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Fox

Chase

Cancer

Center

Robert C.

Young,

M.D., President

Fox Chase Cancer Center, one of 26 National

CancerInstitute-designatedcomprehensive

can-cer centers in the nation, is dedicated to the

missionofreducing the burden of humancancer.

The center's activities includebasic, clinical, and prevention research; detection and treatment of cancer; and community outreach programs.

Fox Chase Cancer Center was formed in

1974 by the union of the American Oncologic Hospital and the Institute for Cancer Research.

Nowknown astheHospital ofFoxChaseCancer

Center, theAmericanOncologicHospitalwasthe first cancer hospital in the nation. Although

can-cer was then considered incurable, a group of Philadelphia leaders established the hospital in

1904 to care for patients and to carry out re-search that would make cancer a manageable disease.

Founded in 1927, the Institute for Cancer Research helped change the course of cancer research, which until then had focused solely on studies of tumor tissues. Institute founder Stan-ley P. Reimann, M.D., believed that to under-stand the abnormal growth processes of cancer cells, scientistsfrom manydisciplinesmuststudy the basic mechanisms of normal cells. This then-revolutionary approach forms the basis for most

cancer research today. With these principles in

mind, the Institute grew during the 1950s, '60s, '70s, and '80s, with scientists eager to research

new programs such as cell and developmental biology, immunology, virology, geneticsand bio-chemistry.

Today, Fox Chase has more than 1,800 em-ployees and an annual budget of $127 million. Research is conductedinmorethan 75 laborato-ries by a staff of more than 300 physicians and

scientists who hold M.D.s, Ph.D.s, or both.

Lo-catedintheresidential northeastsection of Phil-adelphiaand surroundedbya park, Fox Chase's

Address correspondence and reprint requeststo: Dr.Robert C.Young,Fox ChaseCancerCenter,7701 Burholme Ave., Philadelphia,PA 19111,U.S.A.Phone: 215-728-2781; fax: 215-728-2571;e-mail: rc-young@fccc.edu

1997,THEPICOWERINSTITUTEPRESS. Allrightsreserved.

MolecularMedicine, Volume 3, Number 8, August1997 491-495

environment is conducive to interaction

be-tween laboratories and the clinic.

Fox Chase's 100-bed hospital is one of the few facilities in the country devoted entirely to cancer care. More than 130 clinical trials of new

prevention, diagnostic, and treatment techniques

areunder wayatany onetime.Almost1,000new

patients a yearparticipate in clinical trials.

Fox Chase is structured around three divi-sions: medical science, basic science, and popu-lation science. Medical science is committed to providing excellent patient care and conducting

abroad-based program of clinical research. The division ofbasic science is renowned worldwide

for its work in understanding both normal and abnormal cell growth anddevelopment. The goal

of the divisionofpopulation science is to identify people at high risk for cancer and to develop strategiesto reducetheserisksthrough programs

ofpreventionandearly detection. Thisstructure

reflects Fox Chase's belief that collaborations

be-tween disciplines translates research into clinical applications much more quickly and effectively. The center serves as a national resource for translating new research findings into medical applications that may become models for

im-proved cancerdetection, treatment, and

preven-tion. Among the notable accomplishments by scientists at Fox Chase was the discovery of the hepatitis B virus by Baruch Blumberg, who re-ceived the 1976 Nobel Prize in Medicine for his

work. His Fox Chase laboratory also subse-quently helpeddevelop the hepatitisB vaccine-the first vaccine capable of preventing a human cancer, sincehepatitisB canleadtoprimaryliver

cancer.

CELLULAR

AND

DEVELOPMENTAL

BIOLOGY

Fox Chase scientists Robert Briggs and Thomas King's experiments in nuclear transplantation, using embryonic frog cells, resulted in the first

vertebrate "clone" in 1952.

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The first mosaic mammal (a mouse with

genes from four parents), developed byBeatrice

MintzatFox Chasein 1962, providednewways ofstudyinggeneticexpression, birthdefects, and developmental disorders. Using similar tech-niques, Fox Chase scientists produced a normal mouse by usinggeneticmaterial from

teratocar-cinoma cells, thusshowing that thiscancerdoes

not involve irreversible genetic change.

Formorethan 30years, RobertPerry'swork

ontheorganization and expressionofribosomal

protein genes, their transcriptional regulation,

and translational control has contributed toward

understandingof the role of proteinsinthe cell.

Perryand hiscolleaguesatFoxChase have iden-tified specific segments of DNA that play key rolesin gene expression.

