The recent Management Forum meet-ing, The Treatment of Cancer: An Updateon Novel Approaches (17–18 September2001, London, UK), saw several excel-lent speakers and ~40 delegates conveneto discuss existing and novel ways to treatcancer.

The recent biotechnology boom couldat last promise some realistic alternativesfor cancer treatment that are less inva-sive than surgery, and more specific, ef-fective and less toxic than conventionalradio- and chemotherapy regimes. Thefocus of this meeting was the develop-ment, particularly in clinical phases, ofnew anti-cancer agents, and the speakersand delegates included representativesfrom industry, research institutes, acade-mia and the healthcare sector.

Issues with cancer therapyAlan Barge, Global Product Director atAstraZeneca (Macclesfield, UK), kick-started the conference with a generaloverview of development, regulatory issues and marketing considerations foranti-cancer drugs. He summarized thecriteria for determining clinical benefit in oncology as:

• the direct effect of treatment on the

disease (duration, time to progression

and survival); and

• the effects on other clinical conse-

quences of the disease and its treatment

(reduction of symptoms and treatment

toxicity).

Barge also covered the ethical consider-ations that make cancer clinical trials sochallenging. For example, the genotoxicnature of anti-cancer treatments must betaken into consideration when making

treatment decisions; although Hodgkin’sdisease (HD) is regarded as a cancer witha good cure rate, a significant number ofpatients go on to develop leukaemia as aresult of their treatment1. It is also gener-ally impossible to study cancer drugs in healthy volunteers, and cancer trialsmust be designed to ensure that patientsare not put through a bad trial. Manycancer patients are eager to enter intotrials, often out of desperation or an altruistic desire to help others. Barge emphasized that investigators need tothink about what they are expecting patients to go through when designingtheir study.

In another presentation, PabloFernandez (Pharmanet, Princeton, NJ,USA) said that global clinical trials are essential for the global benefit of thera-pies to patients, and also to ensure that drug development is comprehensive. A heterogeneic population, the specialist skills and knowledge of investigators and ‘live’ integrated data capture to ensure feedback to and from ongoing studieswere among the requirements deemedessential for a successful global trial.

David Webb (Great Ormond St Hospital,London, UK) emphasized this furtherwhen he discussed difficulties encoun-tered with paediatric trials, particularlyin the light of recent media attentionsurrounding tissue storage and informedconsent, and concluded that high standards of conduct are increasingly expected and that international trials are the future for childhood cancers.

Where and what should we target?Barge continued with an excellent presen-tation on the current ‘hot’ pathways and

targets in anti-cancer drug discovery anddevelopment. He commented that re-search concentrating on the metastasisof tumours is better than identifyingearly stage targets, such as those in-volved in cell cycle control, because bythe time a tumour is diagnosed, earlystage therapies will be of little use.

Several classes of anti-cancer drugsthat are currently being investigatedwere discussed by Barge, including anti-proliferatives [e.g. growth-factor tyro-sine-kinase receptor (GFR) antagonistssuch as Herceptin® (Genentech, SouthSan Francisco, CA, USA)], anti-angio-genics [e.g. anti-vascular-endothelialgrowth-factor receptor (VEGFR) antibod-ies], anti-invasives [e.g. drugs that targetthe matrix metalloproteases (MMPs)]and work directed at improving the use of cytotoxics. The MMPs have been aparticularly disappointing target class,according to Barge, who explained that,to date, drugs that target MMPs haveshown no benefits in clinical trials andhave yielded no information for furtherresearch [British Biotech (2001) Reportsof clinical studies with matrix metallo-protease inhibitors in cancer. Press Release13 February]2,3.

Barge illustrated his presentation withthe drug development story of Gleevec™(ST1571), the tyrosine-kinase inhibitorthat has been hailed as a wonder drugfor treating chronic myeloid leukaemia.This drug is so successful, Barge said, be-cause it targets the sole oncogenic eventearly in the disease. Work is now underway to study whether Gleevec is a suit-able drug for other targets, such as thestem cell factor, c-kit, which is mutatedin gastrointestinal stromal tumours.

