CaroleHammett Posted April 16, 2008 Share Posted April 16, 2008 Although not mentioned in the first article below, sorafenib (Nexavar) was originally developed for kidney cancer and, in addition to liver cancer, is also used off label in lung cancer, although the mfgr. recently dropped squamous cell types from its lung cancer clinical trials due to adverse reactions (see second article below). Note: I included both articles here because it appears the second (earlier) one hasn't ever been posted to this website. Carole ============ 1. http://www.sciencedaily.com/releases/20 ... 161027.htm Targeted Therapy Combination Overcomes Treatment Resistance In Liver Cancer, Study Suggests ScienceDaily (Apr. 15, 2008) — Researchers at the University of Pennsylvania School of Medicine and Abramson Cancer Center reported April 13 at the annual meeting of the American Association for Cancer Research that combining two targeted therapies overcomes treatment resistance in liver cancer cell lines. The team is currently designing a trial to test the combination in patients. Liver cancer is resistant to many chemotherapies and to cell-death inducing agents. Last year, however, the U.S. Food and Drug Administration approved sorafenib (Nexavar®) as a treatment for liver cancer after a clinical trial showed that the targeted agent prolonged survival in some patients. Unfortunately not all patients respond to sorafenib and the drug does not cure the disease. Therefore, Wafik El-Deiry, MD, PhD, Professor of Medicine, Genetics, and Pharmacology, and co-Program Leader of Radiation Biology in the Abramson Cancer Center, and colleagues have tested other targeted agents in combination with sorafenib. They found that treating liver cancer cells with sorafenib and an antibody or the natural ligand that stimulates programmed cell death via the TRAIL pathway, dramatically increases the rate of cell death. "Sorafenib by itself causes a little cell death, but not that much," Dr. El-Deiry said. "Now you combine sorafenib and TRAIL, and all of the sudden you get massive cell death. It is a real synergistic interaction. It is very profound killing." The combination works regardless of whether the researchers use a monoclonal antibody that stimulates the TRAIL receptor, which resides on the surface of the cancer cells, or the receptor's natural ligand, a small protein called TRAIL. Both the antibody and the TRAIL ligand are currently being tested as single agents in patients. Within the next several months, Dr. El-Deiry's team expects to announce the details for a trial testing the combination in patients. In a healthy individual, the immune system uses the TRAIL pathway to rid the body of unwanted cells, including precancerous ones. Once cancer develops, however, the cells often become less responsive to TRAIL activation, in part because of an overabundance of a protein called Mcl-1, according to Dr. El-Deiry. His team found that sorafenib reduces the amount of Mcl-1 in the cancer cells, restoring their sensitivity to TRAIL-induced cell death. Although the Penn investigators focused their current report on liver cancer, they discovered that the sorafenib-TRAIL combination also kills colon cancer cell in vitro and in animal models. ... --------------------------------------------- 2. http://www.medicalnewstoday.com/articles/97792.php Nexavar Dropped From Lung Cancer Trial by Catharine Paddock, PhD19 Feb 2008 - 3:00 PST Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals have stopped a late stage trial of their cancer drug Nexavar (sorafenib) in patients with nonsmall-cell lung cancer (NSCLC), because it was not showing the hoped for increase in survival. Following a planned interim analysis, the trial's independent data monitoring committee (DMC) concluded that the drug was not going to meet the trial's main goal of improving overall survival. In the phase 3 trial, a group of patients with squamous cell carcinoma of the lung who took the drug in combination with chemotherapy drugs carboplatin and paclitaxel showed a higher rate of death than a group that received chemotherapy alone. The trial, which is called ESCAPE (Evaluation of Sorafenib, Carboplatin And Paclitaxel Efficacy in NSCLC), was otherwise showing safety events generally in line with those previously reported, said Bayer in a press statement. The two drug companies are giving the DMC information to health authorities and other investigators studying the effects of Nexavar and will also be presenting the findings of the trial at a forthcoming scientific meeting. The companies will also be reviewing the findings of this trial, including the DMC review, to see if they impact any other ongoing lung cancer trials using Nexavar. Vice president of Therapeutic Area Oncology at Bayer HealthCare Pharmaceuticals, Dr Susan Kelley said that they were disappointed with this result, but the two companies were still very much committed to widening the scope of Nexavar in treating as many cancers as possible and will continue to extend trials to other cancers. "Nexavar has proven significant clinical benefit for patients with liver cancer and advanced kidney cancer and we will continue to investigate its potential across a wide variety of tumors," said Kelley. The ESCAPE study was a multicentre, randomized, double-blind, placebo controlled phase 3 trial involving more than 900 NSCLC patients at over 140 clinics in North and South America, Europe and Asia. The main outcome sought was overall survival, but secondary endpoints included progression-free survival, tumour response, quality of life, and drug safety. The participants had not received any systematic anti-cancer treatment for lung cancer before the trial, which was open to patients with all types of NSCLC, including squamous cell carcinoma or adenocarcinomas. The patients were randomized to a drug group and a control (placebo) group. The drug group was given 400 mg of Nexavar, orally, twice a day, while the control group had a placebo. Both groups also had two chemotherapy drugs, carboplatin and paclitaxel. Both groups continued with the drug or placebo alone, after chemotherapy had finished (maintenance phase), until symptoms of tumour progression or side effects showed. Nexavar (sorafenib) attacks both the tumour cell and the blood vessels that feed it. In studies before clinical trials, the drug showed ability to target kinase proteins thought to be involved in cell growth and development of blood supply, two essential cancer enablers. The kinases involved include: Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. Nexavar is approved for the treatment of liver cancer in over 30 countries and for the treatment of advanced kidney cancer in over 60 countries. It is being evaluated for use with many other cancers such as breast cancer, metastatic melanoma, and as an adjuvant therapy for kidney cancer and liver cancer. ... Quote Link to comment Share on other sites More sharing options...
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