© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 6, 424-426,
March 21, 2001
© 2001 Oxford University Press
NEWS |
Cancer Drugs in Pipeline Span Wide Spectrum
The pipeline for new treatments for cancer is bursting with agents of a different kind. The cytotoxic mainstays are still there, but new techniques for drug discovery have led to methods of targeting cancer cells with more precision and less toxicity.
The focus is on inducing apoptosis, inhibiting angiogenesis, and boosting the patient’s immune response to his or her tumor. At recent meetings in the United States and elsewhere, presentations of early results of agents in the pipeline, including vaccines, indicate potential for more effective cancer treatments with less toxicity. Some of these new agents are envisioned as monotherapy, but more often as part of combination therapy, investigators say.
Monoclonal Antibodies
After decades, monoclonal antibodies appear to be hitting their stride (see News, Sept. 20, p. 1462–4). Thomas Waldmann, M.D., of the metabolism branch of the National Cancer Institute said at a recent meeting of the American Society of Hematology in San Francisco that the early success of monoclonal antibodies such as Herceptin for breast cancer and the recently approved Mylotarg (gemtuzumab ozogamicin), for older patients with relapsed acute myelocytic leukemia has helped to renew interest in them.
"We’re not on the boundless sea," he said. "But we have a distinct glimpse of the land, which we hope will yield rich treasures for biology and therapeutics."
Almost a dozen monoclonal antibodies have been approved by the U.S. Food and Drug Administration, and 70 to 100 more are in the pipeline, Waldmann said. The ability to "humanize" monoclonal antibodies has made them less likely to cause allergic reactions than the original murine antibodies and also allows them to be used for longer periods of time. They are also being used in new ways, such as for fighting graft-versus-host disease in cancer patients who have received bone marrow transplants and as fusion proteins linked to radioactive molecules.
Antiangiogenesis Drugs
There are seven angiogenesis inhibitors in phase III trials, six in phase II trials, and six in phase I trials, said Judah Folkman, M.D., director of the Surgical Research Laboratory at Children’s Hospital in Boston and a professor at Harvard Medical School.
Folkman, who was the conference co-chairperson at an American Association for Cancer Research meeting on angiogenesis and cancer last fall, said that these agents work by a variety of mechanisms, including inhibition of metalloproteinases, basic fibroblast growth factor, calcium influx, endothelial proliferation, microtubule function, and Na+/H+ exchange. Some also block VEGF signaling or induce apoptosis in proliferating endothelium.
He said that endostatin’s phase I study results, reported at the NCI-EORTC-AACR meeting in Amsterdam in November, indicated that the compound is "very safe."
At the American Society of Clinical Oncology meeting in 2000, Emily Bergsland, M.D., of the University of California at San Francisco, also reported that another antiangiogenic agent, an anti-VEGF antibody developed by Genentech, showed a 24% response in metastatic colon cancer compared with 17% response with chemotherapy alone.
Breast Cancer Drugs
For postmenopausal women with advanced breast cancer, fulvestrant (Faslodex) was shown in a multicenter phase III trial to improve the duration of response to 19.3 months, compared with 10.5 months for those taking tamoxifen.
Preclinical breast cancer drug studies presented at the annual San Antonio Breast Cancer Symposium and ongoing phase III trials in non-small cell lung cancer, suggest that the epidermal growth factor receptor tyrosine kinase inhibitor ZD-1839, or Iressa, may be useful in epidermal growth factor receptor–positive tumors that may or may not overexpress the related receptor erbB2.
Other reports indicate progress:
• Early trials have shown that antigen-pulsed autologous dendritic cells can boost a patient’s repertoire of effector T cells and B cells. Michael Salgaller, of Northwest Biotherapeutics in Seattle, said that further trials of dendritic cells and recombinant human prostate-specific membrane antigen are being conducted in patients with various stages of prostate cancer. In another study of an agent developed by Biomira, dendritic cells pulsed with MUC-1 antigen, a transmembrane glycoprotein that is abnormally expressed in breast cancer cells, elicited responses in breast cancer patients.
• Cancer vaccines are being tested; many are in phase III clinical trials. For example, Biomira’s Theratope for breast cancer is winding up its phase III trials.
• For the anemia that afflicts many cancer patients, FDA approval is expected for Amgen’s Aranesp. The new drug’s much longer half-life is expected to make it more desirable than Amgen’s erythropoietin drug Epogen.
• Newer classes of drugs that promote apoptosis, including retinoids, arsenicals, and signal transduction modulators, are under study.
• Compounds that inhibit cyclin dependent kinases are being investigated by Glaxo Wellcome, Pfizer, and Roche for the treatment of toxicities induced by chemotherapy, such as mucositis, myelosuppression, and alopecia.
• A tyrosine kinase inhibitor, Glivec, inhibits the protein Bcr-Abl. At the hematology meeting, Hagop Kantarjian, M.D., of the University of Texas M. D. Anderson Cancer Center, Houston, reported that, in a phase II study of 532 CML patients who did not respond to interferon treatment, Glivec produced an overall cytogenetic response rate of 37%. In a subgroup of 290 of these chronic phase patients who had completed 6 months of therapy, the response rate was 56%.
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