Fundamental Aspects of Neoplasia PDF
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Fundament0a'l Aspects Neoplasia Fundamental Aspects of Neoplasia edited by A. Arthur Gottlieb Otto J. Plescia David H. L. Bishop Springer-Verlag Berlin Heidelberg New York 1975 Proceedings of a Symposium held May 20-22, 1974 at the Waksman Institute of Microbiology of Rutgers, the State University of New Jersey Library of Congress Cataloging in Publication Data Main entry under title: Fundamental aspects of neoplasia. Includes index. 1. Oncogenic viruses-Congresses. 2. Tumors Immunological aspects-Congresses. 3. Immunological deficiency-Congresses. I. Gottlieb, A(braham) Arthur, 1937- II. Plescia, Otto J. III. Bishop, David H. L. IV. Rutgers University, New Brunswick, N.J. Institute of Microbiology. (DNLM: 1. Neoplasms Congresses. 2. Oncogenic viruses-Congresses. BF698 G297p] RC268.57.F86 616.9'92'071 75-4792 All rights reserved No part of this book may be translated or reproduced in any form without written permission from Springer-Verlag. © 1975 by Springer-Verlag New York Inc. Softcover reprint of the hardcover 1st edition 1975 ISBN-13: 978-3-642-66114-3 e-ISBN-13: 978-3-642-66112-9 001: 10.1007/978-3-642-66112-9 Preface The control of cancer is at once a major public health problem and a problem of fundamental biologic interest. As a result of technologic developments and new insights in the realm of molecular biology, new and important approaches to an understanding of neoplasia are now possible. Several aspects of neoplasia are clearly of microbiologic interest, including the role of viruses in the etiology of cancer, control of the immune response to tumor cells, and the susceptibility of tumor-bearing hosts to overwhelming infection as a result of immuno deficiency. Recent advances in these areas led us to organize this symposium, and, through this publication, to record some of the progress being made in laboratories around the world in understanding some of the basic aspects of the cancer problem. This symposium was held as part of the commemoration of the twentieth anniversary of the Waksman Institute of Microbiology. Dr. Waksman's devo tion to the study of the smallest forms of life and the commitment of the Waksman Institute to the free pursuit of knowledge are the underpinnings of the institute's research eHorts in the broad area of microbiology, including the problem of neoplasia. It is of interest to note that actinomycin, one of the earliest antibiotics discovered in Waksman's laboratory, was also one of the first compounds found to be clinically useful in the treatment of certain types of cancer. In addition, the institute has been the training ground of several key figures in the National Cancer Program, including the current director. In recent years, the institute has developed several programs in virology and immunology that relate to the cancer problem, and several studies of the fundamental biochemical characteristics of tumor cells as well. The interests of the institute faculty in these areas led to the suggestion that it would be appropriate to devote this Twentieth Anniversary Symposium to the problem of neoplasia. Three major themes emerge from the symposium. 1. The impossibility of planning scientific research in such areas as the biology of cancer, areas in which a high degree of uncertainty exists. 2. Several observations suggest that tumors are interesting biologic systems in themselves. Tumor cells can produce a variety of molecules; and some of these molecules may potentiate tumor cell growth and, thereby, be potential targets for chemotherapeutic drugs. 3. Although much has been learned about tumor viruses in animal systems, and although there is considerable indirect evidence that viral particles or v Preface parts of viruses occur in human tumor tissue, the complex interactions of viruses and carcinogenic agents and the respective role that each play in the etiology of cancer remain to be determined. We wish to express our appreciation for the financial support of the Charles and Johanna Busch Bequest, which made this symposium possible. We also J. wish to thank Dr. O. Lampen, Direotor of the Institute of Microbiology, Mr. E. R. Isaacs, Executive Secretary of the Institute, and Mr. Jack Faron, Division of Special Services of Rutgers University, who aided us in our planning and management of the symposium. We are especially indebted to Mrs. Jeanne Nied and other members of the Institute staff, who handled the heavy secretarial burdens, inherent in the preparation of the symposium, with efficiency and dispatch. Dr. Bruce Alberts, Dr. Sheldon Cohen, and Dr. Walter Schlesinger served as able chairmen of various sections of the symposium. Finally, we are indebted to the speakers and their associates who through their efforts provided a valuable and memorable highlight to the institute's twentieth year. A. Arthur Gottlieb Otto J. Plescia David L. Bishop New Brunswick, N.]