Novel EGFR Antibody Outperforms Cetuximab In Mouse Model Of Lung Cancer
Main Category: Cancer / OncologyAlso Included In: Lung Cancer
Article Date: 30 Jan 2007 - 18:00 PDT
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Antibodies that selectively bind and destroy cancer cells represent some of the most promising cancer therapy approaches being developed today. Several of these antibodies have reached the market, including cetuximab (Erbitux®, ImClone Systems), which targets the epidermal growth factor receptor (EGFR) protein. However, a study conducted at the Dana-Farber Cancer Institute and the Ludwig Center at Dana-Farber/Harvard Medical School now suggests that antibodies binding a particular protein conformation, caused by hyperactivation, might have distinct therapeutic advantages over antibodies, like cetuximab, that bind to wild-type (normal) target proteins.
The study, led by Dana-Farber Cancer Institute's Dr. Kwok-Kin Wong, and published in the Journal of Clinical Investigation, is part of a multi-center, international effort to assess the clinical potential of the 806 antibody. The 806 antibody was discovered by scientists at the Ludwig Institute for Cancer Research. The antibody targets EGFR only when the receptor has been activated by mutations, by the protein's over-expression or by amplification of the EGFR gene. In the present study, Dr. Wong compared the action of cetuximab and 806 in a mouse model of non-small cell lung cancer (NSCLC) caused by different activating mutations in EGFR.. The 806 antibody caused a dramatic tumor regression in the mice, while cetuximab did not.
"Cetuximab only works on a subset of patients with lung cancers," says Wong. "We think the 806 antibody might benefit those patients who respond to cetuximab but, more importantly, might also be effective for those patients who don't." According to Dr. Wong, approximately 10-30 percent of patients with NSCLC and 5 percent of patients with squamous cell lung cancers have EGFR activating mutations. Some brain tumors also have EGFR activating mutations that are - in animal studies - responsive to the 806 antibody. A phase I clinical trial of the 806 antibody has been completed in Melbourne, Australia by the Ludwig Institute for Cancer Research co-authors. The antibody was shown to target a variety of cancers, including squamous cell lung cancer, with no targeting of normal tissues and no toxicity.
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The paper's co-authors are Danan Li, Hongbin Ji, Sara Zaghlul, Kate McNamara, and George Demetri of the Ludwig Center at Dana-Farber/Harvard Medical School, Shigeto Kubo, Robert Padera and Kwok-Kin Wong of Dana-Farber Cancer Institute, Shigeto Kubo, Masaya Takahashi and Lucian R. Chirieac of the Brigham and Women's Hospital and Andrew Scott and Lloyd Old of the Ludwig Institute for Cancer Research.
Contact: Sarah L. White
Ludwig Institute for Cancer Research
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Choosing The Best Chemotherapy Drugs
posted by Gregory D. Pawelski on 1 Feb 2007 at 10:37 amCancer cells quickly adapt to toxic environments, they readily alter themselves to assure their continued survival, and they utilize biologic mechanisms to promote cellular immortality. All of these factors make cancer an extremely difficult disease to treat.
Chemotherapy drugs have a high rate of failure because they usually kill only specific types of cancer cells within a tumor or the cancer cells mutate and become resistant to the chemotherapy. Cancer chemotherapy could save more lives if pre-testing were incorporated into clinical medicine.
The respected cancer journals are publishing articles that identify safer and more effective treatment regimens, yet few oncologists are incorporating these synergistic methods into their clinical practice. Cancer patients often suffer through chemotherapy sessions that do not integrate all possibilities.
It is impossible to design a single chemotherapy protocol that is effective against all types of cancer. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.
The objective of pre-testing is to provide the patient with more options to discuss with their oncologist and to bring about multimodality approaches to improve the probability of a successful outcome.
The chemotherapy regimen chosen by most conventional oncologists is based on the type of cancer being treated. However, there are factors other than the type of cancer that can be used to determine the ideal chemotherapy drugs that should be used to treat an individual patient.
Researchers have seen that whether a tumor was a breast tumor, prostate tumor, lung tumor or lymphoma, it didn't correlate to how the cancers interacted with standard anticancer drugs. Their findings suggest that traditional cancer treatments, which have established different drug regimens for brain, prostate, lymphoma or ovarian cancer, for example, should be replaced with therapies that use drugs deemed to be of highest benefit based on the tumor's pharmacologic profile. Treatment choice would be determined by how each patient's tumor reacts to anticancer drugs, regardless of the tumor's anatomical origin.
The drug effect is independent of where the tumor came from in the body. Under current treatment selection methods virtually no chemotherapeutic drug has been successful in more than 50 percent of patients with advanced cancer. But instead of considering a drug that works only ten percent of the time a failure, it would be better to consider such a drug effective for one in ten tumors and to search for the agents among the current arsenal of chemotherapeutic drugs that will work for the rest. 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 goal of chemotherapy is to shrink primary tumors, slow the tumor growth, and kill cancer cells that may have metastasized to other parts of the body from the original, primary tumor. However, chemotherapy kills both cancer cells and healthy normal cells. Oncologists try to minimize damage to normal cells and to enhance the cytotoxic effects on cancer cells. Unfortunately, this delicate balance is too often not achieved.
Clinical studies show that certain types of cancer chemotherapy prolongs survival and increases the percentage of patients achieving a remission. A partial remission is defined as 50% or greater reduction in the measurable parameters of tumor growth as may be found on physical examination, radiologic study, or by biomarker levels from a blood or urine test. A complete remission is defined as complete disappearance of all such manifestations of disease.
The goal of oncologists is to strive for a complete remission that lasts a long time (a durable complete remission). Unfortunately, the vast majority of remissions that are achieved are partial remissions. Too often, these are measured in weeks to months and not in years. Some types of cancer do not show any meaningful response to chemotherapy.
It is highly desirable to know what drugs are effective against your particular cancer cells before these toxic agents are systemically administered into your body. Pre-testing on "fresh" specimens of your cancer cells to determine the optimal combination of chemotherapy drugs could be more beneficial for many cancer patients.
Following the collection of "fresh" cancer cells obtained at the time of biopsy or surgery, cell culture assay is performed on the tumor sample to measure drug activity (sensitivity and resistance). This will determine exactly which drug(s) will be most effective for you. The treatment program developed through this approach is known as assay-directed therapy.
At present, medical oncologists prescribe chemotherapy according to "fixed" schedules. These schedules are standardized drug regimens that correspond to specific cancers by type or diagnosis. These schedules, developed over many years of clinical trials, assign patients to the drugs for which they have the greatest statistical probability of response.
Patients with cancers that exhibit multidrug resistance will likely receive treatments that are wrong for them. A failed attempt at chemotherapy is detrimental to the physical and emotional well being of patients, is financially burdensome, and may preclude further effective therapies.
A cell culture assay uses your fresh tumor cells to determine which drug or drug combination induces apoptosis (cell death) in the laboratory. Each patient is highly individualized with regard to sensitivity to chemotherapy drugs. A patient's responsiveness to chemotherapy is "individualized," eliminating much of the guesswork prior to undergoing the potentially toxic side effects of chemotherapy regimens that could prove to be of little value against an individual's cancer.
Patients, physicians, insurance carriers, and the FDA are all calling for predictive tests that allow for rational and cost-effective use of chemotherapeutic drugs. Given the technical and conceptual advantages of cell culture assays together with their performance and the modest efficicay of therapy prediction on analysis of genome expression, there is reason for a renewal in the interest for these assays for optimized use of medical treatment of malignant disease.
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