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P.O. Box 2370 Pteston, Virginia 22090 Telephone 703-620-4646 DCT BOARD APPROVES REISSUING SURGICAL aNCOLOGY RFA FOR PLANNING, OKAYS NEW AND R ECOMFETING PROJECTS The :,oard of Scietltific Counselors of NCI's Div. of Cancer Treat- ment last week gave concept approval to reissuing the request for applications for planning grants to develop surgical oncology research programs. In doing sm, the Board backed DCT's policy of continuing certain initiatives aimed at stimulating interest in surgical oncology. The Board gave concept approval to more thati $5 million in grant and contract supported projects, including nearly $3 million for five (Continued to page 2) In Brief BARRY PIERCE NEW DCCP BOARD CHAIRP'IAN; ADANISON SEEKS ADs FOR CHEMICAL, BIOLOGICAL CAF2CINOGIENESIS BARRY PIERCE, professor of pathology at the Univ. of Colorado md,former member of the Board of Scientific Counselors of NCI's Div. of Cancer Cause & Prevention, will be the new chairman of that Board, replacing Peter Magee, whose term expired with last week's meeting. Other new members of the Board will be Louise Lorr,bard, veter-nary pathologist with Afrgonne Tational Laboratory; and Lee Wattenberg, an expert in chemical carcinc genesis at the Univ. of Alinnesota.,,. RICHARD ADA.'ttSON, DCCP director, announced that he intends to recruit associate directors for both the Biological and Chemical Car- cinogenesis Programs. Each will have responsibility for extramiiral and intramural research within their respective programs, :.. CORREC- TION: Gertrude Elion is the fourth woman elected president of the American Assn. for Cancer Research, not the third (The Cancer Letter. June 3). 0miited was Elizabeth Miller. McArdle Laboratory, who was president in 1976-77.... AN ACTING CHIEF of the Clinical Trials Section is needed in the Biological Resources Branch of NCI's Bio- logical Response Dlodifrers Program. The job entails planning and derPlopmeni of BRA9 clinical trials, both those conducted at the pro- gram's facility in Frederick, h1d„ and extramural trials at institutions with BRMP master agreements. The Senior Expert appointment pays from 541,277 to $53,661. Those interested should submit Personal Qualification Statement SF-171 with three references to D4s. Cynthia Kauff, Personnel Management Branch, NCI, Bldg. 31 Rrn 3A23, Bethesda, 61d. 20205. Applications must be postmarked by Aug. 15 Phone l:auff for further information at 3C'1-796-6864. ... JO1D~ WEtNER, associate professor of medicine at the Univ. of Southern California, has beeh named administrative director of the Childrens Cancer Study Group. Weiner, a member of NCI's Cancer Clinipl ln- vestigation Revtew Committee, has worked part time with CCSG as a statistician since 19' 1. He replaces Richard Honour, who left for a position in industry. Vol. 9 No. 24 June 17, 1983 I (ciCopvng4t 1983 TneCarrcer Letter Inc. ~ Suhicrrpno,, $125rear NortnArne-lca I S.t 50 y2ar eliewne,e Frei, Freireich Share One GM Prize; Ames, Erikson Win Others ... Page 5 AACI. ASCO, ACCC Hold Moeting With HCFA On DRG Issue ...Page6 DCCP Board Gives Concept Approval To Noncompeting Contracts ... Page 7 RFPs Available ... Page 8 I

mittees which consider surgical applications. We feel DCT BUARD GIVES CONCEPT APPROVAL that these steps will, in time, have a positive measur- TO MORE THAN $5 MI LLION IN PROJECTS able effect on the development of surgical oncology." (Conrinued jrorn page 1) Chabner said the program announcement for surgical oncolo~• R01 s, first p;:blished in 1981, vall RFA's (including the s.irgical oncology planning be reissued periodically. "The ;,resent version has grants), and over $2 million in new and recompeting been revised soinewhat to cL.rify some of the cor.tracts• The Board also approved the concept of wording and to be less apparently restrictive than the noncor.tpietitive renex•aIS for four contract supported original version. The changes in wording are minor. projects costing almost S 1 million. We feel that it is irtrportant to reissue this announce- All cost figures are staff estimates of first year ment periodically and plan to do so four times during awards. the next year to increase awareness of it." DCT Director Bruce Chabner presented an update Chabner reviewed other DCT efforts in surgical on the division's initiatives in surgical oncology. The oncology: RFA for P20 planning grants, originally issued in . Physician Investigator Development Awards 1981, had 28 submissions of which only five were (h08)-The announcement for this award was pub- funded. "Many of the grants that were submitted lished last March as "Clinical Investigators Award." were not planning grants in any real s:nse," Chabner A specific review panel and dales for review are yet said. "Some of the problems here were with applic- to be set. Funds from the Div. of Resources, Centers ants and some with NC) staff. The present version & Community ActAvities are to be supplemented by has been reworded for clarification concerning its DCT monics as necessary in making awards to up to purpose, which remains the planning of research eight surgeons per •'year with meritorious applications. proposals." The awa-ds will be for three years, to a maximum of The new RFA, which will be released sometime S30,000 per year plus up to S 10,000 for supplies. this summer, will allocate 5500,000 for the three The stipulation is that the awardee wiil spend no less year