News. News
Oncologists and cancer researchers last month descended in record numbers on San Diego, where the American Society of Clinical Oncology and the American Association for Cancer Research held their annual meetings. ASCO researchers announced results — many encouraging, some disappointing — from trials of innovative treatment and prevention agents, while AACR scientists described promising strategies on the horizon. Many speakers hailed the growing connections between the laboratory and the clinic, and stressed the importance of the two societies in strengthening those ties. "Basic research in cancer is beginning to pay off, not just in understanding, but also in many of the new therapies and diagnostic tests we are seeing," NCI Director Samuel Broder, M.D., told an AACR audience. "We can truthfully say
Dr. Alan F. Ltt 922
that insights into the process of initiation and promotion are leading to prevention strategies — for instance, using tamoxifen and Proscar — which are now being incorporated in large clinical trials and education campaigns."
Direct Relevance Webster K. Cavanee, Ph.D., AACR program committee chairman, noted with satisfaction that many ASCO members attended the AACR meeting as well. Clinical oncologists are beginning to believe that basic research has direct relevance to their work, he said. Drug resistance is a good example. Based on their knowledge of mechanisms such as the P-glycoprotein "pump" responsible for multidrug resistance, scientists can design therapies to circumvent resistance and make cells sensitive to chemotherapy. Clinical studies, in turn, lead to better understanding of the underlying processes. Alan F. List, M.D., and colleagues at the Arizona Cancer Center, Tucson, and Vanderbilt University Medical Center, Nashville, Tenn., reported at ASCO that cyclosporin-A (a powerful inhibitor of P-glycoprotein), when given with chemotherapy, induced remissions in 73% of 33 acute leukemia patients who had been resistant to conventional therapy. Researchers from Japan, led by Hiroyuki Tsuda, M.D., of the National Cancer Center Research Institute, Tokyo, are targeting another form of drug resistance involving the enzyme topoisomerase I. They found that a new compound, CPT-11, inhibited this enzyme, leading to favorable responses in nearly half of patients with refractory non-Hodgkin's lymphoma.
Dr. Webster K. Cavanee
"Each study gives us clues about the mechanism of drug resistance," Carol A Westbrook, M.D., of the University of Chicago said at a press briefing. "As we learn how to overcome resistance to om treatment, we are getting a better handle on ways to overcome resistance to otha treatments."
More Resistant In the 16th Richard and Hinda Roser thai Foundation Award Lecture, NCI's Michael Gottesman, M.D., described plans to exploit multidrug resistance in; novel way. Instead of making tumor eel less resistant, Gottesman and colleague! will attempt to make patients' bone mai row more resistant to the toxic effects o drugs by putting in the gene, MDR1, thi codes for P-glycoprotein. This gene therapy approach increase survival in mice, Gottesman said, and h now plans to try it in women undergoin autologous bone marrow transplants as part of their aggressive breast cancer therapy. At the ASCO meeting's plenary session, a number of investigators presente Journal of the National Cancer Institul
Downloaded from http://jnci.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 23, 2015
Clinical, Basic Researchers Find Common Ground in San Diego
News News
Price Gouging? Moertel was met with hearty applause when he blasted Johnson & Johnson, the parent company of Janssen Pharmiceutica, which makes levamisole, for charging patients 100 times what the company charges for the same drug when used to deworm sheep (see News, J Natl Cancer (nst, August 21,1991). "I would hope the company would realize that this is just totally beyond
reason," he said, suggesting that oncologists could express their displeasure with Johnson & Johnson's pricing policy by boycotting the company's exhibit. In other major trials, higher-dose adjuvant chemotherapy improved postmastectomy survival in stage U breast cancer patients, and high-dose cytosine arabinoside prolonged remissions in younger acute myeloid leukemia patients. Newer, more complex combinations of drugs for non-Hodgkin's lymphoma proved no more effective, and in some cases more toxic, than the standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). Taxol continues to show promise in a number of tumors, while trials of autologous bone marrow transplant, used to support aggressive chemotherapy, produced mixed results. The Eastern Cooperative Oncology Group reported that taxol is the most effective single agent against non-smallcell lung cancer it has evaluated in the past decade, producing responses in about a quarter of patients. And in a dose escalation study in advanced ovarian cancer patients, Gisele Sarosy, MX)., and colleagues at NCI found that higher doses of taxol along with granulocyte colony-stimulating factor boosted the response rate to more than 50%. Studies at the Istituto Nazionale Tumori, Milan, Italy, and Duke University Medical Center, Durham, N.C., with Cancer and Leukemia Group B suggest that ABMT may boost relapse-free survival in advanced breast cancer patients.