BIOCHEMISTRY

Irwin Rose has worked ontheprotein ubiquitin

found in cells and responsiblefortargetingother protein molecules for disposal. Rose discovered that ubiquitin helps regulate the important

pro-teins that control cell reproduction. When the

apparatusforcontrollingandprocessingcell

pro-teins is better understood, scientists will be able

to compare its function in normal and cancer

cells.

Jenny Glusker has been a leader in

crystal-lography for structural research onproteins and

other substances. Her work concentrates on en-zymes that let thebody convert foodto energy,

on vitamin B12, and on cancer-causing agents

derived from aromatic hydrocarbons, including

componentsofcigarettesmoke. Herlaboratoryis

studying the chemotherapy drug estramustine and chemoprevention drugs such as oltipraz.

IMMUNOBIOLOGY

MelvinBosma's 1980 discoveryofaFox Chase-bred mouse strain with severe combined im-mune deficiency (SCID)andsubsequent

elucida-tion of the developmental genetic defect provided a model for the corresponding human

birth defectandhelpedscientists studyhow cells of theimmune systemdevelop. Since SCIDmice havenonaturalimmunityand cannotreject

tis-suetransplants, theyhave also become valuable

research toolsforstudyingother diseasesbesides

cancer, such as AIDS.

Today, researchers at Fox Chase are explor-ing the cellular and molecular mechanisms

in-volved in the development and production of antibodies. R. Randy Hardy is working on the development and selection ofimmunoglobulinV

gene repertoires insubpopulations of B cells.

PHRMACOLOGY AND MEDICAL

ONCOLOGY

Pharmacology and medical oncologyresearch at

Fox Chase focuses ondeveloping more effective anticancerdrugs and investigating the molecular mechanisms that allow some tumor cells to resist

treatment. Many of the center's current studies inthese areasfocus onbreast, ovarian, and

pros-tate cancers.

Fox Chase staff are among the leaders in developing cancer treatments that use biologic responsemodifiers to helpmobilize the immune system againstcancercells. Thecenterconducted the first clinical trials of monoclonal antibodies designedtotargetgastrointestinal cancer cellsfor

diagnosis and treatment inthe early 1980s. This

workhas ledtothe development of new hybrid "bi-specific" monoclonal antibodies that may al-lowphysicians to deliver activated immune cells directly to a cancer.

VIROLOGY

Most viruses that cause cancer in animals are retroviruses, as are the human T-cell leukemia virus and the human immunodeficiency virus thatcausesAIDS. Several FoxChase laboratories study retroviruses, which reproduce differently than other viruses.

WhenvirologistJesse Summers directed the Institute for Cancer Research in the early 1980s, his work focused on the molecular biology of hepatitis B on woodchucks. Today, Anna Marie Skalka, SeniorVicePresident for Basic Science, is exploring the basic mechanisms of RNA viruses: howthey encode and transcribe genetic informa-tion, and how they produce and process

pro-teins. This program includes studies of the

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FIG. 1. Fox Chase Cancer Center

mechanisms of action and target molecules,

re-searchers may be able to

develop therapies

to

treatorreverseacquiredimmune

deficiency

syn-drome byblocking the viral infection.

Inother areas ofvirology, scientists are

con-tinuing their research on hepadnaviruses in an

attempt to understand the molecular

mecha-nisms of viral infection. This will enable themto

design strategies that interfere with viral repro-duction. Through study of the hepatitis delta agent, one scientist is searching for answers to

this source of serious chronic liver disease and death in people

chronically

infected with

hepa-titis B.

Virologist GlennRall researches the dynam-ics of theimmune response toviralinfections of the central nervous system using neurotropic

murine viruses, with emphasis on infection and function of the blood-brain barrier. He is also interested in the role of adhesion molecules in

the regulation of lymphocyte traffic into the

CNS.

THE

MOLECULAR ONCOLOGY

PROGRAM

Fox Chase'sMolecular Oncology Program is led

by

Dr. Alfred G. Knudson Jr. A geneticist and a

physician,

Knudson isinternationally

recognized

for his "two-hit"

theory

of cancer

causation,

which

explains

the

relationship

between the

he-reditary

and nonhereditary forms of a cancer,

and

predicts

the existence of

anti-oncogenes-genes that can suppress cell growth. This

now-confirmedtheoryhasadvancedunderstandingof

errors in the genetic program that turn normal cells into cancer cells. Knudson divides his time betweenFox Chase and the National Cancer

In-stitute (NCI), where hewas appointedas

special

adviser to Dr. Richard Klausner, Director of the NCI,while

working

withDr.JosephFraumeniin NCI'snewDivision of CancerEpidemiology and Genetics.

