- Email: [email protected]
PET in early clinical trials
1284
Book Reviews/News
Critical requirements of successful photodynamic therapy include adequate means of light delivery and dosimetry. Several chapters address these points. The design of appropriate lasers, power and the wavelength of their outputs, the relation between wavelength of the laser light and tissue penetration, and techniques for measuring photodynamic dose are all covered in some depth. Ultimately, the success or failure of photodynamic therapy rests heavily on the ability to optimise drug and light dosage in the chosen treatment volume. This, in turn, must rest on sound knowledge of the pharmacokinetic behaviour of the photosensitisers. Much attention is paid by some authors to the study of drug transport and localisation, both in tissues and intra-cellularly, stability, and methods of drug delivery, particularly by carrier proteins. While inhomogeneity of distribution is an important factor, there is evidence that useful therapeutic differentials can be obtained in some situations, although there is no exclusivity of uptake in tumour cells. Tumour selectivity in treatment rests much more on the substantial degree of selectivity of light delivery that can be attained in some situations. Several papers address the question of skin sensitivity to photodynamic treatments. Exposure of porphyrins to light of appropriate wavelength leads to the generation of a variety of complement activation products which can, in turn, induce several various types of response in experimental mice. Mechanisms of therapeutic strategies involving treatment of pathological disorders, including psoriasis with photosensitisers and light, are also discussed. While photodynamic therapy of solid tumours is unlikely to have the widespread applicability of radiotherapy with highenergy beams of ionising radiation, evidence is accumulating that it will find a specialised place in the local treatment of some types of lesions. A survey of the use of photodynamic therapy with haematoporphyrin derivative has given encouraging results in the treatment of early stage lung cancer. Similarly, photodynamic therapy of some superficial bladder tumours that failed other primary treatments, have given encouraging results. Details of some ongoing studies of the response of brain tumours to photodynamic therapy are also reported with, as yet, few definitive results. The future scope of photodynamic therapy generally remains admittedly uncertain, but still has promise. Increasing evidence that damage to tumour vasculature is an important feature of the effect, lends support to the view that photodynamic therapy may find an increasing role as an adjunct to other methods of attacking tumour vasculature. Further, indications that morbidity of photodynamic therapy is not exacerbated by previous exposure of the tissue to therapy with ionising radiation is another plus. Overall, this book is a comprehensive introduction to the field of photodynamic therapy. It is informative to a degree in questions of detail without being too indigestible. The reports of the discussions are large enough to be useful, which is not always the case in publications of proceedings of conferences. The book is recommended reading to all participants in the field, as well as to educated outsiders. G.E. Adams MRC Radiobiology Unit Chilton Didcot Oxon OX 11 ORD U.K.
News
PET in Early Clinical Trials The EORTC in collaboration with the UK Cancer Research Campaign has, over the past 10 years, developed a new initiative for the selection, preclinical toxicology and early clinical trials of new anticancer agents. The preclinical development is based on a simple subacute toxicology protocol which only uses rodents combined with pharmacokinetic studies. The system is so rapid and inexpensive that it has enabled 50 new chemicals to be assessed during the period the scheme has been in operation. There are already indications that some of these new chemicals, for example, 4-hydroxyandrostenedione, the anthrapyrazolones and temozolomide, may become established clinically. A major problem in early clinical trials is that methods used to measure tumour response are insensitive and many potentially new classes of chemical may have been lost in the past because their small but important antitumour properties were not detected. Had they been, they would then have been studied further in the laboratory and more effective analogues would have been developed. Position emission tomography (PET) provides the opportunity to measure the regional tissue content and kinetics of antitumour agents labelled with such radionuclides as carbon 11 and fluorine 18. With the availability of suitably labelled methionine, fluorodeoxyglucose, water and thymidine, PET scanning allows small changes in protein synthesis, glucose utilisation, perfusion and DNA synthesis induced in tumours by therapy to be monitored. It has already been shown in some investigations that PET scanning with these chemical tracers can accurately predict the sensitivity of some cancers to treatment. At a meeting between EORTC clinical triallists and the EC Concerted Action group on PET on 14 November 1991 at the Cancer Research Campaign headquarters in London, the two groups reviewed their experience with phase I/II clinical trials and the use of PET in oncology. Various ways in which early clinical trials could be integrated with PET were discussed. Some chemicals at present on clinical trial can be labelled with positron emitters and used for tumour and normal tissue pharmacokinetic studies. Besides using PET to measure early response to treatment and changes in metabolic status induced by therapy, it may also be possible to use PET to measure the therapy resistant fraction of tumours, tumour hypoxia, the multidrug resistance status of tumours and their 06-alkyltransferase content. Further thought is to be given to formulating specific PET projects that could be carried out in parallel with current and future phase I/II trials. In addition, mechanisms for financing such initiatives need to be identified. To this end it was agreed that a workshop should be held in late 1992 to discuss further the use of PET in early clinical trials. Anybody interested in obtaining further details should contact Professor T.A. Connors, MRC Toxicology Unit, Woodmansterne Road, Carshalton, Surrey SMS 4EF, U.K.