Cell Suicide
Dr. Card A. Westbrook
/ol. 84, No. 12, June 17, 1992
One word on nearly everyone's lips at AACR was "apoptosis" (though they still haven't agreed on its pronunciation — is the second "p" silent or not?). The term refers to programmed cell death, or "cell suicide," a normal process by which the body controls growth.
Downloaded from http://jnci.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 23, 2015
findings from large-scale chemotherapy trials designed to answer important treatment questions. Charles G. Moertel, M.D., of the Mayo Clinic in Rochester, Minn., presented a final report from an Intergroup Study on treatment of advanced colon cancer. The combination of 5-fluorouracil and levamisole has already been recommended for these patients, based on the trial's early results and a 1990 National Institutes of Health consensus conference. But Moertel said the maturation of the data shows conclusively that the regimen not only fends off recurrences but actually reduces the death rate by 33%.
Dr. Chartes G. Moertel
Scientists are devoting increased attention to learning which genes and proteins regulate apoptosis. They believe failures of the system can lead to cancer, and hope that by gaining control over the death program, they can develop better therapies. "The fundamental characteristic of cancer is that rates of cell proliferation are higher than rates of cell death," said John Isaacs, M.D., Ph.D., of The Johns Hopkins University School of Medicine in Baltimore. "In some cases, cancer could arise from decreased rates of cell death, rather than increased rates of proliferation. The balance between the two is what's out of control." Isaacs is working to design a more effective treatment for advanced prostate cancer by inducing apoptosis in nonproliferating, androgen-independent cancer cells. These cells present a stumbling block to curing the cancer, because they are not killed by hormone therapy or conventional cytotoxic drugs. By raising levels of intracellular calcium, Isaacs has succeeded in coaxing prostate cancer cells in vitro to turn on their suicide program. If this manipulaNEWS
923
News News
tion works as well in patients, Isaacs said, it might form the basis for a curative therapy for metastatic prostate cancer. Further along the path toward clinical use are antisense oligonucleotides, another promising treatment that depends on knowledge of the molecular events leading to cancer (see News, / Natl Cancer Inst, March 4,1992). Several researchers at AACR reported on their work in progress with antisense, which they hope will thwart cancer by blocking expression of oncogenes.
Success Against AML Jorge Spinolo, M.D., of the University of Nebraska Medical Center, Omaha, is among those vying for the honor of bringing antisense technology to its first clinical triaL Spinolo reported success against acute myeloid leukemia (AML) cells in vitro, and lack of toxidty from antisense in monkeys treated with the drug. Spinolo's molecular target is a surprising one: the normal p53 gene, which is believed to function as a tumor suppressor in most cancers. "This raises some controversy about what we're doing," Spinolo said. "But in AML, the wild — or normal —form of p53 seems to be involved." 924
The tests are currently sold for research only, but Pinkel said FDA approval for clinical applications could come within 2 years, after which he predicts "an explosion in use." — Tom Reynolds
Doctors Change Breast Cancer Treatment Practices Community physicians are thought t require reams of clinical data and long adjustment periods before changing the treatment practices. However, recent research found that many of these physicians quickly adoptet new practices when a consensus confer ence and clinical alert were the sources of the recommendations for treatment change. Physicians rapidly adopted recommc dations on breast cancer treatment from National Institutes of Health consensus conference in 1985 and a National Cancer Institute clinical alert in 1988, accoi ing to research reported at the 28th Annual Meeting of the American Socie of Clinical Oncology by NCI researcha Leslie G. Ford, M.D.
