New Hope To Lung Cancer Patients offered by Drug That Chokes Off Tumor Blood Vessels
Main Category: Lung CancerAlso Included In: Clinical Trials / Drug Trials
Article Date: 18 Dec 2006 - 4:00 PDT
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Patients suffering from the most common type of lung cancer experienced a 20-percent improvement in overall survival in a national clinical trial of a drug that chokes off the blood vessels nourishing tumors, a multicenter study has found.
Dr. Joan Schiller, chief of hematology/oncology at UT Southwestern Medical Center, said: "This is great news for lung cancer patients - they live longer, and the side effects from Avastin are unlike those of conventional chemotherapy. For example, Avastin does not cause hair loss, nausea, or vomiting."
Results of the Phase III trial involving 878 patients that was conducted by the Eastern Cooperative Oncology Group are reported in the Dec. 14 issue of the New England Journal of Medicine. The publication of the study comes two months after the Food and Drug Administration approved the drug bevacizumab, known under the trademark Avastin, as a first-line treatment for patients with inoperable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer. The FDA approval was based on the findings of the study.
The results of the trial showed that patients who received Avastin along with the conventional chemotherapy drugs paclitaxel and carboplatin had a 35-percent chance of responding to the treatment, compared to 15 percent for patients who received chemotherapy alone.
Dr. Schiller is chairwoman of the Lung Cancer Committee for the Eastern Cooperative Oncology Group, which designed and conducted the study.
"Twenty years ago, we thought no treatment could help patients with advanced lung cancer," said Dr. Schiller, deputy director of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. "Ten years ago, we found that chemotherapy could improve survival of these patients. Now, we are finding out that this very unique drug called Avastin can also help improve survival even more. Avastin is the first of this very exciting family of drugs to be approved for lung cancer, and there are several other drugs of this type under development which may prove to work even better."
The drugs in the class that includes Avastin are called anti-angiogenic therapeutics because they target the numerous small blood vessels supplying tumors with oxygen and nutrients and ensuring their continued growth. Anti-angiogenic drugs target a protein that plays an important role in the formation of new blood vessels in tumors. These drugs are called targeted therapeutics and have far fewer side effects than chemotherapy drugs because they spare healthy tissues and zero in on the cancer cells they seek to destroy.
Dr. Schiller said the researchers found that Avastin, developed by San Francisco-based Genentech, works well in combination with chemotherapy for a number of reasons.
"The reason for this is that the blood vessels in tumors normally do not allow the chemotherapy drugs to diffuse into the tumors well," she said. "In addition to choking off the tumor blood supply, Avastin also makes the remaining blood vessels healthier and enables them to diffuse the chemo drugs into the tumor better."
Dr. Schiller, president of the National Lung Cancer Partnership, an advocacy group of researchers and patients focused on raising awareness and research funds to fight the most lethal form of cancer, has dedicated her career as a medical oncologist to finding a cure for lung cancer.
The groups of patients she recruited for the study in conjunction with several major medical centers were seen by Dr. Schiller during her previous employment as a medical professor and lung cancer director at the University of Wisconsin.
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Other researchers participating in the study came from Vanderbilt University, Nashville; Dana-Farber Cancer Institute, Boston; University of Missouri Ellis Fischel Cancer Center, Columbia, Mo.; Johns Hopkins University, Baltimore; University Hospitals of Cleveland; and Mt. Sinai Hospital, Miami.
The research was funded in part by Public Health Service Grants and grants from the National Cancer Institute, National Institutes of Health and the U.S. Department of Health and Human Services.
According to the American Cancer Society, lung cancer will kill an estimated 162,460 people in the United States in 2006 - 90,330 men and 72,130 women - and a projected 174,470 new lung cancer cases will be diagnosed.
About UT Southwestern Medical Center
UT Southwestern Medical Center, one of the premier medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. Its more than 1,400 full-time faculty members - including four active Nobel Prize winners, more than any other medical school in the world - are responsible for groundbreaking medical advances and are committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 89,000 hospitalized patients and oversee 2.1 million outpatient visits a year.
The UT Southwestern Harold C. Simmons Comprehensive Cancer Center combines the highest standards of individual care with innovative programs for cancer diagnosis, treatment and prevention based on UT Southwestern's internationally recognized research coupled with the most sophisticated equipment and advanced technologies available. The expertise of the physicians in the Simmons Cancer Center extends to virtually every cancer in every age group, from breast, urologic, gynecologic, lung, gastrointestinal, head and neck, brain, and skin to lymphomas, leukemia, and bone marrow transplantation.
Dr. Joan Schiller - http://www.utsouthwestern.edu/findfac/professional/0,2356,81890,00.html
Contact: Toni Heinzl
UT Southwestern Medical Center
Visit our lung cancer section for the latest news on this subject.
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Is Vatalanib Better Than Avastin?
posted by Gregory D. Pawelski on 9 Apr 2007 at 6:10 pmIs Vatalanib better than Avastin?
Maybe, for these reasons.
Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. The "targets" that the new "smart drugs" go after can be located on the "inside" or "outside" of a cancer cell. The most common targets on the outside are receptors, proteins that help relay chemical messages. And many targets on the inside are enzymes, proteins that help speed up chemical reactions in the body.
Monoclonal antibodies are "large" molecules that attach to specific proteins on the "outside" of cancer cells but not having a convenient way of getting access to a large majority of the targeted cells. 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. "Small" molecules act on multiple receptors in the cancerous cells.
Angiogenesis is essential for the growth and metastasis 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. 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.
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.
Avastin (bevacizumab) 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.
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).
However, 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, 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.
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 in 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). 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: ASCO web site link (click on "Slides") for slide presentation relating to testing for antitumor and antiangiogenic activity of gefitinib, erlotinib, sunitinib, sorafenib, and bevacizumab in primary cultures of fresh human tumors.
http://www.asco.org/portal/site/ASCO/menuitem.64cfbd0f85cb37b2eda2be0aee37a01d/?vgnextoid=09f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=vm_search_results_view&selectedConfs=&SearchFilter=Speaker&SearchTerm=weisenthal
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