Cancer Research Meeting Focuses on Range of Issues

Saying they were not asking for a lot of money compared to what is being spent in just a few days in the war in Kosovo, officials of the American Association for Cancer Research (AACR) called on Congress this month to double the National Cancer Institute's budget to $5 billion for fiscal year 2000 and increase it 20 percent per year for the succeeding four years. Such a boost would increase the federal government's annual investment in cancer research to $10 billion in five years. The plea came at the end of the AACR's annual meeting, April 10-14 in Philadelphia, at which new research findings were presented and public forums featured opportunities for members of the public to "ask the experts" about cancer research issues. AACR leaders briefed journalists on their quest for increased funding on the final day of the meeting. "We have been caught in the baby boomer catastrophe," declared Anna D. Barker, AACR board member and president and CEO of BIO-NOVA Inc., Portland, Ore. The aging population and changing demographics are expected to increase the rate of cancer diagnoses dramatically over the next decade. Barker said that the AACR is encouraging its members and others to "speak up" to the public and to Congress about the need for greater cancer research. The message to Congress, she added, is: "You've got to act on this, ... and now. This is not something we can wait on." Posters--urging people to contact their government representatives--scattered throughout the conference halls reminded attendees of that message. "One of every two men and one of every three women will get cancer ... [and] by the year 2010, it will cost this country $200 billion annually," said Daniel D. Von Hoff, AACR president and director of the Institute for Drug Development, Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio. Von Hoff acknowledged that the prospects for such a budget increase this year are rather grim, but he said that the increases in cancer diagnoses will undoubtedly affect more and more members of Congress and will "personalize" the need for boosting research funding. "Because our population is aging and we are all living longer, the number of people who will be diagnosed with cancer in the United States will increase dramatically. The number of cancer cases is expected to reach epidemic proportions, with two million new cases per year by 2025," Von Hoff said in remarks prepared for his April 15 testimony before a subcommittee of the U.S. House of Representatives. "It is time to make cancer our highest health-care priority and undertake a national approach to eradicate cancer," Von Hoff asserted. Added Barker at the Philadelphia news briefing: "We're trying to deliver a message here of emergency. ... We think we need a new national cancer act in this country." Von Hoff and Barker stated that the increase in funding could be directed toward more research in prevention and in earlier detection of cancer. Von Hoff also said that one of his personal priorities is to get more clinicians trained. Basic research--including biomedical and behavior cancer research--currently accounts for about 25 percent of the federal grants approved, they said, and it should be increased to a minimum of 45 percent. Von Hoff offered the congressional subcommittee five recommendations for increased funding: Increase the level of funding for investigator-initiated research. Increase the number of NCI-designated Comprehensive Cancer Centers in the United States. Expand clinical trial programs. Attract, educate, and train more cancer researchers. Double efforts in cancer prevention to help stop the epidemic. Von Hoff said the achievements against cancer over the last few years have brought down the rate of cancer deaths and the reduced the percentage of patients who will die from their cancer. "Even though the death rate from cancer is going down, cancer still kills more Americans each year than have died in all the wars we have fought in this century," Von Hoff said. --Larry Hand Genetically altered immature dendritic cells injected into tumor cells help summon the body's immune system to fight cancer. Adding interleukin-12 (IL-12) to those highly specialized immune-system cells strengthens that cytotoxic T-cell response--meaning a potentially more powerful cancer vaccine, reports Hideaki Tahara, assistant professor of surgery, molecular genetics, and biochemistry at the University of Pittsburgh. Tahara and colleagues first injected dendritic cells into mouse tumors. Then they examined the animals' spleens and lymph nodes to measure the immune response. They found that the injected dendritic cells were able to process the tumor antigens at the tumor site, migrate to the spleen and lymph nodes, and present antigens to the lymphoid cells, which released significant quantities of interferon-gamma. Interferon-gamma levels were higher in the animals that received the dendritic cells than in controls, which received saline injections. Modifying the dendritic cells to secrete IL-12 boosted the immune response. "IL-12 can directly enhance the dendritic cell function," Tahara explains, during an interview following a press briefing. He notes that the therapy holds promise because it may work for a variety of tumor types, even when the targeted antigen remains unknown. "This therapy can have the selective immune response specific to the tumor," Tahara notes. "You can induce a specific immunity, even if you don't know the specific gene you are targeting." Tahara hopes the treatment can be approved for clinical trials this year. --Paul Smaglik If BRCA2's broke, it can't fix FHIT. When BRCA2 is mutated in inherited breast cancers, that repair gene fails to mend FHIT, a tumor suppressor gene located on one of the genome's most fragile sites, about 80 percent of the time, reports Kay Huebner, professor at Thomas Jefferson University's Kimmel Cancer Center in Philadelphia. Huebner bases her conclusion on a study she and colleagues conducted of 92 Icelandic women--58 with sporadic breast cancer and 34 with an inherited, or familial, form of that disease. All had some loss of FHIT's tumor suppressor function, but the women with the familial BRCA2 mutations lost it twice as often. The study suggests a complex interaction with repair genes and genes on fragile sites of the genome, Huebner notes. "It's possible that in a normal cell, those fragile breaks all get repaired by normal BRCA1 or BRCA2 and possibly other repair genes. But in these tumors they get repaired improperly." Since FHIT was discovered in 1996 by Huebner and colleagues 1 it has been implicated in a variety of tumor types. Huebner intends to explore the relationship between BRAC1 and BRCA2 and other fragile regions, such as chromosome 16 and chromosome 7. That hunt could unearth other genes that, like FHIT, become defective when the repair genes are mutated. "There are many, many fragile regions in the human genome. This gives us a clue to find other genes that also might be specifically altered in