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SLOAN-KETTERING INSTITVTE FOR CANCER RESEARCH Sloan Awards In May 1957, the Alfred P. Sloan Award in Cancer Research for Recognition of Meritorious Contribution from the Institute to tb e Rdvancement of 1Lnowl edge was again presented. This intramural award was given to the Division of Clinical Investigation in recogni- tion of two outstanding programs. One was represented by the report, Hypophysectomy in the Treatment of Advanced Cancer, by Drs. Olof H Pearson, Bronson S. Ray, Charles C. Harrold, Charles D. West, Min-Chiu Li, John P. Maclean, and Mortimer B. Lipsett; and the other by Studies on Transaminase Activity in Blood, a series of reports authored by Drs. Felix Wroblewski, John S. LaDue, Irwin Nydick, Charlotte Friend, David Molander, and Arthur Karmen. Both of these distinguished studies represent contributions not only to our fundamental knowledge but also to the ability to care for patients. In Acknowledgment The work described in this fourth biennial report has been pos- sible only because of the generous contributions of many individuals and organizations. Among these are the Alfred P. Sloan Foundation, the American Cancer Society, the Andre and Bela Meyer Founda- tion, the Black-Stevenson Fund, the Damon Runyon Memorial Fund for Cancer Research, the Fannie E. Rippel Foundation, the Max C. Fleischmann Foundation, the Samuel H. Kress Foundation, the United States Atomic Energy Commission, and the United States Public Health Service. No less important to the very existence of the Center is the support of hundreds of groups, corporations, and indi- vidual donors whose aggregate gifts make possible a substantial por- tion of the Institute's work. To all of these, as well as to the men and women who work in the laboratories, the Trustees wish to express their profound gratitude.

n SLOAN-KETTERING INSTITUTE'S LABORATORY OPERATIONS ® MEMORIAL HOSPITAL JAMES EWING HOSPITAL PROPOSED BBTH ST. LAB. CENTRAL LABORATORY 377 E. 65TH ST. POLAK BLDG. WOODSIDE PROPOSED SUBURBAN LABORATORY F

i 13 SLOAIt-KETTERING INSTITUTE FOR CANCER RESEARCH Report of the Administrator The continuous drive of the Institute to find better means of cancer control has led to further expansion of work in the scientific areas already proved to be useful. The encouragement received for our program from the Congress and the general public, supported_ by financial aid from governmental agencies and private foundations, has made it abundantly clear that additional quarters would have to be sought for an expanded effort, particularly in cancer chemotherapy. We were fortunate in finding a building owned by and immediately adjoining Long Island College Hospital in Brooklyn. A cooperative agreement was made with Long Island College Hospital, in the fall of 1956, and three laboratory groups from the Institute moved into the Polak Laboratory, a five-story building of approximately 14,000 gross square feet. The laboratories are serving their purpose admi- rably and probably will continue to do so until more permanent quarters can be found. Our animal residence area, in Woodside, Queens, has also been expanded. Because of the usefulness of this area for dog and cat quarantine, as well as long-term maintenance of animals, approxi- matelyone-third o€-the former-1y -rentedgropertywas-purchased:-This area, approximately 200 by 125 feet, allows for considerable increase of the dog, cat, chicken, and goat colony with a possibility of further expansion if we should wish to breed our own rodents for laboratory purposes. Personnel Office The Sloan-Kettering Institute had 607 employees on its payroll as of June 30, 1957, not including a considerable number of individuals actively connected with the organization who receive stipends from other sources. It became evident that a personnel office must become an integral part of the administrative organization. One was opened in March 1957 in renovated quarters adjacent to the main lobby and reception room on the first floor. An experienced personnel officer, Mr. H. N'1'. Hienow, heads the staff. Numerous functions were assigned to the new office. Among the most important are: (1) recruiting, interviewing, and inducting pro- fessional as well as non-professional personnel; (2) centralizing the personnel records of all employees of the Institute; (3) coordinating wage and salary administration; (4) promoting desirable employee U 0 W N J 0 W F

