A study appearing in International Journal of Gynecological Cancer states that Avastin, a biologic anti-cancer agent that prevents tumor growth by interfering with the formation of new blood vessels, may have the potential to improve the efficacy of standard combination chemotherapy in ovarian cancer.

Studies have continued to investigate the activity of novel medications in combination with standard therapy to improve overall and disease-free survival in ovarian cancer patients.

Avastin has been studied clinically and was recently approved as a treatment for metastatic colon cancer and non-small cell lung cancer. Currently, Avastin is also being studied as a treatment to improve patient survival rates for breast and kidney cancers.

Since Avastin has a unique mechanism of action and a favorable safety profile, the medication is not associated with unreasonable levels of toxicity. However, previous studies have reported that gastro-intestinal perforations and hypertension may be a consequence of treatment involving Avastin.

According to Dr. Bram Goldstein, co-author of the study, the results from their research suggest that the combination of Avastin and standard therapy for the treatment of ovarian cancer may be promising, particularly with regard to safety and efficacy.

Source: Vol. 17 Issue 4 of International Journal of Gynecological Cancer.

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.


Effective novel assay-directed drug combination for relapsed ovarian cancer

Two studies reported that the drug combination of Gemzar + Cisplatin identified chemosensitivity analysis that was effective for treating women with relapsed ovarian cancer.

While both drugs are commonly used to treat an array of tumor types, the combination of these two in the treatment of relapsed ovarian cancer patients, including those with platinum resistance, was highly novel.

In the first study, researchers at Rational Therapeutics in California, investigated the results of heavily pretreated patients with relapsed ovarian cancer. The results revealed that the Gemzar + Cisplatin combination achieved a 70% response-rate, with more than 20% of the patients achieving complete remission.

Equally noteworthy was the fact that the patients whose cancer cells demonstrated sensitivity to the drug combination in the laboratory assay were the same patients who benefited the most from therapy.

They were able to achieve positive outcomes for patients, many of whom had virtually no other options, and do this by simply using available drugs more effectively.

The second study, conducted by researchers at Case Western Reserve University, Ohio, and University Hospitals of Cleveland, similarly confirmed the high response-rate for the Gemzar + Cisplatin combination in treating ovarian cancer.

These results further verify the value of drug sensitivity testing in identifying treatment options for all cancer patients who are candidates for chemotherapy. Such results could provide the basis for assay-directed therapies in a wide variety of cancers.

The Gemzar + Cisplatin combination was first identified at Rational Therapeutics and applied by Dr. Robert Nagourney in 1995 to treat heavily pretreated patients with advanced ovarian cancer. The patients, having failed all available therapies, received assay-directed therapy.

Based on the encouraging results from the two studies, a national clinical trial of the Gemzar + Cisplatin combination in treating relapsed ovarian cancer, by the Gynecologic Oncology Group, with support from the US National Cancer Institute, was instituted.

Source: Gynecol. Oncol. 88 [1], 2003