. A. Arthur Gottlieb, M.D. Otto J. Plescia, Ph.D. Professor and Chairman Professor of Immunochemistry Department of Microbiology and Immunology Institute of Microbiology Tulane University School of Medicine Rutgers University New Orleans, Louisiana 70112 New Brunswick, New Jersey 08903 Formerly, David H. L. Bishop, Ph.D. Professor of Microbiology Professor of Microbiology Institute of Microbiology The Medical Center Rutgers University University of Alabama New Brunswick, New Jersey 08903 Birmingham, Alabama Formerly, Professor of Microbiology Institute of Microbiology Rutgers University New Brunswick, New Jersey 08903 vi Prologue: The National Cancer Plan and its Relationship to Basic Research Guy R. Newell I thank you for ilwiting me to share with you this important occasion, which simultaneously commemorates the Twentieth Anniversary of the Institute of Microbiology of Rutgers University and honors the memory of the late Professor Selman A. Waksman. Professor Waksman's name is linked for all time with microbiology and Rutgers, and I was not surprised to learn that Dr. Waksman was associated with Rutgers University for more than half a century, as a student, faculty member, director of the Institute of Microbiology, and professor emeritus. We of the National Cancer Institute are proud of the twelve professionals J. on its staff with degrees from Rutgers, including the director, Dr. Frank Rauscher. I suspect that the interest sparked while he was at Rutgers eventually led to Dr. Rauscher's discovery at the Institute, of the murine leukemia virus now known as the Rauscher virus. Dr. Rauscher immediately made his virus available to many investigators, and it is being widely used in studies of viral neoplasia in laboratories throughout the world. His discovery was one of a number of such advances in the 1950s and 1960s that led to an Institute decision to develop an expanded research program in viral oncology. During that time, the Institute was already conducting broad programs of research on chemotherapy and chemical carcinogenesis. A mandate for a greatly intensified effort was given the Institute by the National Cancer Act of 1971, for a total mobilization of resources, people, and knowledge in a new national program to conquer cancer. At this time, knowledge and technology were believed sufficient to warrant the confidence that progress against cancer could be accelerated. By the 1971 Act, the Institute was charged with developing and coordinating an overall national strategy for cancer research with many members of the scientific community collaborating to produce the National Cancer Program Plan. Now, what is the National Cancer Program Plan-and more importantly, what isn't it? The Plan provides the framework for coordinating, monitoring, updating, and reporting on the progress of the National Cancer Program. It is a progress report, to be updated annually, to reflect new scientific knowledge, new research leads, new opportunities for applying research findings to clinical vii The National Cancer Plan and Basic Research medicine. The fact that the Plan will be updated points out its flexibility in reflecting the state of science, and not directing the art of science. The Plan does not measure the scientific merit of traditional investigator-initiated research; such research is currently and will continue to be, reviewed and measured by the peer review study section system. There is no built-in mechan ism to allow the Plan to stifle new research initiatives. I would now like to highlight briefly for you some scientific advances and opportunities, particularly in the clinical area of treatment, inasmuch as many advances in the more basic areas will be covered during the course of this symposium. There are 44 drugs that produce remissions of clinical cancer. If analogues are subtracted, there remain 27 different chemical structures. Ten of these have been employed in regimens that produce cures or remissions (some quite impressive) in 11 different types of cancer. -{, Unfortunately, these are relatively uncommon tumors. Our question then is: Do these uncommon tumors share a process that is different from the processes in the more common tumors? Research has shown that they do: they are relatively fast growing tumors, with short doubling times. Successful chemotherapy of these uncommon tumors is pointing the way by which common tumors may be manipulated by other regimens to be more susceptible to this kind of chemotherapy. Thus, direction for future research includes: (a) developing and screening new drugs that can act alone or in combination with other drugs. For example, adriamycin, an anticancer drug discovered in Italy, has shown a greater degree of activity against a broader range of tumors than any other single agent previously tested. Studies are under way to test the usefulness of the drug in combination with other treatments and to develop active analogues of adriamycin that are not cardiotoxic. (b) Applying new forms of radiation, such as the the laser beam, that spare normal tissue are not in themselves carcinogenic. (c) Certainly, developing new