planning grants. The staff narrative describing than 75 percent of his or her time in research. MDs the program: and DOs will be eligible, unless they already have a Purpose of this grant is to plan and develop a program for PhD. research in c.:rpcal oncology; The treatment or cancer has • R01 Rcview-Ithe Expenmental Therapeutics evolved as a multidisciplutary effort involving (but not limtted Stud Section has been divided into a reciincal and to) tite disciplines of medical, pediatric, sergrcal and radiation y P oncology. The disciplines of medical, pedtatric and radiation a clinical part. Most of the clinical RO Is submitted oncology have developed strdng programs ir. clinical investiga- by surgeons will be reviewed by the clinical part of tion. but academic development in surgical oncology has not ET. The executive secretary of this committee was kept pace. For most cancers• surgery is the keystone of pri• given a list of surgeons qualified to serve on this study rnary treatment, which is the setting in which advances in section for the review of grants. It is not yet clear multidisciplinary• therapy are likely to occur. Since such ad- vanrPs are an important continued development of the multi- whether onc or mote of these individuals utill he dr.ciplindry treatment of cancer and a long range objective of asked to serve as permanent members of this study tne Div. of Cancer Treannent• the attainment of this goal section, or will be asked to serve in an ad hoc cap- requires subs'antial strengthening of academic programs in acity when the specific need arises. surgical oncology• • Surgery as a Cancer "Activity"-The designation Examples of proposals that NCI considers for suppon in• clude: of surgery as an "activity" would allow for easier -Planrn.•g the development of a research program in tracking of submitted grants by the head of the surgical onc,logy withrn the context of avarlable staff and Surgery Section and would therefore be a significant facilitres• administrative advantage. The NCI Executive Com- -Feasibrlity studies that permit the appLcznt to gathcr mittee has discussed this issue and felt several months data to determine the potential of developing such a protram, and to explore the vahdrty o: various approaches to imptem• apo that the draft of the guidelines describing surgical enttng the program. oncology was too broad to be useft-l. A revised Chahner said that current DCT initiatives toward veision of these guidelines is in its final stages and support of surgical oncology "are along many fronls- this matter will he discussed again with the Executive increasing effectiveness of teaching at medical Comrnatee tas soon as a final version has been drawn schools: training grants for young investrgators; plan- up. ning graots for medical school faculty members; pro- + Professional Oncology Education Programs gram announczments to encourage submission of (R25)-These are grants to schools of medicine, den- surgical onculog}• research gra ntF by established in• tistry, public health and nursing to i,tcrease emphasis vestigators: a more ac•vist approach by DCT advising in cenain areas of health science. The money pays applicants regarding rettisions of unfundable grants; for salanes for indtviduals engaged in these efforts, and assisting t`te Div. of Extrimural Activities in which pmnanly involve teachinF. cour:ce develop• selecting propcr individuals to sit on reviev+• com- mcr,t. etc. Surgical oncolrt.h- haN been added to the The Cenoer Letter Page 2/ June 17. 19113

list of targeted areas, which included epidemiology, nutntion, prevention, cancer control, and radiation oncology. "We feel that this is a potentially fruitful way of capturing the imagination of medical students at a time when their ideas about caree* choices are still very much in f7ux," Chabner sdid. Philip DiSaia, who is retiring as chairman of the Board's Surgical Oncology Research Development Subcommittee since his term on the Board has ex- pired, applauded the division's efforts and said that for the most part SORDS' recommendations had been carried out. "Now we need some long range planning." William Shingleton, a membef of SORDS, agree d. The Board gave concept approval to other new major RFAs,,for the Developmental Therapeutics Program, Radiation Research Program, and Biolog- ical Respcnse Modifiers Program. Disawery arid characterization of multidrug resistant human and other mantmalian tttmor cell lines. A total of $500•000 will be set aside for first ye.ar, awards, with an anti- apated project penod of three years. Developmental Ther- apeutics Drrector John Driscoll said the amount probably would fund four grants. Staff descnption: The develof+tnent of drug resistance in tumor cell popula• tions treated with chemotherapeutrc agents has been recog- nrzed as a majoi frroblem in cancer treatment. Detailed studres in Chmese hamster and murine cell systems have shown that under some selective condtttons,e.g, colchtctne, vincttsttne, or adriamycin treatment, cell populations dt monstrating a plero- troptc or rnultidrug resistant phenotype emerge: In many of these cells, broad spectrum resistance to muluple agents of different modes of action is associated with reduced mt :a• cellular ac.umulauon of drug and the appearanie of a mem• branc glyeoprotein marker. Recently, laboratory evidence has been presented that multidrug resistant,cells occur in human tumor cell populations. This latter evidence is