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Old 10-03-2007, 12:49 PM
Dross Dross is offline
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Default First Multiple Drug Trial to Attack Blood Vessel Formation in Kidney Cancer

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 (Avastin), sorafenib (Nexavar), and temsirolimus (Torisel), Researchers have previously shown these drugs to slow the progression of metastatic cancer when used alone by starving the cells of the oxygenated blood required for growth.

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, sorafenib plus bevacizumab, sorafenib plus temsirolimus, 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.

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.

Last edited by gdpawel : 01-30-2012 at 11:59 AM. Reason: post full article
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Old 10-06-2007, 10:37 PM
gdpawel gdpawel is offline
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Default Attack Blood Vessel Formation in Solid Cancers

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 reactons inside the cell.

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
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Old 09-19-2010, 09:49 PM
gdpawel gdpawel is offline
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Default Cancer Physician Invents Test For New Drugs That Cut-Off Tumor's Blood Supply

The online edition of the Journal of Internal Medicine reports discovery of the first practical laboratory test to guide the use of new-generation drugs that kill cancer cells by cutting-off their blood supply. The new test, called the Microvessel Vascular (MVV) assay, was developed by Larry Weisenthal, MD, PhD., a medical oncologist who operates a cancer testing laboratory in Huntington Beach, California. The test works by measuring drug effects upon endothelial cells which make up blood vessels. Its use could prolong lives, save money, and spare patients exposure to harmful side-effects of ineffective chemotherapy treatments. The MVV test also could streamline development of new anti-cancer cancer drugs and identify effective and sometimes unexpected new drug combinations, such as one reported in the article. Used today principally by cancer physicians, to choose effective therapies on a patient-by-patient basis, the MVV assay also has potential for use as an early-warning screen for a variety of illnesses ranging from heart disease, cancer, diabetes, autoimmune disorders, and many others. Patents have been filed.

Dr. Weisenthal invented his new test after making the discovery that endothelial cells are present in cancer biopsy specimens even after the specimens are reduced to clusters of living cancer cells in order to make them suitable for testing in the laboratory. Endothelial cells form capillaries which carry oxygen and nutrients to cancer cells. Dr. Weisenthal noted that the effects of various drugs upon endothelial cells can be measured separately from the effects of those same drugs upon cancer cells within the same biopsy specimen. Dr. Weisenthal describes this as “anti-vascular effect versus anti-tumor effect.” Using this discriminatory property of his new test, Dr. Weisenthal has published several, original and often unexpected observations about the ways in which various drugs work.

Dr. Weisenthal further describes a logical extension of the MVV test, in which the ability to identify and characterize endothelial cells in mixed-cell populations could lead to early diagnosis and thereby more successful treatment of a broad spectrum of illnesses for which elevated numbers of circulating endothelial cells can be a feature. Potentially included are cancer, heart disease, diabetes, macular degeneration and others. Dr. Weisenthal envisions an accurate and inexpensive test, performed annually and based upon a simple blood draw, which would warn of the possible presence of a medical condition for which additional tests were warranted. The result would be earlier diagnosis of disease and also avoidance of much of the expensive and often unnecessary medical testing which occurs today.

The most immediate application of the MVV assay focuses upon cancer and specifically upon a much-heralded new class of agents called angiogenesis-inhibiting drugs, which work by attacking tumor vasculature and thereby starving cancer cells. A recent NIH listing contained over 800 active clinical trials involving angiogenesis-inhibiting agents. One such drug, called Avastin (Genentech, South San Francisco, CA) had sales topping $2.2 billion in the U.S. alone in 2007. Many more angiogenesis-inhibiting drugs are in development. One problem with these drugs, in addition to their high cost, is determining in advance who will benefit from them. The other problem is learning how to make the drugs more effective by using them in combination. The new MVV test could help on both fronts.

Dr. Weisenthal expresses his belief that cancer can become a chronic and controllable illness through the use of combinations of anti-angiogenesis drugs. He says, “The long-awaited magic-bullet cure for cancer hasn’t materialized. Now we’re thinking more in terms of long-term control such as is the case with high blood pressure or diabetes. The way to make that happen sooner is to use our current ammunition more affectively.”

Dr. Weisenthal’s observations are reinforced by early studies of angiogenesis-inhibiting drugs in animal tumor models. In these studies, single agents produced only sporadic and temporary benefits. However, the effectiveness of these drugs increased substantially when they were administered in combination with other angiogenesis-inhibiting drugs. According to Dr. Weisenthal, the MVV test is the first practical tool that allows for design and testing of new anti-angiogenic drug combinations in human cancer.

Using his new MVV test, Dr. Weisenthal says that he often finds strong synergies among new combinations of different types of angiogenesis-inhibiting drugs, including drugs which were not previously known to have anti-angiogenic properties. One observation, which he reports in the Journal of Internal Medicine article, is that dimethylsulfoxide and ethanol are two compounds which often enhance the activity of anti-angiogenesis drugs in the laboratory. According to Dr. Weisenthal, therapeutic levels of ethanol in the bloodstream theoretically could be achieved simply by drinking wine or another alcoholic beverages in prescribed doses concurrent with receiving angiogenesis-inhibiting drugs. The concept might please some patients and alarm others but Dr. Weisenthal finds support in actual case studies reported in the medical literature. However, he warns that further clinical studies are required.

