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GENENTECH CANCER MONOCLONAL ANTIBODIES WILL ENTER PHASE I

Executive Summary

GENENTECH CANCER MONOCLONAL ANTIBODIES WILL ENTER PHASE I trials early next year as a potential second-line therapy in supressing ovarian and breast cancers, Dennis Slamon, MD/PhD, Jonsson Comprehensive Cancer Center, UCLA, announced Oct. 30. The HER-2/neu proto-oncogene antibodies were developed by Genentech; NCI and the Revlon Foundation are sponsoring the Phase I trial. The tests will be conducted at UCLA. Speaking at a press seminar on "Advances in Cancer Research" sponsored by the National Cancer Institute and Hoffmann-La Roche, Slamon said that he and his collaborators are "in the final phases of protocol design," and they expect approval from FDA and the NCI Biological Response Modifiers Program by Jan. 1, 1991. The trial will study 20 to 40 subjects who have failed traditional therapy and have shown HER-2/neu amplification. The first patients should be entered in the trial in January or February, Slamon added. The planned study derives from findings that extra copies of the HER-2/neu gene are evident in 25% to 30% of cases of human breast or ovarian cancer. Slamon found that breast and ovarian cancer patients "with this gene alteration experience earlier disease recurrence and have shortened overall survival" than those who do not show gene alteration. This indicator "was second only to the number of positive nodes in predicting outcome" in patients, Slamon observed. In ovarian cancer patients, women with one copy of the HER-2/neu gene had a median survival of 1,879 days, compared to 959 days for women with two to five copies and 243 days for women with more than five copies. Subsequent studies on nude mice implanted with human tumors have suggested that amplification of this gene is not merely a marker, but also a cause of breast and ovarian cancer. Also at the NCI/Roche press seminar, Lance Liotta, MD/PhD, chief of the Laboratory of Pathology at NCI's Division of Cancer Biology and Diagnosis, discussed his work with the protein TIMP-2 in blocking invasion and metastasis of cancer cells. TIMP-2 (tissue inhibitor of metalloproteinase) "is in effect a suppressor protein that works outside the cell rather than inside," the NCI researcher explained. Liotta added: "We found that TIMP-2 could markedly, in a dose-dependent manner, abolish the ability of tumor cells to invade in vitro." The protein was discovered by William Stetler-Stevenson, MD/PhD, a member of Liotta's lab team. Liotta contended that TIMP-2 or similarly acting chemical agents represent "a new approach" to cancer treatment, stopping "invasive tumor cells before they develop." Liotta said that "TIMP-2 may potentially act as a chemopreventive agent for cancer and could arrest metastasis through inhibition of blood vessel formation." The protein is also being studied as a "marker for nonmetastatic tumors." Molecular Oncology Inc., a company based in Gaithersburg, Md., is "making a large amount of recombinant protein" so Liotta and colleagues can do toxicology studies on TIMP-2. Liotta estimated that "it's going to be about a year or two years before it goes into patients." Liotta also discussed the discovery of nm23, which he described as "a potential supressor gene for metastasis rather than just tumorigenicity." He explained that nm23 "can potentially modulate signaling in the cell, and this could play a role in modulating a whole cascade of factors involved in metastasis." Another of Liotta's associates, Patricia Steeg, PhD, discovered nm23. In connection with this discovery, Liotta "is investigating a new drug [carboxyimidazole] to block cell signals, perhaps similar in function to nm23 for tumor suppression." The drug is manufactured by Merck. Liotta said carboxyimidazole "will hopefully go into clinical trials within six months to a year. We have all the preclinical experiments done with that and we're just waiting to finish on toxicology."
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