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PHILADELPHIA – In the first clinical trial of its kind, researchers at the University of Pennsylvania School of Medicine and the Abramson Cancer Center will lead a nationwide test of anti-cancer drug combinations that target blood vessel growth in patients with advanced kidney cancer. The trial is being conducted with colleagues in the Eastern Cooperative Oncology Group, a network of researchers, physicians, and health care professionals at public and private institutions.
In addition to these patients, the results from the trial will inform care in many other types of cancer, including breast, lung, and colon cancer. Penn scientists will also use an experimental imaging technique to measure the effectiveness of the treatments.
The BeST trial stands for bevacizumab(Avastinterm), sorafenib(Nexavartermterm), and temsirolimus(Torisel), Researchers have previously shown these drugs to slow the progression of metastaticterm cancer when used alone by starving the cells of the oxygenated blood required for growth.Â
“This trial takes these three proven drugs, and combines them into two drug combinations,†said Keith Flaherty, MD, Assistant Professor of Medicine, who is the primary investigator for the trial. “They all seem to attack blood vessel formation in somewhat unique ways, so we think we could get a more profound effect by combining them.
“In my mind, kidney cancer is truly the anvil on which we will hammer out the issues of anti-angiogenic therapy because it is the disease where we don’t give chemotherapyterm or any other type of drug at the same time and we can still see benefit. It is in this setting that we are going to work out which combinations make sense, are safe, and efficacious. And then move those into other cancers,†Flaherty said.
Flaherty and colleagues will determine which of the drug treatments – sorafenibterm plus bevacizumabtermterm, sorafenib plus temsirolimusterm, temsirolimus plus bevacizumab, or bevacizumab alone – is most effective by looking at how long it takes patients’ tumors to start growing again on treatment. The longer the progression-free survival is, the better the combination.
In addition to this standard measure of effectiveness, Mark Rosen, MD, PhD, Assistant Professor of Radiology, will lead the imaging portion of the trial to test the value of a relatively new imaging technique in evaluating anti-angiogenic therapy. The technique, called dynamic contrast-enhanced-magnetic resonance imaging, or DCE-MRI, relies on a series of rapidly collected images that allow the investigators to calculate the rate of movement of a contrast agent through the blood vessels and into the tumor. Using this information they can estimate the amount and rate of blood flow. Researchers may be able to use that information to learn within a few days or weeks whether a patient is responding to anti-angiogenic therapy, rather than having to wait months to see if a patient’s disease worsens or gets better.
When Rosen tested DCE-MRI in a small group of patients that Flaherty treated in a pilot study with sorafenib, he identified tumor characteristics that predict response to therapy. “We want to know if these characteristics remain predictive in a larger patient population,†Rosen said. “Also, we want to see if we can get high quality DCE-MRI data from multiple institutions. It is one thing to succeed in a small group of patients here, but DCE-MRI is not something that one can get by pushing a button on a machine. Obtaining high quality DCE-MRI results when the imaging is performed across multiple institutions may be more difficult, but is a crucial step in defining the applicability of the DCE-MRI technique in the routine clinical setting.â€
The BeST trial is sponsored by the Eastern Cooperative Oncology Group and supported by grants from the National Cancer Institute. The imaging portion of the trial is supported by the National Cancer Institute as part of the I-2 initiative to improve imaging techniques in cancer care.
For more information on the study and how to enroll, please visit the study website at the National Institutes of Health: http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=499788&version=patient&protocolsearchid=3677344
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Attack Blood Vessel Formation in Solid Cancers
For example, 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.
In some cases, these 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.
There is a "functional profiling" microvascular viability assay for anti-angiogenesis-related drugs. A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents. 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 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.
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. The assay can report prospectively to a physician specifically which agent would benefit a cancer patient by testing that patient's "live" cancer cells. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.
What would be more advantageous is to sort out what's the best "profile" in terms of which patients benefit from this drug or that drug. Can they be combined? What's the proper way to work with all the new drugs? If a drug works extremely well for a certain percentage of cancer patients, identify which ones. If one drug or another is working for some patients then obviously there are others who would also benefit. What's good for the group (population) may not be good for the individual.
Knowing the drug sensitivity profile of a specific cancer patient allows the treating oncologist to prescribe a therapy that will be the most effective against the tumor cells, "before" placing potentially toxic agents into the patient.
Source: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007