News
1285
The European School of Oncology
10th ANNIVERSARY EVENTS 15th - 16th October, 1992 Milan, Italy Bioethics in Oncology Chairpersons: J. Holland (US), M. Slevin (GB) Faculty: Aaronson (NL), Cazzullo (IT)),Fiorentino (IT), Koinuma (JP), Lederherg (US), McDonnell (ICE),Olweny (US), Rothman (US), Vemafridda (IT), Veronesi (IT), Weil (FR) Truth telling in the Western European context; Changing patterns in Japan; Medicine and government; Ethical issues
in developing countries; Euthanasia and other media favorites; Terminal care and ethics in the developing countries; Planning a global research and educational agenda in bioethics. I..
Chemoprevention of Cancer Chairpersons: M. Sporn (US), P Boyle (IT) Faculty:CraigJordan (US), Cuzick (GB), Ki Hong (US), McVie (GB), Moon (US), Powles (GB), Schroeder (NL), Vernnesi (IT), Walker (US), Willett (US)
I-II
Tobacco Carcinogenesis and Control
Chart-persons. P Boyle (IT), M. Peckham (GB), W. Zatonski (PL), H. Zur Hausen (DE)
Faculty: Bartsch (FR), La Vecchia (IT), Mattin-Momno (ES), Maynard (GB), Schwab (DE), Walker (US), Wood (GB)
The epidemiological evidence of cigars, pipes and cigarette smoking and risk of cancer; Differences in the effect of black and blond tobacco on cancer risk; Chemical carcinogenesis and mechanisms;Preventive strategies and their efficacy;Introduction of “European Oncologists Against Tobacco”. .*.
Cutaneous Melanoma Chairperson: N. Cascinelli (IT) Faculty: Anichini (IT), Bajetta (IT), Belli (IT), Cook (GB), Coulie (NL), Giannoui (IT), Illeni (IT), Kirkwood (US), Mackie (GB), Mihm (US), Natali (IT), Parmiani (IT), Rilke (IT), Rovini (IT), Santinami (IT), Soyer (AT), Vaglini (IT), Zunida (IT)
Tamoxifen and prevention of breast cancer, Ongoing studies on tamoxifen in the US, the UK and Italy; Retinoids and cancer prevention; The Milan cancer chemoprevention programme; EUROSCAN; Prevention of prostate cancer; Methodology. 1..
at the Istituto Nazionale Tumori (Milan); Immunological research. ***
Immunodiagnosis of ‘Ibmours
Prostate Cancer 2000
Chairperson:
S. von Kleist
(DE)
Diagnosis of cutaneous melanoma; Utility and limits of prevention campaigns in melanoma; Therapeutic ptngramming
Chairpersons: L. Denis (BE), G. Murphy (US)
Faculty: Bradwell (GB), Buraggi (IT), Denk (AT), Gion (IT), Hertel (DE), Hor (DE), Noujaim (CA), Schwartz (US), Wittekind (DE)
Faculty: Bagshaw (US), Boyle (IT), Coffey (US), Di Silverio (IT), Griffiths (GB). Pagan0 (IT), Scher (US), Schroeder (NL), Walsh (US)
In vitro procedures for immunodiagnosis; New serological marker substances; Immunohistology - a new diagnostical dimension;In vivo technologies for immunodiagnosis;Radioimmunodetection as a model for biologically targeted radio-
Epidemiology of prostate cancer, Prevention; Biology of prostate cancer, Endocrinology of prostate cancer, Radical prostatectomy; Radiotherapy; Endocrine therapy; Chemotherapy; Future considerations.