cwtinsistent with cluucal expertence, particularly with prhviously treated pa• tients, wherein pesistance to multiple agents of different modes of action is observed. W1ule some potentially important collateral sensitivities have been observed among mammalian cell types showing the muitrdrug rests:ant phenotype, it seems likely that additional new agents specifically useful in treating these resistant cells w•dl be needed. In order to establish an evaluation program to identify such agents. NCI will require well charactented multt• drug resrstant human tumor cell lines in whrch new agents can be studied. This is an RFA for grants whrch propose to dis- cover and characteriae multidrug resistant human and other mammaban tumor cell lines that have potential for this purpose. hfulttdrug reststar: tumor cell lines either may be selected in vitro using the techprques de%elo;xd in mammalian cell culture s)ntzms or they may be established drrectlx fiom pa• ttents shown to be chmcally resistant to chemotherapy. Char• acterrzabon of the cell ltnes must rnclude venficatton of the human origin of the cells• deruonstratrom of tumongemcny in surtable ammal hosts, detailed evaluation of the relative drug resistance of the cells tn -itro, and evaluation of the mechan- rsm of resrstance for each cell bne. Paruct1lar attentinn should be paid to the stabibti of the d,ug resistant phenotype- Apphcants will be requested to provide samtiles of each cell line drscovered to the t:Cl Tumor B,rnk and to provide de• taded mfotmauon to NCl on th; discovery and charaiterria• twn of thesc n•lt bncs. Basic research in factors influencrng tilr1R relaxation times. A total of $l million w•ill be sct astde fcr r: •-• akards. with an anticipated ploJect period of three years?Radratron Research Director David Prstenmaa said that amount probably would support six grants. Staff descrrp,ron: Nuclear magnetic resonance unaFrng provides nor only .,natomical cross sectional images but also charactenstrc T1 and T2 paramagnetic relaxat,on times. T 1 rs the time it takes the sample to become polanzed. t.e.• for the magnetic spins of the nuclei in the sample to line up with the strong extemal magnettc field of the pmapng system. It is also the ume con- stant of return of these spins to eqtirbbrrurr• after being sumu- lated by the radio frequency pulse. It is affected by the sur- roundrng environment in the tassue and by the vrbr trons of the molecules in the :Rerghborhood. Typically, TI is longer for more liq rified samples and for pathological uesues (including edema) tl.an for normal solid tissues. 12, on the other hand, is a measure of the time it takes the magnetic nuclear spins to get out of phase with each other after being magnetized be- cause o` the interactions of the local spins on each other. When Tt and T2 ake both measured, the combined result can be found to be characteristic of bor:e, muscle, fat• blood, abscess, or tumor, for example, depending on the values. Such tnformatron has already been used to color code the tissues to distinguish their distributions in the NMR tomograph in both animals and humans. It is hoped that noninvasive differential diagnosis of normal vs. pathological tivue may one day be made possible through these relaxation time measurements. However, more bastc research is heedzd to understand the biophysical and biochemical factors which influence the Tl and T2 parameters as a basis for this capability. In vivo relaxa• uon times are the restYlt of complex contributions from w•ater • lipids, and blood flow, among others. In vivo s:udres:n anrm- als and humans are required as well as in vitro studies of ex• psed tissues to correlate Nh1R findings with histopathology. Fundamental studies in tissue culture may also be helpful. Many other research programs in NMR imaging and MNR spectroscopy are betng supported for their grosvm_e applua- uons in medical imaging and in analytical research. Know- ledge about the conditions which determine Tt and T? wtll contribute to the fundamental understanding of the drffer• ences between normal and abnorntal tissues ar.d will enhance the value of these other NMR activities. Chabner said that the division's current budget for FY 1934 does not include money for this project. Hcwever, NCI Director Vincent DeVita has ascured him that if NCI receives a final appropriation above the President's request, the project would be funded. Board member Theodore Pltillips sard this project "is critical in the development of NMR. There an ?O units going in around the country this year. One million dollars is not much. lt is urgent rh: t money be made a-ailable to help us evaluate these images." Discovery of strategies for the in vitro and in vivo pre• clinical tecting of monoclonal antibodies and their immuno• conjugates for biologic and therapeutic effectiveness. A u,ta i of $500.000 will be set aside for first year anards. whtch Htll be three year cooperatrveagreements. Staff descrrptton. Monoclonal antibody and rmmunoconlug.+te theraf5 hase demonstrated antitumor effectiveness in bo'a animal m; dels and human situations. The potential number of antibodies and rmmunoconjugates that car, be produced is enormous 1 he obrbty to prcdict in vivo efficac% of thcsc aFcnt; in humans t..% a precb ucal testing mechanism would tx of s:gndreant value in the } roccss of d<<eloputt t he best monoclanal ant+tJ%. re agents for uuhtauon in a,ncer treatment. The Cancer Letter Vol. 9 No. 24 ! Page ?