Consensus To Change "When given recommendations on how to improve treatments, community physicians can, and will, change their practice quickly," said Ford, who is chii of NCI's Community Oncology and Rehabilitation Branch. In both cases, reviews of the hospital records of women not on clinical trials reflected changes in treatment practices to include some type of adjuvant therap after surgery for a spetific subgroup of breast cancer patients. In September 1985, researchers at an NIH consensus conference recommended that postmenopausal women with node-positive, hormone receptorpositive breast cancers should receive tamoxifen. An almost threefold increased use of tamoxifen in these women quickly occurred. Around 50% of these women Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 23, 2015
Dr. John Isuci
Spinolo said that for reasons not fully understood, antisense against p53 appears to kill cancer cells, but only temporarily affect normal cells. He said his group is seeking approval from the Food and Drug Administration for a trial in AML patients. Chemoprevention continues to climb higher on the cancer research agenda. A joint symposium of ASCO and AACR included presentations on tamoxifen for breast cancer and retinoid compounds in a variety of tumors. Waun Ki Hong, MJ)., of the University of Texas M. D. Anderson Cancer Center in Houston, presented new findings that 13-cis-retinoic acid (isotretinoin) can stabilize or reverse premalignant oral lesions. Hong and his colleagues prolonged the treatment effect, and reduced side effects, by giving lower doses over a longer time. "We are optimistic about the important role of 13-cis-retinoic acid and other retinoids in preventing cancers of the head and neck, lung, and esophagus, which account for 32% of cancer deaths in the United States," Hong said, adding that larger trials are needed to confirm these benefits. On the diagnostic front, Daniel Pinkel, PhD., of the University of California, San Francisco, led a workshop on the FISH technique, short for fluorescence in situ hybridization. Using FISH, researchers can quickly and easily detect abnormalities in oncogenes, such as translocations and deletions — though not point mutations or other small changes. As an example, Pinkel described how FISH can identify the bcr-abl oncogene, a translocation site important in acute lymphoblastic leukemia.
Oncologists and cancer researchers last month descended in record numbers on San Diego, where the American Society of Clinical Oncology and the American Association for Cancer Research held their annual meetings. ASCO researchers announced results — many encouraging, some disappointing — from trials of innovative treatment and prevention agents, while AACR scientists described promising strategies on the horizon. Many speakers hailed the growing connections between the laboratory and the clinic, and stressed the importance of the two societies in strengthening those ties. "Basic research in cancer is beginning to pay off, not just in understanding, but also in many of the new therapies and diagnostic tests we are seeing," NCI Director Samuel Broder, M.D., told an AACR audience. "We can truthfully say
Dr. Alan F. Ltt 922
that insights into the process of initiation and promotion are leading to prevention strategies — for instance, using tamoxifen and Proscar — which are now being incorporated in large clinical trials and education campaigns."
Direct Relevance Webster K. Cavanee, Ph.D., AACR program committee chairman, noted with satisfaction that many ASCO members attended the AACR meeting as well. Clinical oncologists are beginning to believe that basic research has direct relevance to their work, he said. Drug resistance is a good example. Based on their knowledge of mechanisms such as the P-glycoprotein "pump" responsible for multidrug resistance, scientists can design therapies to circumvent resistance and make cells sensitive to chemotherapy. Clinical studies, in turn, lead to better understanding of the underlying processes. Alan F. List, M.D., and colleagues at the Arizona Cancer Center, Tucson, and Vanderbilt University Medical Center, Nashville, Tenn., reported at ASCO that cyclosporin-A (a powerful inhibitor of P-glycoprotein), when given with chemotherapy, induced remissions in 73% of 33 acute leukemia patients who had been resistant to conventional therapy. Researchers from Japan, led by Hiroyuki Tsuda, M.D., of the National Cancer Center Research Institute, Tokyo, are targeting another form of drug resistance involving the enzyme topoisomerase I. They found that a new compound, CPT-11, inhibited this enzyme, leading to favorable responses in nearly half of patients with refractory non-Hodgkin's lymphoma.
