Angiogenesis is essential for the growth and metastasis (spread) of cancer. A growing tumor requires nutrients and oxygen (angiogenesis), which helps it grow, invade nearby tissue, and metastasize. To reach these nutrients, the tumor builds new blood vessels. In fact, growing tumors can become inactive if they can't find a new supply of nutrients.
Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Avastin works by choking off the blood vessels that provide a tumor with oxygen and nutrients. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent which works by blocking VEGF.
Angiogenesis starts when cancer cells produce a variety of growth factors and other activators (biologic molecules that begin a process). Growth factors cause endothelial cells (the cells that line blood vessels) to produce chemicals that break down the nearby tissue and the extracellular matrix (the spaces between cells). Then, the endothelial cells divide into more cells and begin building new blood vessels. Other elements, such as stromal cells (cells that form connective tissue), provide structural support for the new blood vessels.
Because angiogenesis is necessary in the growth and spread of cancer, each part of the angiogenesis process is a potential target for new cancer therapies. Avastin, used by itself and in combination with other drugs, shows that the angiogenesis-blocker boom in on. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.
There are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis. Tumors can acquire a blood supply by three different mechanisms: angiogenesis; co-option of existing blood vessels; and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.
Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process, called co-option, cannot be stopped with drugs that inhibit new blood vessel formation. Some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process, called vasculogeneic mimicry.
The realization is that starving tumors by shutting off their blood flow requires that all three mechanisms be addressed. However, there are so many agents out there now, doctors have a confusing array of choices. They don't know how to mix them together in the right order.
Having a good tumor-drug match not only would improve survival rates, it would be cost-effective, and the high cost of the newer cancer therapies reinforces the necessity of choosing the right therapy the first time around. The tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing the individual properties of each patient's cancer.
Drugs like Avastin can be tested with a bio-marker test called AngioRx™ Microvascular Viability / Angiogenesis Assay, because the target of Avastin is not the cells themselves, but rather a hormone (VEGF) secreted by the tumor cells. The Avastin complexes with free VEGF and blocks its action. The AngioRx™ Microvascular Viability / Angiogenesis Assay can discriminate between the activity of different targeted drugs and identify situations in which it is advantageous to combine the targeted drugs with other types of cancer drugs.
A major modification of the DISC (cell death) assay allows for this study of anti-microvascular drug effects of standard and targeted agents, such as Avastin, Nexavar and Vatalanib. The assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from solid tumor specimens. The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect. CD31 cytoplasmic staining confirms morphological identification of microcapillary cells in a tumor microcluster.
The principles and methods used in the assay include: 1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from an individual cancer patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparision of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity. 5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.
It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.
This kind of technique exists today and might be very valuable, especially when active chemoagents are limited in a particular disease, giving more credence to testing the tumor first. After all, cutting-edge techniques can often provide superior results over tried-and true methods that have been around for many years.
Reference: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007.
http://weisenthalcancer.com/Professionals%20Pages/AngioRxPro