In September, the US National Cancer Institute(NCI) officially announced that it has awardedco-operative agreements to set up a new CancerGenetics Network (CGN). This major researchinitiative will create a national network of centersthroughout the US to specialize in the study ofinherited predisposition to cancer.

Eight institutions have been given networkawards that will fund the CGN for five years. Forthe first of these five years, the NCI is providing$5.8 million in total costs (Table 1) and $1.28million for the Informatics and InformationTechnology Group (Table 2).

The purpose of the network is to supportcollaborative investigations into the genetic basisof cancer susceptibility, to explore mechanisms tointegrate this new knowledge into medical practice,and to identify means of addressing the associatedpsychosocial, ethical, legal and public healthissues. Richard Klausner, NCI director, said, ‘Thenew network, which builds on recent progress inisolating genes linked to inherited cancers, willallow us to attempt to answer the many clinicalquestions that these discoveries raise.’

Hoda Anton-Culver, chief of UCI’sEpidemiology Division (University of California,

Irvine,USA) isdirector ofthe UCI CancerGenetics Network Center andis responsible for the Informatics Programme.‘The CGN Center at UCI will consist of fivedivisions: basic research, molecular genetics,clinical research, genetic epidemiology andbiostatistics, and genetic counselling andeducation. The committees to decide theimmediate tasks of all five divisions are alreadyin place and we expect our center and the wholenetwork to be up and running within six months,’she said.

The UCI center aims to recruit and tracknearly 15 000 study participants from populationgroups that might be genetically susceptible tocancer. Anton-Culver’s team also plans todevelop new techniques for detecting geneticmutations related to cancer susceptibility, and toexpand the university’s existing biospecimenrepository to ensure an adequate supply of tissuesamples for the major research programmes.Another major priority will be to provide geneticcounselling and education to families whoparticipate in the study. New and better methodsof communicating cancer genetics information topatients and their families, and incorporatingcancer genetics resources into medical practice,will also be developed, and are expected tobenefit patients and their community physiciansalike.

As the informatics center for the CancerGenetics Network, UCI will develop one of themost comprehensive human cancer geneticsresearch databases ever envisaged. The systemwill hold data on hundreds of thousands of peoplewho have a genetic predisposition to cancer, aswell as tissue samples, educational materials andother resources designed to contribute to theinternational effort to understand the genetic basisof cancer.

Not surprisingly, the mix of genetic testing andthe generation of a massive information databasehas not escaped controversy. Many scientists seethe value of the network but they wonder ifenough is known about the implications of testresults to be able to offer adequate advice andtreatment. Some patients who undergo genetic

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New US Cancer GeneticsNetwork announced

Table 1. Institutions involved in the Cancer Genetics Network

Main institution Principal investigator

University of California, Irvine, CAa H. Anton-Culver

Duke University Medical Center, Durham, NCb J.D. Iglehart

Georgetown University Lombardi Cancer Center, Washington, DC C.E. Lerman

Johns Hopkins University, Baltimore, MDc G.M. Petersen

Fred Hutchinson Cancer Research Center, Seattle, WA J.D. Potter

University of Texas MD Anderson Cancer Center, Houston, TX L.C. Strong

University of Pennsylvania, Philadelphia, PA B. Weber

University of Utah, Salt Lake City, UTd R.L. White

Collaborating institutions:aUniversity of California, San Diego, CA.bEmory University, Atlanta, GA; University of North Carolina, Chapel Hill, NC.cGreater Baltimore Medical Center, Baltimore, MD.dUniversity of New Mexico, Albuquerque, NM; University of Colorado, Denver, CO.

Table 2. NCI funds awarded to the Informatics and InformationTechnology Group

Institution Principal Fiscal year investigator 1998 awards

University of California, Irvine, CA H. Anton-Culver $481 809(total costs)

Massachusetts General Hospital, D.M. Finkelstein $519 342Boston, MA

Yale University, New Haven, CT P.M. Nadkarni $279 270

testing also fear that patient records might not bekept anonymous, and that companies could refusethem health insurance if they were found to carrygenes that predispose them to cancer.

‘We are very sensitive to the ethical andsocial issues that this programme raises,’stressed Anton-Culver. ‘Ethicists andrepresentatives of cancer patients were involved

in the decision-making process behind setting upthe new network. The consent forms have beendesigned with great care and we hope thatpeople’s fear about the network will be allayedwhen the benefits become apparent. In 2–3years’ time I expect to be participating in aresource that will provide support on severallevels. Scientists will gain increased knowledge

about cancer susceptibility, patients will receiveimproved genetic counselling as a result ofbetter feedback, and practising physicians willhave access to an infrastructure that will allowfast and efficient transmission of relevantinformation.’