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Something old and something new:taking cancer therapy forwardJoanna Owens, joanna.owens@drugdiscoverytoday.com

Drug targeting and resistance remainthe greatest challenge to anti-canceragents, but Barge pointed out that newtechnologies such as positron electrontomography (PET) will help us to under-stand how drugs exert their effects andenable us to use combination therapiesmore effectively. He added, however,that with recent advances in biotechnol-ogy, our ability to clone cells and mol-ecules has outstripped our ability to understand the underlying biology.

In 2000, cancer was second only tocardiovascular disease as the diseasewith the highest morbidity rates in theWestern world (http://www.who.int/whr/).Barge envisaged a future where we donot have oncology doctors, but rather,people who treat specific genetic disor-ders. He suggested that the ultimatecombination of: (1) the identification ofthe molecular pathology of all cancers;(2) the development of improved diag-nostics and imaging; (3) improved drugdiscovery; and (4) cancer patients beinggenetically profiled, could lead to cancerbeing relegated nearer to the bottom ofthe morbidity ‘league table’ in the 21stcentury.

Gene targetingA promising area of cancer drug discov-ery is the development of agents thattarget genes involved in cancer patho-genesis4. David Thurston (University ofLondon School of Pharmacy, London,UK) gave a detailed overview of this ex-citing field, and described potential genetargets (e.g. oncogenes, drug resistancegenes, DNA processing and repair en-zymes and genes involved in metastasis).He also described some of the strategiesavailable for targeting at the gene level(the antigene approach), such as designerproteins, peptide nucleic acids (PNAs)and triple-helix-forming oligonucleotides(TFOs), in addition to the RNA level (theantisense approach, e.g. ribozymes andoligonucleotides).

Although macromolecular approachesare highly selective for their target genes

and have provided promising in vitrodata, Thurston pointed out that thereare issues with the cost, stability, deliveryand pharmacokinetics of these agents.An alternative is to use small moleculesto avoid the problems associated withmacromolecules.

Thurston and colleagues have beendeveloping small-molecule agents thatinteract within the minor groove ofDNA, most of which are based on natu-rally occurring heterocyclic moleculesderived from Streptomyces species.Thurston described a particular class ofantitumour antibiotics, the pyrrolo[2,1-c][1,4]benzodiazepines (PBDs), whichform an aminal bond with a guaninebase thus resulting in a DNA adduct.Thurston’s group is now using solid-phase and combinatorial approaches todesign and synthesize different forms ofPBDs extended in length so that theycan recognise and bind to unique se-quences in specific genes thus down-regulating or ablating expression of thetargeted gene. It is hoped that this com-binatorial chemistry based platformtechnology will have widespread use notjust in cancer but in other diseases wheresingle genes can be usefully targeted(i.e. novel antibacterials and antiviralsetc). At present, effort is concentrated on optimizing sequence-specificity andstructure–activity relationships. However,one candidate molecule, SJG136, withrelatively modest sequence selectivity(i.e. spanning six base pairs), is expectedto enter Phase I clinical trials in both theUSA and UK in 2002. This study will bethe first to attempt to link the sequencespecificity of an agent of this type to itsantitumour activity, and will use DNAmicroarray analysis technology to meas-ure gene expression profiles in patients’tumour cells as a pharmacodynamicendpoint in the Phase I trial.

Development of novel therapiesRisa Harman (GlaxoSmithKline, Ware, UK)gave a detailed presentation on themany preclinical tests that are required

for progression of a cytotoxic anti-cancer drug through early development,and highlighted issues that needed to beconsidered when testing combinationtherapies. Harman’s presentation initiallydealt with small molecules, but she wenton to discuss the special requirementsneeded in the development of biophar-maceuticals, using gene-directed enzymeprodrug therapy (GDEPT) as an example.

