and prevents it from interacting with its receptor on the endothelial cell. Despite early excitement, initial clinical trials did not match expectation. The drug seemed to work better in combination with chemotherapy rather than single agent. Dr. Beth Overmoyer, Assistant Professor, from the Ireland Cancer Center in Ohio, during her cancer center grand rounds given at University of Pennsylvania on Sept 3, 2003, explained that she believes bevacizumab just "prunes" the vascular tree and serves to "normalize the tumor's capillary bed" so that chemotherapy, when given in conjunction to bevacizumab, is delivered more efficiently and directly to the tumor bed. She says that the bevacizumab changes the tumors blood supply to the "prevascular state" where organization and direction are still preserved.
The results of bevacizumab studies seem to be mixed. The most notable success has been in previously untreated metastatic colorectal cancer. In a study presented this year at the American Society of Oncology (ASCO), bevacizumab plus standard chemotherapy (5-fluorouracil/leucovorin/ irinotecan) significantly improved the survival in these patients when compared to chemotherapy alone. Furthermore, the addition of bevacizumab to standard chemotherapy was well tolerated. From the side effect profile seen in its earlier studies, only hypertension was noted in this trial. Of note, the hypertension was easily controlled with oral medication.
Similar trials for metastatic breast cancer could not tout the same success. These patients were previously treated with one or two different chemotherapies before being randomized to receive either capcitabine (Xeloda, Roche) alone or in combination with bevacizumab. Although the response rate was greater in the group who received bevacizumab, there was no difference in overall survival, survival without tumor progression, or time to tumor progression in the two groups.
Currently the Eastern Cooperative Oncology Group (ECOG) is doing a study in Non Small Cell Lung Cancer where bevacizumab is added to the standard therapy of carboplatinum (Paraplatin) and paclitaxel (Taxol, Bristol-Myers Squibb). These data are not yet available.
Another coup for bevacizumab has been in renal cell carcinoma. Although a rare disease, it can be devastating. Patients with metastatic renal cell carcinoma were divided into three groups: placebo, low dose bevacizumab, and high dose bevacizumab. The trial was so successful it was stopped early as patients receiving bevacizumab had a much longer time to progression of disease than those receiving placebo. The higher dose seemed to be slightly better than the lower dose but at a borderline statistical significance.
It is difficult to explain why the data are so mixed. Some argue that the reason bevacizumab did not show such success in breast cancer is that the patient group was heavily pretreated as opposed to the colon cancer group of patients for whom this was the first therapy. Others contend that perhaps tumor biology is important and the drug will act differently in different tumors. Many more bevacizumab trials are ongoing with these and other malignancies as more data are needed. Bevacizumab is currently under consideration for FDA approval for metastatic colorectal cancer. More clinical trials are needed to fully evaluate this new agent and identify the appropriate targets for treatment.