Kathryn Senior

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Kosan Biosciences (Burlingame, CA, USA) hasreceived a Phase I Small Business InnovativeResearch Grant from the US National CancerInstitute to support their work on thebiosynthetic pathway of the epothilones, agroup of polyketides first isolated from the soilmyxobacterium Sorangium cellulosum, aspotential alternatives to the anticancer drugpaclitaxel (Taxol).

‘We would anticipate that epothilones, ifproven to be safe and effective, would find useas a treatment for Taxol-resistant tumors andother tumor types found to be responsive toTaxol. Taxol is particularly effective in ovarianand breast cancers, and its range of applicationsis expanding,’ says Michael Ostrach, ChiefOperating Officer of Kosan.

During cell division, a dynamic process oftubulin polymerization and depolymerizationtransforms cytoskeletal microtubules into the

mitotic spindle. The epothilones, like paclitaxel,stabilize microtubules by binding to tubulin,thus preventing spindle formation and blockingmitosis. ‘Two decades after the discovery ofTaxol, epothilones represent the first class ofcompounds that mimic the microtubule-stabilizing effect of the taxane structure,’ saysOstrach.’ Unlike paclitaxel, the epothilones donot appear to possess endotoxin-like properties,which may be responsible for some of thedrug’s side effects.

Between five and 50 bacterial enzymes andcarrier proteins are involved in the biosynthesisof polyketide molecules, and are collectivelyknown as polyketide synthases (PKS). EachPKS is encoded by a gene cluster, so once acomponent of the gene cluster has beenidentified, the whole cluster can be sequenced,thus providing the code for the entirebiosynthetic pathway.

Scientists at Kosan will develop anover-expression system, probably inStreptomyces spp., Escherichia coli, or yeast, toproduce the epothilones in large quantities fortherapeutic use. Small amounts of epothilone –sufficient for in vitro and animal studies – havebeen produced by fermenting myxobacteria, butthe organisms grow too slowly and do notproduce sufficient quantities of epothilone forindustrial production. ‘We would hope thatmore developed production organisms would bemore economical,’ says Ostrach. Future plansinclude the production of epothilone analoguesby modifying the gene cluster.

Sharon Dorrell

Towards the biosynthesisof an alternative to Taxol

A new collaboration between the Hoechst–ARIAD Genomics Center (Cambridge, MA,USA) and the Center for the Prevention ofCardiovascular Disease (CPCD, HarvardSchool for Public Health, Boston, MA, USA)will use functional genomics to find targets forthe development of new therapies forcardiovascular disease.

Dr Arthur Lee (Director, CPCD), and hiscolleagues have developed a model foratherosclerosis based on the murine cell lineMonc-1, in which proliferating cells are inducedto differentiate into smooth muscle cells. Anumber of genes are switched on during thisprocess and researchers at the CPCD have foundthat genes in aortic smooth muscle cells behavein a similar way. Our idea is that atherosclerosiscan occur when the normal cells have been de-differentiated so they begin to proliferate. We

are trying to find the genes that cause thisproliferation,’ explains Dr Mark Zoller (Director,Hoechst–ARIAD Genomics Center).

The research teams led by Dr Zoller and Dr Lee plan to identify the genes differentiallyexpressed in the differentiated andundifferentiated cells by hybridizing the mRNAproduced by the cells to DNA chips. ‘The geneson the chips represent every known gene todate, from full-length cDNA sequences,genomic sequences, expressed sequence tags orpartial cDNA sequences. The goal is to have achip with one fragment from each gene,’explains Zoller. At present, the chips containapproximately 30–40% of known human andmouse genes and, if necessary, they can be biasedtowards genes expressed in specific tissues.

Once the differentially expressed genes havebeen identified, cell culture systems and animal

models will be used to investigate the effects ofstimulating or inhibiting the expression of thesegenes. It will then be up to the drug developmentteams at Hoechst Marion Roussel and ARIADPharmaceuticals to design therapies to targetthese genes or the proteins they encode, therebypreventing vascular smooth muscle cell (VSMC)proliferation and atherosclerosis.

Researchers at Hoechst Marion Roussel inFrankfurt are also attempting to characterizethe signals produced by vascular endothelialcells that trigger proliferation of smooth musclecells. VSMC proliferation is also closelyinvolved in tumor angiogenesis, so it is quitepossible that a useful byproduct of this effortwill be compounds that block tumorneovascularization.

Sharon Dorrell

Muscling in on atherosclerosisSp

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