therapy. I
For further information contact: The Secretariat, European School of Oncology, Via Venezian 18, 20133 Milan, Italy Tel: (+39 2)70835923-2364283 Fax: (39 2)2664662
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News
EORTC Breast Cancer Cooperative Group-Manual and Fellowship A manual for clinical research in breast cancer* was published by the EORTC Breast Cancer Cooperative Group on the occasion of the 5th EORTC Breast Cancer Working Conference in Leuven, September 1991. The manual is now used as the principal source of reference for designing and running the group’s trials. It sets out standards for the assessment of patients, acquisition of clinical information and for undertaking investigation including mammography and steroid receptor analyses. Histopathological examination, tissue sampling and reporting are dealt with in detail. Standards are also described for good practice in surgery, radiotherapy and adjuvant systemic treatment for early disease for which the end-points of recurrence and cosmesis are also defined. Similarly, standards for the systemic treatment of metastatic disease are detailed together with criteria for determining response, physical toxicity and evaluating quality of life. The manual concludes with guidelines for the design of clinical trials and the processes for running, monitoring and analysing the results. The group has now organised five major working conferences on breast cancer since 1975, which have been the main European forum for discussions on all aspects of breast cancer. So far, the conferences have been held every 4 years, but it is now planned for the next one to be held in 1994 and every 2 years thereafter. This will ensure a more satisfactory frequency for this important disease and that better continuity is maintained from one conference to the next. A further initiative of the group has been to establish a research fellowship in the Data Center. Fellows will be qualified medical practitioners undergoing specialist training in either surgery, radiotherapy or medical oncology. They will be assigned to work on those studies of the group most related to their own research interests and they will act as the principal link between the trial coordinators, participating centres and the Data Center. The fellowships will provide an unrivalled opportunity for experience in clinical trial methodology and analysis, for participation in authorship of the group’s publications and to work towards a thesis for a higher doctorate. Enquiries should be addressed to the Chairman of the group, Professor R.D. Rubens, Guy’s Hospital, London SE1 9RT, U.K. * Order forms for the manual for clinical research in breast cancer can be obtained from the Administrative Secretariat, EORTC Breast Group, LJZ St Rafael, Gezwelziekten, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
Mutant Oncogenes: Targets for Therapy? This conference brought together clinicians and scientists to review new data on normal and abnormal oncogenes and to discuss potential therapies with mutant oncogenes and their products as targets in specific cancer therapy. Oncogenes are normal genes which when mutated could cause important events in carcinogenesis. Dominant oncogenes may be involved with growth control suppressor or recessive oncogenes which under normal circumstances can suppress cancer growth, but when mutated or deleted allow the development of cancer. The international conference entitled ‘Mutant Oncogenes: Targets for Therapy?’ held in September 1991 at the Royal College of Obstetricians and Gynaecologists attempted to translate laboratory developments into potential clinical application.
The conference started with a discussion of cytoplasmic oncogenes by N. Lemoine (Imperial Cancer Research Fund, Hammersmith Hospital). Ras oncogenes are some of the most frequently activated of the dominant acting oncogenes in human cancers. Activating point mutations can occur at an early stage in some tumours and may represent initiating events, whilst in others, they occur late in the disease and may be related to metastasis. Different tumour types may have different patterns of rus and clearly mutant rus is a potential target for molecular and designer drug therapy. Novel therapies against rus were highlighted by J. Hancock, (Royal Free Hospital, London) who discussed blocking posttranslational modifications and by I. Gibson (University of East Anglia) who discussed the potential of antisense oligodeoxynucleotides and ribozymes against rus. Rus proteins must undergo post-translational modifications in order to be translocated from their site of synthesis in the cytosol and their site of action in the cell membrane. These include farnesylation of a C-terminal cysteine, C-terminal proteolysis and methyl esterilication. It may be possible to develop inhibitors to block the expression and activity of the mutated form of the rus oncogene. Lovostatin, a new drug currently tested for its lipid lowering capabilities, could block farnelysation of rus and cause growth arrest. Another approach described was that ofinhibiting methyl transferase, inhibition of which should be more active against cells containing dominant negative rus proteins rather than normal rus. Chemically synthesised oligonucleotides can potentially inhibit prokaryotic and eukaryotic cells. Natural oligonucleotides are rapidly degraded in the serum or after entry into cells and considerable effort is now directed towards making oligonucleotides more stable in viva. Although inhibition of tumour growth has been demonstrated in nude mice by the use of antisense oligonucleotides, these effects have been of short duration. I. Gibson suggested that in some systems there was rapid uptake of the oligonucleotides by the cell, possibly due to specific receptor binding. More recently, ribozymes have been developed; these are catalytic RNA sequences that can form triplexes (triple strand helixes with RNA and DNA molecules) and even inactivate the gene. The potential therapeutic use of antisense oligonucleotides and ribozymes will continue to provoke interest. Immunotherupy M. Ritter (Royal Postgraduate Medical School) described the