breast cancers--the genes that are at the other weak links." M. Ohta et al., "The FHIT gene, spanning the chromosome 3p14.2 fragile site acid renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers," Cell, 84 :587-97, 1996. A research team led by AACR President-elect Tom Curran, chairman of the department of developmental neurobiology of St. Jude Children's Hospital in Memphis, Tenn., recently discovered a mechanism by which fos, first identified as an oncogene about 15 years ago, turns normal cells into tumor cells. First published in January, 1 the findings identify a major fos pathway, involving the gene DNA methylcytosine transferase (dnmt1), that's both necessary and sufficient to cause oncogenesis in cells. "We were kind of surprised that we identified one gene that was capable of doing so much," said Curran at an April 14 AACR news briefing. Also surprising was the apparent action of fos: It causes cell transformation by reducing gene expression via hypermethylation through the Dnmt1 protein, rather than by somehow increasing gene expression as was previously hypothesized. "Now instead of looking at genes that come on during transformation, we're looking at genes that will be switched off," Curran said of current fos research. There are, however, other players besides dnmt1. Curran's team is interested in seeing how the various targets of methylation are regulated and how they may be regulated by other genes that modify DNA or chromatin. "We'll be using different strategies to look for low-expressed versus high-expressed genes," remarked Curran. He added that the discovery of a fos mechanism that involves methylation brings his work closer to human applications since there's been a great deal of research on the role of methylation in human cancers. Curran's research may have been indicative of a major theme at this year's AACR meeting. Webster Cavenee A.V. Bakin and T. Curran, "Role of DNA 5-methylcytosine transferase in cell transformation by fos," Science, 283 :387-90, Jan. 15, 1999. The American Association for Cancer Research presented the following research awards and lectureships during the annual meeting in Philadelphia: Mina J. Bissell, director of the life sciences division of the Lawrence Berkeley National Laboratory at the University of California, received the Clowes Award for her demonstration that the extracellular matrix in breast tissue is a complex system of interacting control signals that determine whether the cells grow, die, remain normal, or become malignant. Her award lecture was entitled "The structural basis of tissue specificity: the interaction of genome and the microenvironment in normal breast and malignant tumors." J. Martin Brown, director of the program in cancer biology at Stanford, received the Bruce F. Cain Memorial Award for his tumor therapy research involving ways to exploit the fluctuations in oxygenation in tumors due to variations in blood flow. His award lecture was entitled "The hypoxic cell: a target for selective tumor therapy." Carlo M. Croce, director of the Kimmel Cancer Center at Jefferson Medical College of Thomas Jefferson University, received the AACR-Pezcoller International Award for Cancer Research for discoveries in the field of cancer genetics, including the first identification of the genetic alterations responsible for Burkitt's lymphoma, the first isolation and identification of the bcl-2 cancer gene, and the discovery of the FHIT gene (see "Studies target fragile genome regions," above). His award lecture was entitled "Genetics of human cancer." John Kuriyan, Howard Hughes Medical Institute investigator and Patrick E. and Beatrice M. Haggerty Professor at the Rockefeller University, received the Cornelius P. Rhoads Memorial Award for his biophysical studies looking into the structure and interactions of critical genes and control factors involved in transcription. His award lecture was entitled "The structural mechanism of the regulation of the Src family of oncogenes." John Mendelsohn, president of the University of Texas Anderson Cancer Center, received the Joseph H. Burchenal AACR Clinical Research Award for his accomplishments in basic and translational cancer research--especially those involving growth factors that interact with cancer cells--which have led to the establishment of several strong clinical research programs in the U.S. His award lecture was entitled "Blockade of receptors for growth factors as anti-cancer therapy." Bandaru S. Reddy, chief of the division of nutritional carcinogenesis at the American Health Foundation, delivered this year's DeWitt S. Goodman Award lecture, an honor given in recognition of his research on the role of nutrition and other protective factors in colon cancer. His lecture was entitled "Novel approaches to prevention of colon cancer by nutritional manipulation and chemopreventative agents." Dennis J. Slamon, director of the Revlon/UCLA Women's Cancer Center Research Program at UCLA's Jonsson Cancer Center, received the Richard and Hinda Rosenthal Foundation Award for his research establishing the relationship between the Her-2/neu gene and the prognosis for patients with an aggressive form of breast cancer. His award lecture was entitled "Alteration of the Her-2/neu gene in human breast cancer: diagnostic and therapeutic implications." Alice S. Whittemore, director for epidemiology at the Northern California Cancer Center at Stanford University, received the AACR American Cancer Society Award for her novel integration of genetic information and improved statistical methods in epidemiological studies, an approach that has led to the identification of new causative factors for several types of cancer. Her award presentation was entitled "Genetically tailored preventative strategies: an effective plan for the twenty-first century?" Yue Xiong, an assistant professor of molecular biology and biotechnology at the University of North Carolina's Lineberger Cancer Center in Chapel Hill, received the B. Elion Cancer Research Award, given annually to a nontenured scientist, for his proposal "Tumor suppression by the Rb and p53 pathways." Fang Liu of the Center for Advanced Biotechnology and Medicine, assistant professor in the department of chemical biology of the laboratory for cancer research at Rutgers University, received the AACR National Foundation for Cancer Research Career Development Award for a proposal entitled "Role of TGF-beta-inducible gene regulation in tumorigenesis." Renata Pasqualini of the Burnham Institute received the AACR-Susan Komen Breast Cancer Foundation Career Development Award for a proposal entitled "Targeted delivery of genes to angiogenic vasculature." James J. Fiordalisi, a postdoctoral fellow in radiation oncology at the University of North Carolina, received the Gerald B. Grindey Young Investigator Award for his abstract "High affinity for Ftase and alternative prenylation contribute individually to K-Ras resistance to FTI's."

Cancer Research Meeting Focuses on Range of Issues

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