regimens for BCG and other forms of immunotherapy, both alone and in combinations. (d) Determining new combinations of known effective drugs to be administered at a time when a large majority of tumor cells are irretrievably committed to DNA replication and thus susceptible to differential kill by chemotherapeutic agents. Drugs may also be used as adjuvant therapy, given immediately following surgery for the removal of the primary tumor mass or irradiation and directed toward eradicat ing microscopic foci of metastases. This is a particularly exciting area with great * Drugs: Cyclophosphamide, nitrogen mustard, thiotepa, 6-mercaptopurine, methotrexate, vincristine, actinomycin D, mithramycin, procarbazine, and prednisone. Types of cancer: Wilms' tumor, choriocarcinoma, Burkitt's lymphoma, retinoblastoma, mycosis fungoides, acute lymphocytic leukemia, Ewing's sarcoma, Hodgkin's disease, rhab domyosarcoma, histocytic lymphoma, and embryonal testicular cancer. viii The National Cancer Plan and Basic Research future promise. (e) Combining such modalities as surgery, irradiation, chemo therapy, and immunotherapy. Results of research in the fields of cellular and molecular biology, and especially in immunology and virology, will be highlighted during this sym posium, so, now, I would like to present in broader terms how the National Cancer Act affects basic research. Several conditions following enactment of the National Cancer Act of 1971, and relating to the conduct of research, created sensitive issues for the Institute and for our colleagues in the scientific community. Because the Act directed the Institute to include within the National Cancer Program not only the programs of the Institute but related programs of other research institutes and federal and non-federal programs, we do have a responsibility to relate and respond to a much broader scope of activity than we previously had. This implies that the Institute is responsible for all cancer research done in the United States, in one way or another. Numerous departments, other than Health, Education, and Welfare, of which we are a part, and other federal government agencies fund or support cancer research and control. Many private voluntary organiza tions, such as the American Cancer Society, support cancer research and con trol. We are making every effort to establish meaningful liaisons with these other groups and agencies, and, at the very least, to try to assure that funds provided to the Institute are not used in research that duplicates other research. Other sensitive issues related to budget, to ways of funding, and to our rela tionship to other institutes within the National Institutes of Health. These issues cannot be treated separately. The Act specifies that the director of the Institute prepare and submit an annual budget estimate for the National Cancer Program directly to the President; and that the Director receives from the President and the Office of Management and Budget directly all funds appropriated by Congress for obligation and expenditure by the Institute. We have a legal and a moral responsibility to specify the amount of money we think the Institute can use to greatest effect. But the federal dollar is limited, and we recognize this. As a result, many people think cancer is being given such a high priority that other important areas of biomedical research are being neglected. No one, to my knowledge, has shown that this is, in fact, true. But the ordering of priorities is of great concern to us. We do not want resources for cancer to be increased at the expense of other disease-oriented and basic biomedical research. It seems to me that the key question to be asked is: If funds allocated to cancer research during the past few years had not been earmarked for cancer, would they have been provided to other areas of bio medical research? The faot is that the answer to this question will never be known. We sincerely hope that our advocacy of large sums of money for cancer research will help other research areas and that advocates for other ix The National Cancer Plan and Basic Research diseases and research areas will be successful in obtaining their own funding. At the same time, we believe that information from cancer research will neces sarily provide important leads in other disciplines and for categorical diseases and vice versa. If we look at the numbers of grants awarded for both the Institute and the National Institutes of Health from 1962 through 1973, one readily sees that the trend was one of rapid decline. Since the National Cancer Act was passed, in late 1971, we have done considerably better, and funding for the National Institutes of Health has leveled off. We are hopeful, and even confident, that we shall both show further increases in grant-supported activities. To assure that no promising research that may be related to the fundamental process of cell transformation goes unfunded, we have established a firm, dual-assignment policy. Thus, if projects related to cancer cannot be funded