Study finds thalidomide shows promise for treatment of recurrent ovarian cancer

Feb 27, 2008

Thalidomide, a drug blamed in the 1950s for causing birth defects, is now showing promise as a safe and effective treatment for women with recurrent ovarian cancer, according to a study led by a University of Minnesota Cancer Center researcher.

Levi Downs, Jr., M.D., principal investigator for the multicenter, randomized Phase II clinical trial, has published the findings of this research study in the current issue of the journal Cancer. Downs is an assistant professor and a researcher of gynecologic oncology at the University of Minnesota Medical School and Cancer Center.

“For some women, ovarian cancer has become a chronic disease,” Downs said. “The standard chemotherapy regimens can put recurrent cancer in remission, often more than once. However, when the cancer resists the standard treatments, we need new options for treatment.”

The study compared the effectiveness and safety of the combination of thalidomide and topotecan, a chemotherapy often used for ovarian cancer, versus topotecan alone for treatment of recurrent epithelial ovarian cancer in patients who had received prior treatment. Epithelial ovarian cancer is a disease in which cancer cells form in the tissue that covers the ovary.

The study evaluated 75 women who were randomly assigned to receive either the combination of thalidomide and topotecan or only topotecan. This is the first randomized clinical trial to test thalidomide for recurrent ovarian cancer. Other clinical trials have shown thalidomide to be effective for treatment of multiple myeloma, a cancer of the bone marrow.

“We found that patients who received topotecan plus thalidomide showed an overall response rate of 47 percent compared to 21 percent response in patients who received only topotecan,” Downs said. “In patients receiving topotecan plus thalidomide, 30 percent achieved a complete response, meaning the cancer went away, compared to 18 percent for patients only getting topotecan.

“Furthermore, patients getting topotecan plus thalidomide had a longer cancer-free period after treatment than those receiving topotecan alone,” he said. “What all of this means is that while thalidomide may not cure ovarian cancer, it may broaden the treatment options available to physicians and provide more hope to women diagnosed with the cancer.”

Ovarian cancer is the fifth most common cancer among women. This year in the United States, more than 25,000 women will be diagnosed with ovarian cancer, and about 16,000 will die from it. About 78 percent of women diagnosed with the cancer survive one year after diagnosis, and more than 50 percent survive five years after diagnosis.

The results of this study have led to the development of a new clinical trial at the University of Minnesota that will test the safety and effectiveness of a newer member of the class of drugs containing thalidomide properties for treatment of recurrent ovarian cancer.

Source: University of Minnesota

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not rated yet Feb 29, 2008
The Role of Endothelial Growth Factor (EGF)

Endothelial growth factor (EGF) is a receptor on many normal tissues cells, and also on many cancer cells. It is a growth hormone, locally secreted by cells. It attaches to a receptor on the cell membrane called epidermal growth factor receptor (EGFR). It then activates so-called signalling pathways within the cell - a cascade of biochemical events, including phosphorylation of proteins, leading to cell growth/proliferation/division. One type of an enzyme which is involved in the pathway which is involved in protein phosphorylation is called "tyrosine kinase."

EGF is an important activator of angiogenesis. Like the name indicates, EGF causes endothelial cells to grow. Research has shown that oncogenes (genes that help cancer cells grow), cytokines (substances produced by the immune system), and hypoxia (a low-oxygen environment, which is common in tissues around solid tumors), can all directly or indirectly activate EGF, thereby starting angiogenesis.

EGF 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 reactions inside the cell. Because EGF is so important to angiogenesis, it is a target of new cancer treatments. For example, the drug Avastin blocks a receptor for EGF.

In addition to EGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to EGF (angiogenesis inhibitors or anti-angiogenesis agents). Typically, these drugs are given with other types of therapy, such as traditional chemotherapy. More than one drug combination from different cancers may be the most synergistic. For example, women with relapsed ovarian cancer may respond to a combination of a pancreatic cancer drug and an ovarian cancer drug. Another, a metastatic pancreatic cancer patient, can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast and colorectal cancer.

Researchers have tested how well women with relapsed ovarian cancer would respond to a combination of a pancreatic cancer drug and an ovarian cancer drug. They found the combination worked on a number of women, and testing cells in petri dishes predicted which women would respond to this combination and which wouldn't. A metastatic pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast and colorectal cancers.

Thalidomide (Thalomid) appears to stop endothelial cells from forming new blood vessels and is a treatment for multiple myeloma and other types of cancer. Lenalidomide (Revlimid), a drug that is similar to thalidomide, is potentially more active than thalidomide and is being tested in clinical trials. Many other angiogenesis inhibitors are being tested in clinical trials to treat a variety of cancers, including colorectal cancer, multiple myeloma, renal cell carcinoma (a kidney cancer), liver cancer, Kaposi's sarcoma, leukemia, lymphoma, lung cancer, prostate cancer, and pancreatic cancer.

The EGF system is a target for a number of new anti-cancer drugs, including Erbitux, a monoclonal antibody which binds to EGFR (the EGF receptor) and Iressa and Tarceva, the latter two being inhibitors of the EGFR-activated tyrosine kinase.

Functional, cell culture-based assays are vastly more informative for virtually all drugs than marker-based tests, including multi-gene tests. Functional assays are the best available tests in the world for anti-vascular drugs, such as Avastin, Sutent, Nexavar, Tarceva, Iressa, Tykerb, Gleevec, Tamoxifen, Thalidomide, etc., both as single agents and in combination with each other and with traditional cytotoxic agents.

Functional assays can provide more valuable information today than will be provided with marker and genomic-based assays ten years from now. It simultaneously tests for direct anti-tumor activity and for anti-vascular activity against the microvascular present within the three-dimensional tumor cell clusters.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007