14 SLOAN-KETTERINO INSTITUTE FOR CANCER RESEARCH relations; and (5) developing effective communications within the organization. Significant progress has been made in all these areas, and definite improvement has been reported in the filling of staff vacancies. The Institute works constantly to attract and retain the services of the best qualified men and women in all parts of the organization. The increasing number of scientific research organizations competing for the limited number of science graduates makes it necessary to keep pace with the latest developments in research personnel admin- istration and to provide leadership in that area. Improvement in Procedures The unusual complexity of Sloan-Kettering lnstitute's account- ing system, due to the need for accounting on the expenditure of many special funds, made it desirable to establish still better fiscal control. An assistant administrator has been employed, whose task it is to establish better control over expenditures. We are indeed fortunate to have been able to work out with the National Cancer Institute of the U.S. Public Health Service a system of submitting applications and receiving grant awards from them on a divisional organization basis. This replaces in some part awards to individual investigators and permits a much needed flexibility for the division chiefs in assigning funds to the various laboratory sec- tions within the division. Four divisional applications were sub- mitted in 1956 and awarded in 1957. The remainder of the divisions submitted applications to the National Cancer Institute this year, and we expect to have essentially all grants-in-aid from that source awarded on a divisional basis in 1958. We are also in the early stages of negotiating with the National Cancer Institute the terms and details of several research contracts - - t roug the ancer Chemotherapy National Service Center. This is a new type of support offered by the National Cancer Institute and we are watching this development with great interest in order to determine its potential effect on the future support of Sloan-Kettering Institute. We continue to enjoy most pleasant relations with the many offices of the federal agencies as well as with such organizations as the American Cancer Society and the Damon Runyon Memorial Fund. Bernhard L. Mecke Administrator

15 SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH Report of the Director SUMMARY I. Cancer Prevention 6y Defrnition and Rernoval of Cause A. INTERNAL CAUSES 1. Hormones in cause and control of cancer a) Steroid hormones (1) Hormonal influences on blood components b) Pituitary hormones 2. Natural resistance to cancer and its enhancement a) Immunochemical studies (1) Analysis of immunological components b) Resistance to implanted cancer in man c) Resistance to transplanted cancer in animals (1) Zymosan studies d) Virus studies (1) Vaccination (2) Fluorescent antibody studies B. ENVIRONMENTAL CAUSES 1. Lung cancer and cigarette smoking a) Cigarette filters b) Reduction of burning temperatures of cigarettes c) Treatment of tobacco d) Identification and removal of cancer-causing agents 2. Other studies of environmental cancer induction II. Crrre of Cancer A. LOCALIZED CANCER 1. Early diagnosis a) Enzymes in diagnosis (1) Detection of precancerous change

s 16 SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH 2. Treatment a) Improvement of surgical supportive techniques b) Improvement of radiation techniques B. DISSEMINATED CANCER 1. Analysis a) Nucleic acids (1) Uptake studies b) Biophysical analytical techniques (1) Spectrometer (2) Analysis of trace substances in tissues (a) X-ray fluorescence (b) Radio-autography 2. Synthesis 3. Trial a) Laboratory trials (1) Improvement of test methods (a) Transplanted human cancer: in the labo- ratory animal and in the fertilized egg (b) Spontaneous cancer: in the mouse and in the hamster (c) Resistant cancer (d) Combination chemotherapy (2) New agents in laboratory trial b) Clinical trials (1) Improvement of methods (a) Technique for measurement of response (b) Natural history of cancer (2) New agents in clinical trial (a) Disseminated cancer (b) Acute leukemia in children (c) Acute leukemia in adults (d) Breast cancer c) Special studies (1) Viruses (2) Melanoma studies (3) Effects of hormone alteration

