Angiogenesis blockade is a 30 year old concept, but it will soon make the leap from lab bench to pharmacy shelf.
Thomas Morrow, MD
A new class of drugs that blocks the growth of a tumor's blood vessels will soon become available in the United States — and, at the same time, will define a new niche in the treatments available for cancer.
We know that all cells need a way to obtain nourishment and oxygen as well as to eliminate wastes, and that this is accomplished through the vascular system. The vast majority of cells belong to organs that have access to the vascular system, but for some specialized structures like the cornea, cellular respiration is accomplished through tear production.
When a tumor develops, the accompanying blood supply grows with it, as does the risk of metastasis. Angiogenesis is the formation of new blood vessels, and a complex cellular signaling process regulates this growth. The concept of using this mechanism to control cancer was first described nearly 30 years ago. This relatively young field has experienced significant growth, however, with more than 50 angiogenesis inhibitors in development for cancer listed on the Genentech Web site.
This new class of drugs works by blocking the development of new blood vessels, effectively starving the tumor of its needed blood supply. Vascular endothelial growth factor (VEGF), a protein that is released from cells that are lacking oxygen, binds to receptors on blood vessels, stimulating the formation of new blood vessels. VEGF was first discovered in 1989 by Genentech scientist Napoleone Ferara.
The first such agent expected to gain approval from the FDA is bevacizumab (Avastin) manufactured by Genentech. It will be indicated as a treatment for colorectal cancer. This drug is a rhuMAb-VEGF (Recombinant Humanized Monoclonal Antibody) that targets the vascular endothelial growth factor. Once bound to the VEGF, the antibody complex prevents the VEGF from binding to other blood vessels, potentially limiting the growth of the blood supply and hence reducing tumor growth.
On fast track
Studies are under way investigating this drug for safety and efficacy in prostate, renal cell, non-Hodgkin's lymphoma, and others. This drug has been awarded FDA "fast track" status, which facilitates the development of drugs and expedites the government approval process. It is granted for drugs that are intended for the treatment of serious or life-threatening conditions. In addition, the drug must address an unmet medical need. This is especially true of colon cancer.
According to the American Cancer Society (ACS), colorectal cancer is the third most common cancer diagnosed in the United States in both men and women. The ACS estimates that there will be more than 100,000 new cases diagnosed this year. Although the death rate has been falling for the past 15 years, probably due to extensive screening and early removal of polyps, this dreaded disease will result in 57,000 deaths in 2003.
As true of all cancers, if caught early, the five-year survival rate is high, nearly 90 percent in early stage. But in late stage cancer, after it has spread to distant sites, the five-year survival is less than 10 percent.
Put to the test
One study released at the May 2003 American Society of Clinical Oncology meeting excited oncologists as well as Wall Street when it revealed that patients treated with a regimen called the Saltz regimen plus bevacizumab fared considerably better than those treated with the standard Saltz regimen alone (20.3 vs. 15.6 months survival). Although this may seem insignificant in the big scheme of things, Durado Brooks, MD, director of prostate and colorectal cancer for the ACS, was quoted as saying these results are extremely significant because outcomes with existing chemotherapy agents are poor.
This was the first phase III trial for any anti-angiogenesis treatment. Wall Street responded by pushing Genentech's stock price up by 45 percent on May 19.
Genentech completed the Biologics License Application for Avastin on Sept. 26, 2003. Another study published in November demonstrated that patients given the active drug took 67 percent longer to develop a worsening of their condition. Side effects appear to be mild, with hypertension developing in 11 percent of recipients. Hypertension was managed with standard medications.
More growth factors
In addition to VEGF, there are lymphatic vascular endothelial growth factors as well. Lymphatic-VEGF appears to be important for the growth of lymphatic vessels (lymphangiogenesis). It has long been observed that the lymph nodes are one of the first sites that cancer metastasizes to.
According to research conducted by Michael Detmar, MD, a dermatologist at Massachusetts General Hospital's Cutaneous Biology Research Center (CBRC), tumors that release the highest levels of VEGF form the greatest number of lymphatic vessels, thus allowing for early spread through these channels. Detmar said, "There is almost a 100 percent correlation between this VEGF level and metastasis."
Research on other growth factors is currently under way. One of note is rhuFab-VEGF, a potential treatment for age-related macular degeneration (AMD), which is a major cause of painless central visual loss and is the leading cause of blindness for people over age 65 in the United States and Europe. The hallmark of AMD is the growth of blood vessels beneath the retina and the resultant leakiness. RhuFab binds to VEGF, thus blocking its ability to induce blood vessel growth.
Obviously, many hurdles remain before this approach becomes the accepted form of therapy. In addition, it does not appear that current therapies will be abandoned. Avastin will most likely be tied to concurrent use of traditional chemotherapy. To demonstrate some of the challenges, Sugen, a division of Pfizer, announced that it was aborting Phase III trials for its drug SU5416, a small molecule, due to failure to demonstrate clinical results. It shows that angiogenesis is not a simple process and is not governed by one factor.
It appears that we will soon be blessed with a totally new approach to malignant tumors and a host of other diseases. This technology, made available through the discoveries of the Human Genome Project and associated advances in biotechnology, will dramatically change the way medicine is practiced. Although none of the treatments currently in development is expected to result in a cure, these substances are adding to our ability and knowledge to finally conquer these dreaded diseases as we begin to experience tomorrow's medicine.
Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 19 years of managed care experience at the payer or health plan level.