r g1 Current teclmiques available for the prechnical evaluation of the effects of monoclonal antibodres and tmmunoconju• gates on tumor cells include in vitro cyKntoxrcity studiej, soft agar cloning assays, Winn assays, rodent xenografts, and the subrenal capsule assays. Evaluation of nVonoclonal antibodies and immunoconjugates in each of these assays has not been extensive and it remains to be determrned whrch will be hclp- ful and effective in defining, elucidating, or predicting mech- anisms of activity andlor clinical effectiveness. Proposals are sought that will define the predictive capability of these assays or develop new assays with the ability to predict antrtumor efficacy of monoclonal antibodies and ilmmunoconjugates. A further goal of the studtes should be to provide information relevant to understanding the mode of action and biologcal mechanismsby which effective antitumor monoclonal anti• bodies or immunoconjugates exert their effects in cancer treatment. The Biological Response Modifiers Progam, through a contract, has a number of monoclonal antibodies and anti• bodytoxin conjugates available ior study. The program has the desire ajtd the need to explore and develop strategies for prechnicar. testing and to correlate these with ongoing clinical and animal mode) trials. BRbfP also has an ongoing precbmcal common tract screen whfch evaluates for biological respnse modification in assays of T and B cell function, NK cell activ ity and macrophage cytotoxicity. Plans are under way to de- velop a specific tract screen for such agents as monoclonal antibodies, for whrch the common tract screen would be in• appropriate. Cooperative agreement holders would be re• quired to interdrgitate with the activities of both screens. A substantial amo,utt of federal involvement will be required to accomplish this goal. Because of tttis, we propose the use of the cooperative agreement mechanism. Discovery of new biological evaluadqn models for the Drug Development Program. A total of $425,000 wili be set aside for first year awards, with an anticipated project period of three years. Staff description: There is a need to discover new models to identify better anticancer agents. Despite remarkable advances in the surgical and radiological treatment of pnmary neoplasms and the use of aggressive adjuvant therapies, most cancer patients die of metastatic disease. Altl'ough considerable progress has been made in finding agents ;o treat and even cure some forms of cancer, there remains a critical demand for effective therapies for the major solid tumo-s, includinethose of the breast, colon and lung. The current stratcgy of the drug development pro- gram is to screen 10.000 carefully selected materials in an in vivo P388 leukemia prescreen followed by an evaluation of about 250 compounds m a screen consrstmg of a panel of four in vrvo tumor models (L1210 leukemra, B16 melanoma, btX•1 human mammary xenograft and the b95076 tumor). Other tumor models, sach as the CD8Fl mammary or Colon 38. are used for special studres, such as the evaluation ot closely related structures to deterrnme the one with the most desirable properties for clinical development. The in vttto human tumor colony forming assay also is being evaluated as a parallel screening system. NCI is interested in drscovenng new in vrt ru and in vivo models for drug evaluation at etther the prescreen or screening levels. Proposed projects must address relevance to the cancer problem and potential for use as an evaluation system for new anticancer agents. Reproducibihty. labor, matenal and equipment requirements should be considered. Recent ad- vancesm our knowledge concerning the rdentufrcatton of oncogenes, the processes associated with cellular drfferentua• tron, novel assays fos tissue specific cytotortns, the g.routh of genetrc mutant cell cultures, and the gro.+ tb of human mmors whrch metasrasrre in nude mice provtdc somc cKamplrs of research areas ti.'lu.h otrer opportunities for tne The Cancer Letter Page 4 i June 17, 1983 develupment of new methods or tumor models for application in the drug deselopment program. NCI will provide a number of suitable compounds for evaluation in the proposed assays. Because of the anticipated substanttal involvement of NCI in the development of protocols for the proposed models and drug supply, the cooperative agreement mechanism is pro- posed. "How does this differ from the Drug Discovery Program?" Phillips asked. "This money might better be Spent by adding to that, funds for which are in- adequate." (The new initiative, in w'hich NC] %vill help- estab- lish multidisciplinary Drug Discovery Groups, w•ill get under way with issuar.~,e of the RFA in July. The DCT Board approved the concept of that program last year.) "This program v.ill develop models, not drugs; " Driscoll said. "There is a continuing need for new models." "If we don't have new models, we'll come out with the same things over and over," Board member Paul Calabresi said. The Board approved two new concepts which will be funded by contracts. Development of an in vitro screening system using human tumor cell lines. Proposed first year award, $:00,000, three and a half years. In vitro screening methods offer several poter.tral advan- tag: s over screening in animal models. These tnclude. lower cost: shorter assay time. easier laboratory control and assay standardization, and the requirement for .'en small amounts of test compound. Addrtionally, in vitro models based on the use of human tumor cells can be readrh developed. Recent drugscreerring tnak Hith a human tumor colony forming assay (clonogenic assay) have identified a number of active compounds, including novel structural leads. which were nagauve and relatively nontoxic in the munne P388 teukemta prescreen. Thrs result suggests that either the cell culture system is more sensttve than the current prescreen or that it ts identifying a different class of agents. Further in vno testing of