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Old 10-25-2007, 02:20 PM
Dross Dross is offline
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Default 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.

Surprisingly, the team also uncovered some unexpected insight into the nature of these observations. The current hypothesis to explain these drug-induced molecular changes is that they are tumor dependent, possibly because blocking blood flow would starve tumors of oxygen, which in turn would cause tumors to produce more proteins to recruit new vessels¯, says John Ebos, a doctoral student in Medical Biophysics at the University of Toronto and lead author of the study. However, our study shows that the same molecular changes occur in normal mice, that have no tumors, and come from multiple organs - suggesting that these changes come mainly from the body not the disease¯.

The study also found that, in addition to the molecular changes observed in the clinic, there were many other proteins that were also elevated after treatment. Ironically, many of these have been shown to have angiogenesis promoting properties and Kerbel's team is now investigating the possible implications of these findings. The fact that these molecular changes occur independent of the tumor and involve many proteins that are unrelated to the drug activity, could explain why they have not been useful so far as predictors of patient benefit.

They could also contribute to some of the observed drug associated toxicities seen with these drugs, play a role in drug resistance, and even may explain some recent observations where tumors rapidly regrow in some patients when therapy is stopped, using antiangiogenic drugs¯ says Dr. Kerbel, who is also a professor in the Departments of Medical Biophysics and Laboratory Medicine/Pathobiology at University of Toronto. We are testing these hypotheses now¯.

In the study, the research team used a class of drugs designed to block the activation of receptors (known as receptor tyrosine kinase inhibitors¯, or RTKIs) activated by an important regulator of angiogenesis called vascular endothelial growth factor (VEGF). The drug they used is called sunitinib (Sutent) which is used for the treatment of kidney cancer, and is now being evaluated for its effects on many other types of cancer. Dr. Kerbel's results have led to collaborations between his team and several medical oncologists leading clinical trials at Sunnybrook's Odette Cancer Centre involving late stage kidney cancer and early stage breast cancer therapy with the aim to determine if these preclinical findings are observed in patients, and if so, how the results might be exploited in the future to improve the benefits of antiangiogenic drugs for cancer treatment. This is a major goal of the Toronto Angiogenesis Research Centre established at Sunnybrook with the support of an infrastructure grant from the Canadian Foundation for Innovation (CFI)

Last edited by gdpawel : 03-11-2014 at 09:55 AM. Reason: Post full article on forum board
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Old 10-26-2007, 10:23 PM
gdpawel gdpawel is offline
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Default Bio-Marker For Anti-angiogenesis Drugs

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

Biomarkers of Antiangiogenic Therapy

[url]http://cancerfocus.org/forum/showthread.php?t=3372

Last edited by gdpawel : 03-11-2014 at 09:58 AM. Reason: additional info
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