The MVV test is applicable to cancer patients whose bodies harbor cancer cells which are obtainable though biopsy. Currently, the test is available only through Dr. Weisenthal’s laboratory, the Weisenthal Cancer Group. Dr. Weisenthal says that he provides his testing services more like a medical practice and less like a typical reference laboratory. Although he regularly performs testing for cancer patients in the U.S. and also from several foreign countries, he intends to to stick to medicine and leave marketing of the MVV test to others. Dr. Weisenthal says that he would like to see the test become available to patients worldwide through service agreements with larger laboratory companies or with a biotechnology company which might develop a testing kit for sale to hospitals and laboratories. He also would like to license the test to pharmaceutical companies for use in new drug development.

Bibliography relevant to AngioRx/Microvascular Viability assay (MVVA)

1. Weisenthal, L. M. Patel,N., Rueff-Weisenthal, C. (2008). "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood." J Intern Med 264(3): 275-287.

2. Weisenthal, L., Lee,DJ, and Patel,N. (2008). Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166. Slide presentation at: [url]http://tinyurl.com/weisenthal-breast-lapatinib

3. Weisenthal, L. M. (2010). Antitumor and anti-microvascular effects of sorafenib in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors. J Clin Oncol 28, 2010 (suppl; abstr e13617)

4. Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010. from [url]http://hdl.handle.net/10101/npre.2010.4499.1
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Old 11-08-2012, 01:53 PM
gdpawel gdpawel is offline
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Default Nexavar may stunt heart's ability to repair itself

Scientists for the first time have evidence showing how a widely used type of "targeted" cancer drug can be dangerous to the heart.

Studying mice with the equivalent of a heart attack, researchers found that the drug sorafenib (Nexavar) - which inhibits proteins called tyrosine kinase receptors (RTKs), and is used in kidney and liver cancer treatment - can interfere with heart stem cell activity, affecting the heart's ability to repair itself after injury. The findings suggest that sorafenib and other similar drugs that target these kinds of protein receptors may raise the risk for heart attack for some cancer patients with underlying heart disease, as well as affect the heart's ability to repair damage. By understanding how these cancer drugs can affect the heart, scientists and clinicians may be able to devise new treatment strategies to lessen such potentially damaging effects of often vital cancer drugs.

"The goal is not to take the drug off of the market - it's a very good and useful drug that cancer patients need. We're trying to understand how this cancer drug and others like it can affect the heart, and what types of individuals might be at risk for problems," said senior author Steven Houser, PhD, Professor and Chair of Physiology at Temple University School of Medicine and Director of Temple's Cardiovascular Research Center. "Our results are beginning to provide a clearer picture of some of the potential physiological mechanisms at play."

Dr. Houser, first author Catherine Makarewich, a graduate student, and their co-workers reported their findings at the Late-Breaking Basic Science Session at the American Heart Association's Scientific Sessions in Los Angeles.

Sorafenib is a member of a broad class of anticancer drugs called targeted therapies that halt cancer growth, rather than necessarily trying to eliminate the disease. Termed a "multi-kinase" inhibitor, sorafenib blocks the activity of a range of protein enzymes and specific targets in the cell that can contribute to the development and growth of cancer. In this case, sorafenib inhibits several RTKs, including c-kit, a receptor found on cardiac progenitor cells in heart and bone marrow, and can prevent the cardiac stem cell population from growing. Such progenitor and stem cell populations play important roles in cardiac repair.

Mortality Rates Following Induced Heart Attacks

The researchers wanted to see if they could better understand the mechanism behind these toxic effects. In the study, normal mice were given sorafenib for a week before being made to have the equivalent of a heart attack, and compared to mice that had a heart attack without receiving the drug. After one week, the mice that received sorafenib had significantly worse heart damage than the other group. Only 40 percent of those mice, versus 72 percent of the other group, were alive after one week. According to Dr. Houser, the doses were equivalent to those cancer patients would typically receive. Sorafenib by itself had no discernible effect on the mice prior to heart attack.

"Our study was to see if such a drug would put individuals with cancer and ischemic heart disease at extra risk for a heart attack," he said. "Mice given sorafenib and then made to have the equivalent of ischemic disease and a heart attack had much poorer heart function and survival. The drug put the animals at much greater risk for heart damage and death compared to animals without the drug."

Cancer patients tend to be middle-aged and older, and often have other significant health issues, including underlying heart disease. As a result, in patients with ischemic heart disease, there is already damage under repair. Drugs such as sorafenib may block or slow this repair process and increase the risk for a heart attack, Dr. Houser said.

Repair Process Inhibited

The researchers subsequently treated bone marrow stem cells, heart stem cells, and heart muscle cells (myocytes) with sorafenib in the laboratory dish. The drug blocked both types of stem cells from growing, but had no effect on normal heart muscle cells. This meant that the drug likely doesn't affect normal heart cells that were not damaged and under repair, Dr. Houser pointed out. "Injury activates the proliferation of the stem cells," he said. "We think it's something about the repair process that the drug affects."

He and his team would like to find drugs that could be taken alongside cancer drugs such as sorafenib that would reduce adverse effects on heart stem cells. At this time, they are developing a program to screen candidate agents. "Ideally, we could help physicians predict which patients are at higher risk for these effects, and find better ways to screen patients," Dr. Houser said.

The investigators next plan to test therapies to stimulate repair and protect hearts from potential damage from such cancer drugs.

References:

Others contributing to this research include Thomas Force, Jason M. Duran, Thomas E. Sharp III, Ronald J. Vagnozzi, Remus M. Berretta, and Hajime Kubo, Temple University School of Medicine.

The research was supported by grants from the National Institutes of Health and the American Heart Association.

Temple University Health System. "Targeted Cancer Drug May Stunt Heart's Ability To Repair Itself." Medical News Today. MediLexicon, Intl.
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