these agents is current)y under way wluch should clarify this situation. In either case, such in titro testing would seem to be an effective way of rdentify:ng compounds which would otherwise be lost to the screening program. Gecause of the technical complexity ar.d associated cost of the colony forming assay, it is not fcasible to test all of the P388 pre- screen negative. nontoxic compounds (current)% zbout 5.500 per year ) in this system. The purpose of thrrs project is to develop and c%aluate a simpler in vitro screemng sYstem based on rire ux ui iuurid, t.uuvr uii ilnc:• Uld', im" be J;:.ad on a large scale to screen these compounds. Investigators will be requested to de%elop three to five human cell lines fur use as an in vitro screening panel. A larFe number of wcll characterized human tumor cell lima a:e cur• rently available through the'vCl Tumor Bank as wcll as commercial and pr:vate collections. Tlan) of these ret3tn ddfetentrated charactenstres m vitro and therelore offer thc potential for evaluation of the efre;ts of actnc agents on drf• ferentiatton in a secondan' level of testing. Various human tumor cell lines and normal hun,a;, tihroh:ist bncs deir:on• strate significant drfterences in sensrttvrty to estahlrshed agents These dtffere tco have been relered tu drfferences in 1)KA repair phenotvpc as we!I as numerous other cellular properties lAtarlcd nmotocoh for mrasurcment of deuccffc.ts hak'J ,•n rnhrhru"n ,d c,•l,v n larr..!h• r. r; an cudporn' of inmrJret*h' s1nsttr.n~ .1~711 hc requltt' ; lot ca,:r ~ell hne

r considered for inclusion in the cell hne panel. Pro:.nols will include provision for metabolic actnatron in at leatit one elernent of the cell line panel, for erample, a continuous human hepa(om'a cell ltne has recently become a+rarlable which demonstrates broad ability to activate procarcinogens and anticancer drugs such as cvclophosphamide. Thrs rell line offers a unrque opportunity to prrnrde human cell mediated metabolic activation in a very practical way. A drug sensitivity profile wrll be established foi each can- didate cell Irne based on response to a battery of standard anticancer drugs. Cell hnes will then be selected for inclusion in the final sc.reening panel based on sensrttv»y and repro- ducibility of response to the standard agents. Production of a liposome pharmaxutical for the delivery of agents capable of acti-ating pulmonary macrophages and the development of lipo~mes capable of delivery to the liver. Proposed 1'rrst year award, 5250,000, two years. liposomes (phosphobpid vesicles) are effective biological carners of agents. Dned phophohpids swell, upon rehydratton. to form multilameliar structures into which a variety of agents rnay be incorporated. Depending on charge and composiuon. bposomes may be targeted to and incorporated by a variety of internal cellular components. Lposomes may be prepa:ed from a variety of phospha lipids but the major components are usuarly phosphatrdyl- cholrne, cholesttrol and charged cell bvrds. Vanauons in lipid composition, membrane charge, and carbohydrate determrn• ants on the vesicle surface can affect in vivo tissue distribution. Multilamellar vesicles of defined composirion and charge have been developed and targeted to the alveo!ar macrophage. These liposomes, containing macrophage activating factor, muramyl dipeptide, or muramyl tnpepttde phosphatidylethanolamtne, are effective in activating murine alveotar macrophages in vrtro or in vivo and are therapeutically effective in reducing pulmo- nary metastases in murine models. Component A of this RFP will be directed towards the procurement of a pharmaeuucal for clinical tnals consisting of a ltposome preparation contaur- inean agent capable nf activating human alveolar macrophages. Methods exist for varying surface composition for targeting liposome delivery to liver and spleen although, in general, the fAr>CM REV1131111 FIGUOS ARE ESrBM3[ES ONLT: IFPs, >fI{As NUT 79T AYAUeAKE The dollar estimates .ith each concept revier brnught before the variau boa>ads of scir:ntifi oamtselors are not interded to represent ttaximma or exact amwnnts wbieh .ril1 be t on tbose pro-{ ects. ~ey are inteaded oniy as es for board t»eehers to help in dete:miniag the value of the px+jects sa relation to resoorces available to the entire progssm or divishon. Responses sboold be based on the .orkscope aad dest:ription of goals ttnd metbods incltrded in the IFPs (contracts) irred Ii!~'As (grants and cooperative agreements). Availability of ~ r1iZ' and RFAs wi11 be amiotmced t.hen the Institote is ready to release them. retrculoendotheha) system in these orFans 1s the system re- sponsrble for Lpsome removal. Experiments armed at demon stratrng therapeutic effectiveness with hepatrc metastases have not been performed. Component $ of this RFP will support expenments armed at the development of bposome prep:.ra- uons with proven efficacy in the activation of hepatrc macra phapes. The relauonah,p of the snuauon (versus activation of blond monocyKes) in the treatment of hepatic metastases can then be explored. Recompetitions and noncompelitive Procurements approved by the Board will hc published nei t.