Fox Chase's molecular oncology researchers

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divisions tostudy the molecular andgenetic

fea-turesofcancer in humansandanimals,the basic

molecular mechanisms of growth in the patho-genesis of cancer, and whether it is possible to

reverse the process at the molecular level. Spe-cific areas of study include genetic alteration in

cancers, hereditary predisposition to cancer,

on-cogenes and tumor suppressor genes, transduc-tion of growth signals, and control of the cell

cycle.At thesame time, thepractical experience and observations of physicians treating cancer

patientshelp formulate basic scientific questions. Insights gained from the program's approach, includingclinicalstudies of thebiology of human cancer, allow researcherstoexplorenewwaysto treat cancerpatients orprevent cancerwith ge-netic tools.

In some areas of special interest, Fox Chase

scientists are involved in defining in molecular termsthecellular aspects ofexpression of the p53 gene that account for its function as a tumor

suppressorindiverse human tissues.Two funda-mentalareasof cancerbiology-themechanisms that a cell uses to avoidthe killing properties of chemotherapeutic drugs and how cells transmit the internal signals that control basic activities such as growth-are another focus inmolecular oncology.

Acontinued efforttoidentify genes involved

in the pathogenesis ofmalignant mesothelioma hasalso been made at Fox Chase. Inotherwork, investigators conducted a large-scale,

multi-centerstudy ofalterations of theAKT2oncogene in ovarian and breast carcinomas. Amplification and overexpression of this gene were identified

innearly 15% of ovarian tumors but were rarely observed in breast cancers.

THE

HUMAN GENETICS

PROGRAM

AT

FOX

CHASE

The world of genetics is a very different place than when Jack Schultzwasthe first staff

mem-beratthe InstituteforCancerResearchworking

ongenetics. Schultz theorized the role of genetics

in cancerwith Drosophila (fruit flies). Rapid

ad-vances in the field of molecular genetics and geneticepidemiologyhave made thestudy of the genetic basis of common human diseases

in-creasingly practical.

The combination of detailed genetic maps composedofeasilycharacterized "markers" with

powerful biomathematical methods has allowed the identification ofgenes responsible for many

"single-gene" diseases. The unifying theme of molecular genetics research at Fox Chase is the application and extension of these methods to

better understand the genetics of complex "multi-gene" diseases, which are responsible for

most of the common human cancers, and to

elucidate the interactions between genetic and environmental factors. This information can

then be used to identify people at high risk for

cancerandtodevisepotential strategies for

pre-vention and treatment. Fox Chase continues to

beapioneer in the field of prevention researchas

the understanding of prevention's role becomes

a more clear and necessary expansion of the future of medicine.

Underthe leadership ofKenneth H.Buetow, Fox Chase's moleculargenetics research is

com-mitted in a large partto the construction of hu-mangenetic maps anddistribution of thesemaps to the scientific community. This effort is an essential component of the Human Genome

Project, aninternational effort to map all human chromosomes and identify specific genes

associ-atedwith cancerand other diseases.

To generatethese maps, Dr. Buetow and his colleagues are developing new, semi-automated map construction procedures. Fox Chase is also responsible for providing computer-based tools

thatfacilitatethe storage, retrieval, and interpre-tation of the genetic map data as well as the primary data from which the maps are derived.

Forthis unique effort, Dr. Buetow and his team received the Computerworld Smithsonian Award for science in 1995.

Some human geneticists are now research-ingthe role of the metabolism of homocysteine,

a key cellular chemical. High plasma levels of homocysteine placeindividuals at risk for a wide variety of developmental diseases. In addition, defects in homocysteine metabolism are fre-quently observed in human tumor cells. Fox Chaseinvestigatorsinthehuman genetics work-ing group are also interested in identifying, clon-ing, and characterizing genesinvolved in tumor progression, metastasis, and chemotherapeutic drug resistance.

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varia-tions between the two groups. She is further sequencing the "high-risk" and "low-risk" gene variants to identify their differences at the

mo-lecular level.

All three divisions at Fox Chase-basic

sci-ence, medical science, and population science-are involved inmolecular medicine research

to-wardthe goal of reducing the burden of human cancer.

ACKNOWLEDGMENT

References

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