Dr. Webster K. Cavanee
"Each study gives us clues about the mechanism of drug resistance," Carol A Westbrook, M.D., of the University of Chicago said at a press briefing. "As we learn how to overcome resistance to om treatment, we are getting a better handle on ways to overcome resistance to otha treatments."
More Resistant In the 16th Richard and Hinda Roser thai Foundation Award Lecture, NCI's Michael Gottesman, M.D., described plans to exploit multidrug resistance in; novel way. Instead of making tumor eel less resistant, Gottesman and colleague! will attempt to make patients' bone mai row more resistant to the toxic effects o drugs by putting in the gene, MDR1, thi codes for P-glycoprotein. This gene therapy approach increase survival in mice, Gottesman said, and h now plans to try it in women undergoin autologous bone marrow transplants as part of their aggressive breast cancer therapy. At the ASCO meeting's plenary session, a number of investigators presente Journal of the National Cancer Institul
Downloaded from http://jnci.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 23, 2015
Clinical, Basic Researchers Find Common Ground in San Diego
News News
Price Gouging? Moertel was met with hearty applause when he blasted Johnson & Johnson, the parent company of Janssen Pharmiceutica, which makes levamisole, for charging patients 100 times what the company charges for the same drug when used to deworm sheep (see News, J Natl Cancer (nst, August 21,1991). "I would hope the company would realize that this is just totally beyond
reason," he said, suggesting that oncologists could express their displeasure with Johnson & Johnson's pricing policy by boycotting the company's exhibit. In other major trials, higher-dose adjuvant chemotherapy improved postmastectomy survival in stage U breast cancer patients, and high-dose cytosine arabinoside prolonged remissions in younger acute myeloid leukemia patients. Newer, more complex combinations of drugs for non-Hodgkin's lymphoma proved no more effective, and in some cases more toxic, than the standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). Taxol continues to show promise in a number of tumors, while trials of autologous bone marrow transplant, used to support aggressive chemotherapy, produced mixed results. The Eastern Cooperative Oncology Group reported that taxol is the most effective single agent against non-smallcell lung cancer it has evaluated in the past decade, producing responses in about a quarter of patients. And in a dose escalation study in advanced ovarian cancer patients, Gisele Sarosy, MX)., and colleagues at NCI found that higher doses of taxol along with granulocyte colony-stimulating factor boosted the response rate to more than 50%. Studies at the Istituto Nazionale Tumori, Milan, Italy, and Duke University Medical Center, Durham, N.C., with Cancer and Leukemia Group B suggest that ABMT may boost relapse-free survival in advanced breast cancer patients.
Cell Suicide
Dr. Card A. Westbrook
/ol. 84, No. 12, June 17, 1992
One word on nearly everyone's lips at AACR was "apoptosis" (though they still haven't agreed on its pronunciation — is the second "p" silent or not?). The term refers to programmed cell death, or "cell suicide," a normal process by which the body controls growth.
Downloaded from http://jnci.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 23, 2015
findings from large-scale chemotherapy trials designed to answer important treatment questions. Charles G. Moertel, M.D., of the Mayo Clinic in Rochester, Minn., presented a final report from an Intergroup Study on treatment of advanced colon cancer. The combination of 5-fluorouracil and levamisole has already been recommended for these patients, based on the trial's early results and a 1990 National Institutes of Health consensus conference. But Moertel said the maturation of the data shows conclusively that the regimen not only fends off recurrences but actually reduces the death rate by 33%.