+eek in The Cancer l.etrcr. FREI, FREIREICH SHARE ONE GM AWARD; AMES, ERIKSON WIN THE OTHER TWO Four scientists w•ere r3amed tais week as winners of the 1983 General !sfotors Cancer Research Foun- da,ion Aw3rds, Each of the a+,~ards offcrs a gold medal, S 100.000 in cash. plus SS 0,000 to support a workshop. Fmil (Tom) Frei and )riril (Jay) Freireich. who together developed the first cure for leukemia and whose studies profoundly affected modern cancer chemotherapy, were named winners of the C}:arles F. Kettering Price: for the Titost outstanding recent contribution to the diagnosis or treatment of cancer. They will share the S 100,000 prize. Bruce Ames, who developed the world's most widely used lest to determine whether a chemical damages DNA artd therefore may cause cancer, vron the Charles S. 1C+lott Award for the most outstanding recent contribution to the causes and ultimate pre- vention of hurrlan cancetr. Raymond Erikson, tlre first scr:ntist to identify a chemical made by a cancer gene, won the Alfred P. Sloan Award for the most outstanding recent basic science conttibution to cancer. Frei is director and physician in chief of the I)ana- Fdrber Cancer lnstitute and professor of medicine at Harvard Univ. School of Mf dicine. Freireich is pro- fessor of developmental therapeutics and chairman of the Dept. of Developmertt+al 7herapeuttcs at the Univ. of Texas System Cancer Centerhl.f). Anderson Hospital & Tumor Institute. He is also professor of medicine at the Univ. of Texas Medical School. Ames is professor of biochemistry at the Univ. of California (Berkeley). Erikson is professor of cellular and developmecttal biology at Harvard. "There are more than 1C1,000Arnerican children aTive today who, born at oy other time in history would have died of leukemia," the GM Foundation said in a news release. "-their cures are dramatrc proof of the significant improvements that have comc to the treatment of childh+ood leukemia in the past feW decades. Much of the pioneering re>earc!, that led to this achievement •a•as the work of Frei and Freireich. These researc}iers, working together for 17 years. detelope'd the first treatrncnt for Icui,e:r,,., tiwt truly cured patients. In the pro:ess. they estabhshcd nearl% all the prtnciphrs ot screnufr< <hemotherapy tnals for cancers of all k_unds. "The type of therar)• they devised- u,,rng many dtvgs in cornMnatton-v irtually, resoluUrnuzcJ can:er medicine and is now one of the matnctay> of tteat- ment for most types of cancer. Combination therap~ for lculxrnia'has saied the hxrs cf more can:cr patients than ar»• other advance over the pas' =5 %ear,,.' comrncnted ( h.rrles Mocrtel& hclcl of wr.ol og~ at the Mayo Chnt;. "Frrt anu Freircrch hcgan thcrr %ctcntrti, cjrcc:• ,it \CI. ' I hr% n..rdc a f.j,,~tnaunE tcaru 10 >,.it0h.' The Cancer Let>Ger Vol 9 No ,4 : Pane 5

5 said Gordon Zubrod, w•ho hired them then and who was, at the time, )vCl's clinical director. ' T heir inter- actions and collaborations were so combined that the research arose from the two of them. It was truly 2 synergistic association. Their contributions are im- portant not only in curing acute lymphocyUc leukemia, but because they profounJly rniluenced the chemotherapy of Hodgkin's disease and the whole of present day chemotherapy.' "The life and death of minute bactena living in trny petri dishes in a laboratory in Berkeley has triggered a worldwide revolution in environmental health," the GM release continued. "High powered legal battles, nationwide health legislation and billion dollar industry cleanups to remove possible environ- mental carcinogens from food, clothing and other common products have tumed on the seemingly un- eventful lives of these one celled microbes. "The special bacteria were genetically engmeered by Ames, who used them to develop a test that has become the world's most widely employed screen for determining whether a chemical is likely to cause cancer. The test measures mutations in bacteria. The Ames test is usually the first in a series of evaluatrons of a chemical which rye used to estimate its cancer causing potential to man. Tests in mice and other animals as well as epidemiological studies itt man are necessary also. "Ames work 'has formed the foremost current approach to the screening of environmental factors and chemicals aiid has represented a major contribu- tion to human health and basic understanding of the etiology of cancer,' said Thomas Edgington, profes- sor of immunology at the Scripps Institute; In ad- dition to developing the screening test, Ames estab- lished the relationship between a chemical's ability to cause mutations and its potential for causing cancer. He also helped clarify how mutations of DNA occur and, recer.tly, began to identify naturally occurring anticancer substances. "The Ames test is currently used in more than 3.000 government, industry and unnersity laborat- ones throughout the world as an early warning sys- tem for detecting mutagens and possible carcinogens. In the 12 years since its developing, more than 5.000 chemicals have been screened with the Ames test. "Sctentists are on the bnnk of understanding how cancer beCins." the GM relense continued. "A number of startling dtscovenes in the past few years have revealed uhat eems to he a common bio• chemical change in the cell that triggers the first steps toward mahgnanc}.. Ar, understanding of this process may eventually help cancer specialists de- velop new ways to diagnose. treat and even prevent cancer. "The eN: ytcment felt by mam hyoloFy~tc is :r- The Caricor Letter Page 6 I June 17, 1983 Ilected in the awarding of the Alfred P. Sloan Prize to Erikson. A leader in the emerging field of cancer genes, Erickson is the 0rst scientist to identify the chemical made by such a gene. uncover its unique hMOloFical propcrties and shovA that it could alter ccll metabolism, producing changes associated with cancer. "Erikson's research has been a systematic attack on the problem of identifying exact4, what happens in a cell when a cancer gene is switched on. 'Unques- tionably, Dr. Erikson's proup has made the major advance in basic cancer research in the past five years,' said William Rawls, professor of pathology at McMaster Univ. in Hamilton, Ontario. 