Test Identifies Patients who Benefit from Targeted Drugs

[gdpawel]

Clinical study results published at the annual meeting of the American Society of Clinical Oncology (ASCO) show that a new laboratory test has accurately identified patients who would benefit from treatment with the molecularly-targeted anti-cancer therapies gefitinib (Iressa) and erlotinib (Tarceva).

The new test, called EGFRx ™, predicted accurately for the survival of patients treated with the targeted drugs. The finding is important because the EGFRx ™ test, which can also be applied to many emerging targeted cancer drugs, could help solve the growing problem of knowing which patients should receive costly, new treatments that can have harmful side-effects and which work for some but not all cancer patients who receive them. (The test 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

The new test relies upon what is called "Whole Cell Profiling" in which living tumor cells are removed from an individual cancer patient and exposed in the laboratory to the new drugs. A variety of metabolic and apoptotic measurements are then used to determine if a specific drug was successful at killing the patient's cancer cells. The whole cell profiling method differs from other tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using combined metabolic and morphologic endpoints. Other tests, such as those which identify DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process.

The whole cell profiling method makes the statistically significant association between prospectively reported test results and patient survival. Using the EGFRx ™ assay and the whole cell profiling method, can correlate test results which are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.

Patients prospectively identified as favorable candidates averaged 485 days of life after treatment with the targeted therapy drugs. In contrast, patients identified as unfavorable candidates for the drugs averaged 75 days survival after receiving the drugs. This compares to 76 days average survival among patients identified as unfavorable candidates and who did not receive a targeted therapy drug. Survival among patients identified as unfavorable candidates was similar regardless of whether or not they received the targeted drugs.

Over the past few years, researchers have put enormous efforts into genetic profiling as a way of predicting patient response to targeted therapies. However, not gene-based test as been described that can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can a gene-based test identify situations in which it is advantageous to combine a targeted drug with other types of cancer drugs.

There is a growing array of targeted drugs to choose from. Most patients today are treated not with a targeted therapy drug alone but rather with a combination of chemotherapy drugs. Therefore, the existing DNA and RNA tests do not reflect the way cancer medicine actually is practiced today.

These so-called "smart drugs" focus their effects on specific, identifiable processes occurring within cancer cells. The new drugs are highly promising in that they sometimes provide benefit to patients who have failed traditional therapies. However, they do not work for everyone, they often have unwanted side effects, and they are all extremely expensive. Patients, physicians, insurance carriers, and the FDA are all calling for the discovery of predictive tests that allow for rational and cost-effective use of these drugs.

The EGFRx assay holds the key to solving some of the problems confronting a healthcare system that is seeking ways to best allocate available resources while accomplishing the critical task of matching individual patients with the treatments most likely to benefit them. Not only is it an important predictive test, it is also a unique tool that can help to identify newer and better drugs, evaluate promising drug combinations, and serve as a "gold standard" correlative model with which to develop new DNA, RNA, and protein-based tests that better predict for drug activity.

Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117

http://www.weisenthal.org/asco_06_egfr_gefitinib_nsclc_weisenthal.htm

http://weisenthalcancer.com/Professionals%20Pages/EGFRxProfessionals.htm

[gdpawel]

Angiogenesis is essential for the growth and metastasis (spread) of cancer. A growing tumor requires nutrients and oxygen, 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.

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. The assumption is that if a drug can stop the tumor from receiving the supply of nutrients, the tumor will "starve" and die.

Anti-angiogenesis drugs work by blocking the activity of vascular endothelial growth factor (VEGF) to prevent the growth of new capillaries into the tumor and thereby sustain tumor growth. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.

VEGF causes angiogenesis by attaching to special receptors (proteins on the outside of cancer cells that act like doorways), and this action starts a series of chemical reactons inside the cell. Because VEGF is so important to angiogenesis, it is a target of new cancer treatments.

Since tumor growth is dependent on angiogenesis, and angiogenesis is dependent on VEGF, a drug like Avastin directly binds to VEGF to directly inhibit angiogenesis. 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 like Avastin which works by blocking VEGF (Avastin "sensitive" tumors). It potently inhibits the formation of new blood vessels.

Vatalanib (PTK/ZK) 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 potently inhibits the formation of new blood vessels (angiogenesis).

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, such as Avastin, Nexavar and vatalanib. The 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.

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

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.

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

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