Dr. Chartes G. Moertel
Scientists are devoting increased attention to learning which genes and proteins regulate apoptosis. They believe failures of the system can lead to cancer, and hope that by gaining control over the death program, they can develop better therapies. "The fundamental characteristic of cancer is that rates of cell proliferation are higher than rates of cell death," said John Isaacs, M.D., Ph.D., of The Johns Hopkins University School of Medicine in Baltimore. "In some cases, cancer could arise from decreased rates of cell death, rather than increased rates of proliferation. The balance between the two is what's out of control." Isaacs is working to design a more effective treatment for advanced prostate cancer by inducing apoptosis in nonproliferating, androgen-independent cancer cells. These cells present a stumbling block to curing the cancer, because they are not killed by hormone therapy or conventional cytotoxic drugs. By raising levels of intracellular calcium, Isaacs has succeeded in coaxing prostate cancer cells in vitro to turn on their suicide program. If this manipulaNEWS
923
News News
tion works as well in patients, Isaacs said, it might form the basis for a curative therapy for metastatic prostate cancer. Further along the path toward clinical use are antisense oligonucleotides, another promising treatment that depends on knowledge of the molecular events leading to cancer (see News, / Natl Cancer Inst, March 4,1992). Several researchers at AACR reported on their work in progress with antisense, which they hope will thwart cancer by blocking expression of oncogenes.
Success Against AML Jorge Spinolo, M.D., of the University of Nebraska Medical Center, Omaha, is among those vying for the honor of bringing antisense technology to its first clinical triaL Spinolo reported success against acute myeloid leukemia (AML) cells in vitro, and lack of toxidty from antisense in monkeys treated with the drug. Spinolo's molecular target is a surprising one: the normal p53 gene, which is believed to function as a tumor suppressor in most cancers. "This raises some controversy about what we're doing," Spinolo said. "But in AML, the wild — or normal —form of p53 seems to be involved." 924
The tests are currently sold for research only, but Pinkel said FDA approval for clinical applications could come within 2 years, after which he predicts "an explosion in use." — Tom Reynolds
Doctors Change Breast Cancer Treatment Practices Community physicians are thought t require reams of clinical data and long adjustment periods before changing the treatment practices. However, recent research found that many of these physicians quickly adoptet new practices when a consensus confer ence and clinical alert were the sources of the recommendations for treatment change. Physicians rapidly adopted recommc dations on breast cancer treatment from National Institutes of Health consensus conference in 1985 and a National Cancer Institute clinical alert in 1988, accoi ing to research reported at the 28th Annual Meeting of the American Socie of Clinical Oncology by NCI researcha Leslie G. Ford, M.D.
Consensus To Change "When given recommendations on how to improve treatments, community physicians can, and will, change their practice quickly," said Ford, who is chii of NCI's Community Oncology and Rehabilitation Branch. In both cases, reviews of the hospital records of women not on clinical trials reflected changes in treatment practices to include some type of adjuvant therap after surgery for a spetific subgroup of breast cancer patients. In September 1985, researchers at an NIH consensus conference recommended that postmenopausal women with node-positive, hormone receptorpositive breast cancers should receive tamoxifen. An almost threefold increased use of tamoxifen in these women quickly occurred. Around 50% of these women Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 23, 2015
Dr. John Isuci
Spinolo said that for reasons not fully understood, antisense against p53 appears to kill cancer cells, but only temporarily affect normal cells. He said his group is seeking approval from the Food and Drug Administration for a trial in AML patients. Chemoprevention continues to climb higher on the cancer research agenda. A joint symposium of ASCO and AACR included presentations on tamoxifen for breast cancer and retinoid compounds in a variety of tumors. Waun Ki Hong, MJ)., of the University of Texas M. D. Anderson Cancer Center in Houston, presented new findings that 13-cis-retinoic acid (isotretinoin) can stabilize or reverse premalignant oral lesions. Hong and his colleagues prolonged the treatment effect, and reduced side effects, by giving lower doses over a longer time. "We are optimistic about the important role of 13-cis-retinoic acid and other retinoids in preventing cancers of the head and neck, lung, and esophagus, which account for 32% of cancer deaths in the United States," Hong said, adding that larger trials are needed to confirm these benefits. On the diagnostic front, Daniel Pinkel, PhD., of the University of California, San Francisco, led a workshop on the FISH technique, short for fluorescence in situ hybridization. Using FISH, researchers can quickly and easily detect abnormalities in oncogenes, such as translocations and deletions — though not point mutations or other small changes. As an example, Pinkel described how FISH can identify the bcr-abl oncogene, a translocation site important in acute lymphoblastic leukemia.