The development of biopharmaceuti-cals was discussed further by HeinzZwierzina (University of Innsbruck,Innsbruck, Austria) who considered newinitiatives for the development of drugsthat will treat molecular abnormalitiesrather than the whole disease, includingnew measurements that should be determined in early phase trials and surrogate markers as alternatives to tumour response endpoints.

Continuing with the biopharmaceuti-cals theme, Gunnel Hallden (ImperialCancer Research Fund, Imperial College,London, UK) discussed gene therapyusing viral vectors, with particular refer-ence to the use of dl1520 (ONYX-015).Dl1520 is an adenovirus in which theE1B-55kD gene has been deleted, whichmeans that the virus can only replicateand cause toxicity in p53-deficient can-cer cells. Hallden described a Phase I/IIclinical development strategy for the useof dl1520 for head and neck cancer,both as a single agent and in combi-nation with cisplatin and 5-fluorouracil.The data presented suggest a promisingfuture for this type of therapy.

Cancer in the clinicPeter Harper, Consultant Medical Oncol-ogist at Guy’s, King’s and St Thomas’Cancer Centre (London, UK) providedan overview of the difficulties en-countered in cancer clinical trials, withparticular reference to lung cancer, andhighlighted the increasing need for sup-portive therapies to improve the qualityof life of patients. This was further em-phasized by David Webb, who explainedhow supportive care for childhood

update conferences DDT Vol. 6, No. 23 December 2001

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cancer patients greatly improved be-cause of the creation of a national networkof children’s cancer centres across the UK.

Harper was among others at the meet-ing to predict that cancer will become achronic disease, and highlighted the potential use of CNS treatments for se-vere fatigue, erythropoietin to preventhaemoglobin depletion and appetitestimulants to counteract the debilitatingeffects of chemo- and radiotherapy.Maintenance of haemoglobin levels during radiotherapy has actually beencorrelated to an improved prognosis fordisease5. Harper suggested that morefunding in the future should focus onpalliative care rather than on findingcures for cancer alone.

New paradigms for cancer therapyDuring his keynote lecture, Karol Sikora (Global Clinical Expert – Cancer,AstraZeneca, Macclesfield, UK) discussedthe global explosion of technology that

will hopefully lead to many new effectivetherapies. He listed the cancers that aremost curable (e.g. Hodgkin’s disease,acute lymphoblastic leukaemia and tes-ticular cancer) as only 5% of all cancercases. However, Sikora added, the num-ber of anti-cancer drugs in preclinicaland Phase I trials has increased dramati-cally within the last decade, mainly because of the advent and developmentof technologies such as sequencing and bioinformatics, expression vectors,three-dimensional structural biology,HTS, combinatorial chemistry and plat-form approaches to drug discovery.These have resulted in a huge increase inpotential drug targets and Sikora pre-dicted an explosion in investigationalnew drugs (INDs) in the next five years.

Sikora concluded the keynote with aconsideration for the unmet medicalneed of developing countries. He com-mented that we need a ‘McDonald’s’type solution to cancer therapy in

underprivileged countries, using theanalogy that a hamburger tastes thesame in any country even though itsprice might differ greatly. However, thequestion remains as to who will fundsuch a solution when the costs associ-ated with ameliorating the side effects ofcancer treatment are often more thanthe chemotherapy itself.

References1 Sont, J.K. et al. (1992) Increased risk of

second cancers in managing Hodgkin’sdisease: the 20-year Leiden experience. Ann.Hematol. 65, 213–218

2 Hughes, S. (1999) Bayer drug casts shadowover MMP inhibitors in cancer. Scrip DailyNews Alert, 40301

3 Brown, P.D. (2000) Ongoing trials withmatrix metalloproteinase inhibitors. ExpertOpin. Investig. Drugs 9, 2167–2177

4 Thurston, D.E. (1999) Nucleic acid targeting:therapeutic strategies for the 21st century. Br.J. Cancer 80 (Suppl.), S65–S85

5 Littlewood, T.J. (2001) The impact ofhemoglobin levels on treatment outcomes in patients with cancer. Semin. Oncol. 28 (Suppl. 8) 49–53

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