SLOAN•KETTERINO INSTITVTE POR CANCER RESEARCH SCIENTIFIC PROGRAM I. Cancer Prevention hy Dcfrvitio» and Removal of Cause One phase of the Institute's program is directed toward definition and removal of the causes of cancer, with the ultimate goal of cancer prevention. There are two approaches to this objective. First, we try to define and control specific internal chemical functions of our own bodies which cause cancer or determine whether or not a partic- ular individual is susceptible or resistant to the disease. Second, we seek the identification and removal of external, environmental factors which cause or predispose toward certain kinds of cancer. Progress has been and is being made in both these areas of research. INTERNAL CAUSES Hormones in Cause and Control of Cancer All living tissue is built up of an orderly honeycomb of living cells, each type with its own special abilities and functions. Some cells, such as those of the sex and adrenal glands, have the particularly important task of making hormones-those peculiar chemicals a hich control sex, size, and many other characteristics. This function, like all others of the cell, is governed by the cell's genes, minute struc- tures passed on from parent to offspring. They contain special ar- rangements .of unique chemicals, functioning as codes, which spell out in detail the development, structure, and function of all living things. Recent evidence shows that inherited defects in the genes result in errors in the coded messages sent out by these master control boards. The garbled instructions may result in the production of hormones abnormal either in quality or quantity. There is evidence that such abnormalities may cause a number of disorders, including cancer. Steroid Hormones At the Sloan-Kettering Institute, new methods of defining and measuring the details of hormone production in man have been devel- oped by laborious research. The steroid hormones produced by the sex and adrenal glands have been studied with particular care. Many different hormonal products excreted by patients with congenital dis- orders of the adrenal gland have been isolated and identified chemi- cally. Some contain the same imperfection. It is as if an automobile assembly line turned out car after car, differing in style and color,

SLOA\-KETTERI\C I\STITVTE. FOR CAN' CER RESEARCH but each one missing a vital part, owing to a flaw in the master template. In the human body, this template is the gene. Similar studies have been made of a group of women suffering from a peculiar body abnormality, hirsutism, a common and often distressing condition which appears to be hereditary in nature. This also seems to be linked to abnormal hormone production; in this case the error is a quantitative one, a difference in the amounts of hormone produced. It is as if the master plan for hormone produc- tion contained one tiny error, resulting in the overproduction of one small but specially important group of steroid hormones. Its remote and extreme consequence manifests itself in a physical deformity as, for example, the bearded lady of the old-time carnival. Much evidence has been accumulated linking to cancer devel- opment the body's hormones, particularly the steroids. Cancer tends to develop in hormone-dependent tissues, such as the breast, ovary, uterus, and prostate gland. It occurs somewhat more frequently at puberty and at the menopause, when hormone production and utiliza- tion are undergoing basic changes. Certain varieties of cancer in man can be controlled temporarily by the administration of sex or adrenal hormones, or conversely, by removal or neutralization of hormone sources. Hormone administration has been demonstrated to cause a wide variety of cancer types in animals. Most of the Institute's work with hormones over the past twelve years has been devoted to the development of techniques by which the production and action of the steroids can be studied. This has involved the evolution of new methods of chemical separation and analysis, including the use of radioactive tracers and new syntheses of related compounds. Today most of the hormones formed by the adrenals and testes have been identified, and their normal breakdown products defined. Similar studies of the hormones formed by the ovaries are going forward. Each step forward not only brings new insight, but also takes us deeper into this complex field of study and turns up important applications to the other fields of disease. It is increasingly certain that there exist in the body, hormones of even greater potency; perhaps undreamed-of activity, and that their discover awaits only further technical development. As this program goes forward, we should be able to reconstruct in increasing detail the gene's master blueprint of hormone production and to recognize in it the defects which, if not corrected, may lead to many serious disorders, including cancer.

