Targeted therapy and chemotherapy shrinks breast cancer metastases in brain [Archive]

gdpawel

12-27-2007, 11:55 AM

In normal tissue, new blood vessels are formed during tissue growth and repair, and the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.

Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.

Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.

About 15 proteins are known to activate endothelial cell growth and movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (acidic and basic), interleukin 8, prostaglandin E1 and E2, tumor necrosis factor-, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 ( and ß), interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinase-1 and -2. (TIMP-1 and -2).

At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

Angiogenesis is also related to metastasis. It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion.

Research has shown that controlling production of new blood vessels can restrict tumor growth, often prolonging the life of the cancer patient. Perhaps the most widely-used anti-angiogenic agent to emerge to date has been the drug Avastin.

Avastin was approved by the FDA for use in combination with intravenous 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic colorectal cancer.

However, Avastin has also shown activity in many other solid tumor types such as breast, lung, and ovarian cancer. One of the most popular combinations for brain tumors is Camptosar (CPT-11) and Avastin.

As with most "targeted" therapy drugs, Avastin does not necessarily benefit every patient and it is expensive. Until now, there were no tests that existed to show reliably who would benefit from anti-angiogenic agents.

There has been an bio-marker assay (AngioRx™) developed for microvascular viability to identify potential responders to Avastin, Nexavar, Sutent, and other anti-angiogenic drugs. It was discovered that endothelial cells are present in tumor microclusters and it appears that drug effect upon these cells can be assessed in the new microvascular viability assay.

The assay has a morphological endpoint which 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 the patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparison 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.

Confirmatory activities are ongoing. It is being offered currently to selected clients on a research basis and as an adjunct to a standard assay or a tyrosine kinase assay.

Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of these tests are being encouraged by growing patient demands, scientific advances and medical ethics. These tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007