'He has made an important breakthrough in the understanding of the precise molecular mechanism of oncogenesis.' "Erikson's work is a recent discovery, but it has already stimulated a new field of study investigating the biochemical ways normal cclls become cancerous. Since his initial report in 1977, other researchers have discovered several additional chemicals made by cancer genes, most of which affect cells in the same unique way. This is an important conceptual ad- vance for cancer specialists. They have long suspected that, though there are more than 100 types of cancer, a single mechanism would be found by which all cancers arise. Tnough it isn't certain yet that this is the c~-se, evidence suggests that one or a few bio- chemical changes may be characteristic of most cancers." AACI, ASCO, ACCC HOLD "USEFUL" (VIEETING WITH HCFA OfN DRG ISSUE Representatives of the Assn. of American Cancer Institutes. American Society of Clinical Oncologists and Assn. of C ommunity Cancer Centers met with officials of the Health Care Finance Administration last week to express their concerns over DRG reimbursement for cancer treatment. Francis McI:ay, associate director for administra- tion and finance of Fox Chase Cancer Center, represenied AACI: John Potter. director of the Vincent Lombardi Cancer Research Center at Georgetdwn Univ., represented ASCO: and Robert Enck, director of oncology at Our Lady of Lourdes Hospital in Binghamton. N.Y.. represented ACCC. The three met with Michael Maher. director of the HCFA Office of Reimbursement Policy, which is in the process of developing guidelines for implement- ing DRG reculalior.s. includtng the eueptrons ahuh th<• HHS sccrctan ntay by law make for certain instttutions. Participants agrred it %+as a "very useful" metting. They explained ho.k 1)RG can unfairh' tmpact cancer care hrovtJers. esprciall\ those v.ith patients on -esearch p rotocols and the centers wtth ,~ ht>•h per- .'entace of teruarx car; ;atn•nts. "I'm ionfidvnt Hc'FA Nill m,,l,c som:

dation." h9cl:ay said followin& the meeting. "It's too early to tell if ttat will he acceptable. however." On another Washington front, the House commit- tee report on the Health Research Extension Act of 1983, the Waxman bill which among other things extends ihe National Cancer .•tict, called attention to tlte fact that the budget resolution recently passed by the House for FY 1984 "includes, at the recommen- dation of the Committee, sufficient funds to pre- clude the elimination of support for 16 cancer centers." The report deals with an authorization, not an appropriation, bill, but it does demonstrate the support in the House for additional NCI funds above the President's budget to restore money cut frorrm the center core grant budget. The Waxman bill provides a line item authariza- tion for center core grants, a provision opposed by the Administration. The attempt to drastically cut core grant funds supported the case of those who have argued for the line item. "The specific authorization of appropriations for cancer research and demonstration centers indicates the Committee's strong suppott for the cancer center core grant program," the repoft said. "The Corn- mittee believes that cancer center core grants are essential to the National Cancer Program and should, during per.ods of fiscal restraint, not incur program reductions disproportionate to other institute ac- tivities." The Senate Appropriations Committee, in a 1983 supplementai appropriations bill, has added $9.4 million to the NIH budget for research on AIDS, includir,g $3.3 million for NC1• The committee report on the bill noted that the extra money would permit NCI to fund 73 percent of approved AIDS-related grants. "The research grants would include studies on the nature of the defective regulators of immunity in AIDS, cause and reasons for loss of disease fighting capabilities of AIDS patients, and herpes viruses and immune responses in male homosexuals," the report said. "Intrarnural research efforts would be expanded to isolate a causative virus frorfi AIDS patients. In addition, facihties would be modified to provrde the proper isolated research environment." The committee also expressed concern about high cancer rates among Hawaiians. "The committee has recenth• Iearned that peoples of Hawaiian ancestry have the highest incidence of cancer in eur nation. The rate of cancer cases among Hau•.,iian men is reported to be 465 per 100,000 and that for Hawaiian women 408.5 per 100.000. This compares to :i71.6 for cauca.cian men and 301.2 for caucasian women. The committee was very concerned to lcarn of these statistics and urges the National Cancer ln- sti;ute to give greater attention to this native Hawaiian population. The committee also dtrrcts NCI to revieu its effons tc address the unique needs ot'all ,L nauve Amerrcan peoples :n the Pacific basin ~egon• in light of the native Hawaaan data." DCCP BOARD GIVES CONCEPT APPROVAL TO 18 NONCOMPETITIVE CONTRACTS lvoncompetitive contracts receiving concept ap- proval last week from the Board of Scientific Coun- selors of NCl's Div. of Cancer Cause & Prevention totaled 18, with first year costs estimated at $2 million and the total for the lives of the prniectc at $6.8 million. Five of the concepts wer^ for new procurements: • U.S. cancer mortality rates and trends, 1950- 79. Environmental Protection Agency Health Effectc Research Laboratory, S 110.000, one year. • Epidemiologic studies of :ancer in China. Chinese Cancer Institute, S3d5,000 first year, totai $975,000, three years. • Comparison of mechanisms of carcinogenesis by radiation and chemical agents. A three day workshop- symposium cosponsored Wtith the Div. of Cancer Treatment, to cost each division an estimated $:5,000. • Third NCI/EPA/NlOSH collaborative v.•orkshop: Progress on joint em•ironmental and occupational cancer studies. Cost estimate, S'_5,000. • Procurement of byproduct human specimens from normal surgical and clinical procedures and pathology data from patients with primary hepato- cellular carcinoma and chronic active hepatttis. First yearestimatee cost, $130,00G, total $5:0.000 for four years, This material will be made available to grantees and others on a payback basis. Because much of this material is in shvre supply, it will not be compcted in the usual sense. Institutions where it is available will be invited to submit proposals which will be re- vieweN by technical review committees. Noncompetitive renewals of ongoing projects were 9ven concept approval, as follows: • Study of human health consequences of pol) - brominated biphenyls contamination of farms in Michigan. Centers for Disease Control, 5165.000 first year cost estimate, total $530.000, thtee years. • Studies of radiation induced chrom,icome damage in humans. Dept. of Energy, 5100.000 fir>t year. Staff had asked for three years at that rate which v+•ould have expanded the study to m~~rc populatinn groups. 