19 SLOAN-KETTERING INSTITVTE FOR CANCER RESEARCH HOk\IONAL INFLUENCES ON BLOOD COMPONENTS Studies of certain types of lipoproteins, fatty particles isolated from one blood fraction, have given further evidence of a hormonal imbalance underlying at least one form of cancer. Women with in- operable breast cancer weie discovered to have lower levels of one lipoprotein (alpha) and higher levels of another (beta) than healthy women of the same age. More detailed studies of a larger series showed that statistically significant differences in the lipopro- teins could be found among women with (1) normal breasts, (2) benign breast disease, (3) early operable breast cancer, (4) breast cancer spread to soft tissues, and (5) breast cancer spread to bone. Since there is overlap among the groups, the differences are not yet of diagnostic usefulness. What they do reveal, however, is some com- mon underlying problem; the tiny lesion associated even with benign breast disease or early operable cancer must be not the cause but the reflection, in the lipoprotein pattern in the blood, of some constitu- tional change. Lipoproteins are known to be influenced by the hormones of sex and adrenal glands. Women normally have higher alpha lipoproteins than men and lower beta lipoproteins. These differences are thought to account for the higher inctdence among men of arteriosclerosis and consequent heart disorders. Administration of estrogen to men results in a lowering of the beta level. Studies were made of lipoprotein levels in women with breast cancer before and after the ovaries (the source of estrogen) were removed. A change in levels toward normal resulted. Apparently the levels of these blood constituents reflect some complex imbalance of hormones that was partially righted by removal of the ovaries. Conceivably the imbalance is the cause of the cancer, a possibility long suspected. Pituitary Hormones During the past year in our laboratories, a new principle has been discovered which may make it possible to alter specifically the individual components in the body s hormone pattern. This new ability may become the key to future prevention as well as cure of many presently uncontrollable diseases due to defective body chem- istry. The hormone used in this pilot study is TSH (thyroid-stimulat- ing hormone), one of five or more produced by the pituitary, the minute "master gland" at the base of the brain. TSH has two char- acteristic properties: it localizes in the thyroid gland and, once ~ 0 W N v O A Cf O

20 SLOAN-KETTERING IA'STITUTE FOR CATCER RESEARCH attached, it stimulates the gland to produce, in turn, its peculiar hormone, thyroxin, a wholly different substance. In order to study TSH, our investigators extracted this complex protein-substance from animal pituitaries and attached to it a radioactive atom as a tag, which would indicate where in the body the hormone traveled and localized. In order to add the radioactive atoms, a minor change had to be made in the chemical structure of the TSH. The TSH, thus changed, was administered to laboratory animals. The treated ones showed none of the usual effects of thyroid stimulation, but when their thyroid glands were examined, it was found that the modified and radioactive material had localized as well as ever. The two characteristic abilities of TSH, to localize and to stimulate, had been separated. When normal untreated TSH was given to the animals which had previously received and held the changed hormone, still no evidence of thyroid stimulation could be found. The localization of the altered material in the thyroid had left no room for the normal thyroid-stimulating hormone (TSH). Hence, the force normally driving the thyroid was removed, and the gland began to decrease its output. When altered TSH was given to animals over a period of time, their thyroids grew small and thyroid deficiency resulted. A most encouraging fact is that in preliminary trials in man, the altered TSH has also blocked off from the thyroid the normal TSH. Consequently, our changed hormone may have value in the treatment of thyroid disorders in man, including thyroid cancer. At the very least, an important new principle has been established, capable of extension. Our new technique, using altered,TSH, is the first known way to destroy accurately the function of a hormone without surgical removal of the gland that manufacturers it. Now it has been clearly demonstrated for the first time that the two outstanding properties of hormones, localization and stimulation, are not inseparable, as was previously thought. The path has been opened for attempts at simi- lar control of the other hormones of the body. ENVIRONMENTAL CAUSES Many causes of cancer are already well known and some can be eliminated with consequent cancer prevention. There is nothing new about the facts, although they seem to be forgotten frequently. Not- able examples of environmental causes of cancer are at hand in the pitiful group of women, watch-dial painters, who died of bone cancer from ingesting radium by.moistening their radium-covered I