by other institutes, they are also assigned to the Institute. Their priorities as determined by NIH Study Sections or by other institutes, are considered along with the priorities of applications coming directly to the Institute. If their priorities are higher than the Institute's cut-off point, they are funded with cancer dollars. We currently support between 3.5 and 4.0 million dollars worth of research this way. In fiscal year 1971, before the new National Cancer Program began, the Institute had a budget of $233 million. In 1972, the first year of the new Cancer Program, it was $378 million. In 1973, it was $432 million; and in 1974 our operating level was $589.2 million, including impounded funds released by the President. I would like to further break down the allocation of these funds. Although most of the available money is in extramural programs, more than 15 percent is used in intramural research and direct operating costs, and, thus, it does not enter the competitive arena. For fiscal year 1974, $39.0 million (6.6 percent) was used to support our intramural scientists, and $51.9 million (8.8 percent) paid for our own direct operating costs plus our share of the National Institutes of Health management fund. A small amount (2.4 percent) supported cancer re~earch performed by other federal agencies; this is effected by an Interagency Agreement. But, clearly over 50 percent of extramural funds are expended in support of grants, and, if Interagency Agreements are excluded, the ratio is 58 percent grants and 42 percent contracts. A comparison of research and research-supported activities by grant and by contract is of interest, as follows: Funds for total research grants, including traditional grants, cancer centers, and off-campus task forces, increased from 50 percent of grant and contract funds in 1972 to 55 percent in 1974, for an amount of $217.7 million. Of the $91 million for cancer centers, only $20 x The National Cancer Plan and Basic Research million was for core support; the remaining $71 million supported regular competitive research projects, which could just as well be shown in the category above. The figure of $217.7 million for research grants does not include all money funded through grants. Additional grant funds (amounting to about $70 million) are included with other activities, such as training, cancer control, and construction. I should also point out the sizable increases in funding for regular research grants from 1972 to 1974. On the contract side, about one-half of the research contract funds were for support activities, and these went to support grantees as well as other contractors. Research contracts and research support contracts decreased from 50 percent in 1972 to 45 percent in 1974, for an amount of $175.8 million. In addition, we managed to enhance our fellowship and training program to $25.6 million, surpassing the $20 million figure in 1972, which was our previous peak year for the support of training. You should be aware that Mr. Benno C. Schmidt, the chairman of the President's Cancer Panel, has championed the cause for the restoration and maintenance of training programs for the benefit of all of the National Institutes of Health. A review of the history of the Institute grant support from 1964 through 1973 highlights the fact that the number of grants funded increased from 884 in 1970 to 1424 in 1973, from $63.8 million to $138.2 million. These figures also show that the rate of grant support has increased commensurate with the rate of contract support. Is this increase enough? Certainly not. Is good research going unfunded? Yes, it is. The point is that, along with the increase in funded grants, there has been a threefold increase in the number of applications submitted, which means a larger number of unfunded applicants. There is no doubt that some investigators, who would not have done so, are now gearing their work toward cancer. Balance is, of course, the key question. What is the appropriate cut-off level for funding approved applications to assure that the best research is done with the finite resources available? What is the best combination of grant and contract support to assure that knowledge is applied in clinical medicine, to be delivered to the American people? These are questions we grapple with every day, and we solicit your suggestions and and recommendations. A final point is that substantial support is given by the Institute to research projects of young investigators. In fiscal year 1972, 52 percent of the appli cations of investigators 35 years of age and under were approved and funded: 32 percent of the applications of investigators over age 35 were approved and funded. For those under 35, only 35 percent of applications were disapproved, whereas 55 percent for those over 35 were disapproved. The average dollar amount was slightly more for the over 35 group ($47.6 thousand) than for the young group ($36.4 thousand). This seems reasonable, since the older xi
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