7 he Board asl.cd for a more detaiied justification for expano.ng the stud)• to hc presented at its September mecrirg. • R-diation dosimetn for epiJemroloFic studic.. ltniv.of Tcxzs NLD. Anderncn. S,f'.0UP fir,t }i.,r• $-100.000 total• five years. • Radiation risk eslinrancn in l.rjc•li .I:jt.:rci irradiated for tmca capiu. Chami•Shch:,%1rd r;,l ('enter. 51 15.000. one X.car• • Intrnunologr, s;udws of lnF)) n•;. Is, ur• l m The Caneear Letter Vo!. 9 No 74 - Page 7

formed Services Univ of Health Sctences• S505,000 first year estimate, S2.525 million total, five yeatrs. • Epidemiolocic studies of cancer in Alaskan natives. Centers for Disease Control, $60-000 first year, total S 120,000, two years. Staff had asked for five years and S3;t0,000. • Study of DuPont chemical workers bladder cancer screening program. E.1. DuPont, 520,000, one year. • Support sen•pces for a mortality study of workers exposed to formaldehyde. Westat fnc., $150,0G0. • Chemical carcinogen reference standard reposit- ory. I1T Research Institute. This involves a memo of understanding with the Coordinating Research Counc;l, a nonprofit corporation supported by the American Petroleum Institute and Society of Auto- motive Engineers. CRC will provide 20-25 nitro- PAHs a year to the repository operated for tiCl by I1T Research Institute. The compounds will he made available to ir.vestigators on a payl:ack basis. • E:pidemiolc-tic study of mesothelioma risk factors utilizing populztion based tumor registries. Univ. of Southern California, $50,000, one year. • Epidemiologic study of mcsothel:ioma risk factors utilizing obpulation based tumor registries. New York State U;nt• of Health, one year, 110 additional cost. • Services for a case control study utilizing VA files-mesothelioma and employment. Veterans Ad- ministration, one year• 5160,000. • Mesothelioma and employment: Utilization of SSA quarlerly earni:rgs file- Sc,ial Security Admin- istration. S1 1.200, one year. Pathology review for the mesothehoma studies will cost an estimated 5100.000. RFPs AVAILABLE Requests for proposa/ oiescribed herepertain to contracts planned foraward by the National Cancer lnstitute unless otherwise noted Write to t.he ContractingOff,cer ar ConXract Specialist for copies o1 the RFP, citing the RFP number• lYC/ lrsbngs wilt show the phone number of the Contracnng Ol. .+icer or Contract Specialist who u,ll respond to questions. Address requests for NCI RfPs to the ir.drvidual named, fhe B/air buildrng room number ahown. Narional Cancer Insu¢ute, tlS0C Co%svil/e Rd., Sjlver Spring, Md. 70910 RFPannounce, ments from other sgencies reportrd here Poll intlude the com• plere maii ng address at the end of each. RFP C1-83-0336 Title: (-arcinogPnic testing in the scrtcar and strarn ..A ., ntu'e Deadline: .'1'ot a railablc The use Of sencar (sensiuWe to -:arcinomas) and sArarn A mouse models in t`,z past fi.•e years in EPA t4boratories have shot~n considerable promise in allowing EPA to evaluate the carcinoFenic potential of organic concentrates of water samples taken from potable water supphes, v,3ter concentrate fractrons using alternate disinfectants, samples for test ing ef- ficacy of gac filtration, humic substances• and coal tar and asphaltic paints. In this project the carcinogenic potency of water related environmental samples will be studied using the sencar and strain A mice. ]n the scncar mice, the samples will be tested in one or all Of three typ;s Of tumor stt.dies. They are 11) initiabon,'promolion study, (2) promoting potential study, and (.3 ) a com- pDete carcinogenicity study. For bcth the sencar and strin A studies positive control and vehicle control groups will be included in each study. Appropriate doses of the test samples are administered either topically, subcutaneously or orally (for sencars) and either orally or interperito- neally (for strain A) depending on the nature of the test substance. Tumor incidence is charted from weekly observation of *.he sencar animals. Lung adenoma counts are made in the stra:n A mice fol- loHing sacrifice of the animals at 9 months. The total exposure period for sencars including the initiator and promotor applications H ill be 20 to 30 weeks. Aprroximately seven months thereafter the mice are sacrificed and complete gross and srlccted histopathological examinations are made. The end- ,,,ars ts for sencar studies include (1) number Of mice with tur.zors. (2) number,,f tumors per mouse, (3) titne to first tumor, (4) characterization of tumors, and (5) histopathological diagnosis of tumors. Strain A mice are exposeo lhre^ doses per weck for eiy.ht weeks. They are sacrificed at nine months of age and lung adettoma counts are made. Endpoints for strain A studies tnclude: (l) number of turnors per per animal. (2) number Of tumors, and (3) htsto- patholopcal evaluation of tumors. Interested courcrs are invited to submit a writWr, request for a copy of the RFP. Tlus procurement shall be screened for a possible smal1 business set a~ide. All prospecu.e offerors shall include in their response their company S}3.a classification when requesting an RFP. F'urther scre;ning shall he done for .+ possible labor surplus area set aside. Cuntracts 11anageriicnt 1)il. Contracts Branch A Emironrnental Prorcitiun Ace^.c. Cincinrra ti Of l 4526S TheCanCetr L.telter _Editor Jerry D fioyd c',t~.,5•,Fn rOr,v-e,p*: ornes a.-_al LIV 1nP iS'1cP' t P11P' -,. r 0 h_ .: 3';'- RP,i,r.- v•p rcr•„y-,p pf inP C,-cs G+..~,.. lPar. Afl r.d'qs-PSrrBJ. 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