Study shows blood markers can help choose best dose for antiangiogenic drugs

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Study shows blood markers can help choose best dose for antiangiogenic drugs

Scientists at Sunnybrook have new information that may help to improve the use of anti-cancer drugs designed to block the growth of new blood vessels in tumors, a process called angiogenesis that is critical to tumor growth. While these antiangiogenic drugs are effective, at present there are no reliable methods for determining whether they are working, if the right dose is used, or if a patient will benefit (or not) from treatment.
A team led by Dr. Robert Kerbel - a senior scientist in Molecular and Cellular Biology at Sunnybrook and Canada Research Chair - has just published a paper in the October issue of the Proceedings of the National Academy of Sciences which may help to answer these questions. ?In the clinic, patients receiving these antiangiogenic drugs have a number of blood plasma proteins that rise and fall after treatment, so it is speculated that they could be used as surrogate biomarkers to tell us about drug activity and efficacy - our studies in mice show that this is correct?, says Dr. Kerbel. In the study, Kerbel?s team found that drug-induced molecular changes observed in mice occurred at the same doses that had the best anti-tumor effect, suggesting that monitoring these changes in patients could predict the optimal dose of drug.

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Anti-angiogenesis drugs work by blocking the activity of VEGF to prevent the growth of new capillaries into the tumor and thereby sustain tumor growth. VEGF causes angiogenesis by attaching to special receptors, and this action starts a series of chemical reactions inside the cell.

The ability of various agents to kill tumor and/or microvascular cells (anti-angiogenesis) in the same tumor specimen is highly variable among the different agents. 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.

Avastin is a monoclonal antibody, a type of genetically engineered protein. Monoclonal antibodies are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside which are protected from the drug. The cells may pass small molecules back and forth.

However, Vatalanib is a "small" molecule tyrosine kinase inhibitor with broad specificity that targets all VEGF receptors (VEGFR), the platelet-derived growth factor receptor, and c-KIT. It is a multi-VEGFR inhibitor designed to block angiogenesis and lymphangiogenesis by binding the intracellular kinase domain of all three VEGFRs, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). Vatalanib is a targeted drug that inhibits the activity of all known receptors that bind VEGF. The drug also potently inhibits angiogenesis.

Even with Vatalanib, do the drugs even enter the cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In some cases, these and other drugs, kill tumor cells without killing microvascular cells in the same time frame. In other cases they kill microvascular cells without killing tumor cells. In yet other cases they kill both types of cells or neither type of cells. The ability of these agents to kill tumor and/or microvascular cells in the same tumor specimen is highly variable among the different agents.

A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents. This Microvascularity Viability 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 Microvascularity Viability 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.

A "fresh" sample tumor can be obtain from surgery or biopsy (Tru-cut needle biopsies). At least one gram of fresh biopsy tissue is needed to perfom the test, and a special kit must be gotten in advance from the lab. Arrangements have to be made with the surgeon and/or pathologist for preparation and sending of the specimen. Upgrading clinical therapy by using a drug sensitivity assay measuring "cell death" of three dimensional microclusters of live "fresh" tumor cells, can improve the conventional situation by allowing more drugs to be considered.

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. Photomicrographs in the assay can show that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. Functional profiling in the assay measures the net effect of everything which goes on (Whole Cell Profiling). Are the cells ultimately killed, or aren't they?

Each of these new targeted drugs are not for everybody. According to the National Cancer Institute, those who benefit substantially from "targeted" drugs is approximately 10% to 20%. What if you are one of those few? 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.

Source: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007