mechanisms for normal immune surveillance and traffic of intracellular antigens as a basis for designing an effective immune response against mutated oncogenes. Immune surveillance entails the patrolling of the body by the recirculating pool of lymphocytes that are functionally mature and tolerant to cells. Encounter with non-self antigens can lead to clonal expansion of antigen-specific lymphocytes and destruction of the target by a variety of mechanisms. The nature of the antigen determines the nature of the response. For intracellular antigens there are two main routes by which they can reach the immune system; they can be released from dying cells and as free molecules can directly activate B cells. Also, free molecules can be endocytosed by antigen presenting cells (APC; macrophages, dendritic cells) processed to produce peptide fragments and following association with host cells MHC class II molecules, be presented as exogenous antigen on the antigen presenting cell surface to
News activate CD-4 positive cytokine-secreting T cells. Alternatively, intracellular protein antigens can be processed endogenously, to produce peptides that associate with MHC class I molecules. These, when at the cell surface, can activate the CD-8 positive T cells leading to lysis of the presenting cell. For intracellular oncogene products, immunogenicity will be determined by factors such as the nature and degree of difference between them and the normal proto-oncogene product, the ability of cells to process the mutant oncogene to appropriate peptides and the individual major histocompatibility complex peptide interaction. H. Stauss, from the ICRF, addressed whether mutant rus proteins can function as tumour antigens that can be recognised by helper and cytotoxic T cells. He showed that peptides corresponding to sequences of normal or mutant rus stimulate CD-4 positive MHC class II restricted helper T cells. These cells were either strictly specific for the mutant peptides or showed some cross-reaction with normal rus peptides. Peptide immunisation can therefore stimulate cytotoxic T cells. These, however, were unable to distinguish between mutant and normal rus peptides. The potential immunogenicity of peptides was explored further by the use of poliovirus as a vaccination system. Viral chimeras expressing a variety of epitopes from pathogens including HIV, HPV-16, Chlumydiu zruchomatis or cancer antigens, led to immune responses in model systems. This provided a great deal of encouragement for the future development of cancer vaccines.
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quickly develops into blast crisis with Ph’ chromosomes. Survival following blast crisis is very short only lasting on average l-2 months. B. Young described experiments in which antisense oligonucleotides introduced into cells inhibited the production of a novel CML-related fusion protein. This approach promises to be valuable for treating CML bone marrow cells ex viva. It may eventually be possible to deliver antisense oligonucleotides in viva for systemic treatment of CML. Tumour suppression genes
Tumour suppression genes were in the forefront at the conference. Work on the retinoblastoma (RBl gene) was reviewed. J. Yandel (Harvard, USA) described germ line mutations of RBI gene associated with a hereditary predisposition to retinoblastoma and other tumours. Somatic mutations have also been found in many common tumours other than retinoblastoma including sarcomas and breast, bladder, prostate and lung cancers. Chromosome 17
Abnormalities on chromosome 17 have been implicated in many cancers, particularly involving breast cancer. c-erb-2 is significant as an independent poor prognosis marker in breast cancer. On this chromosome also lies the nm23 metastasis suppressor gene. Allelic deletion or reduced expression of the gene can allow expression of a metastatic phenotype in several common cancers. Although the ~53 gene on 17p and the c-erb-2 gene on 17q have excited great interest, there are other genes on chromosome 17 which merit further examination.
Epidermal growth factor (EGF) receptor
The c-&-l proto-oncogene encodes a receptor tyrosine kinase (the EGF receptor) which appears to play a central role in the pathogenesis of many human cancers. The fact that the epidermal growth factor receptor is expressed on the outside of the cell surface membrane of cancer cells is attractive for the design of monoclonal antibody-directed therapy. Experiments were described by J. Park (Genentech, California) that provide a basis for immunotherapy of human cancers expressing high levels of EGF receptors. It is already known that the c-erb-2 oncogene which is amplified and overexpressed in many adenocarcinomas is a marker of poor prognosis in breast cancer. Because of its relative tumour specificity, it is a good target for immunotherapy. Several monoclonal antibodies have recently been described which can be used therapeutically. Preclinical studies of radiolabelled antibody have already shown successful localisation in tumour xenografts. Furthermore, bispecific antibodies have also been constructed which combine an anti-c-crb-2 specificity with an anti-CD3 specificity to enhance T cell mediated cytotoxicity. Chronic myelogenous leuhuemiu (CML)
The ABL proto-oncogene is implicated in the cause of leukaemias that carry the Philadelphia chromosome (PH). Abnormal cells usually have two altered chromosome translocations in chromosomes 9 and 22, designated T (9;22). In CML, breaks on chromosomes 22 are restricted to a small region of DNA. This restricted location is termed the break point cluster region (BCR). B. Young, (ICRF Molecular Oncology Unit, St Bartholomew’s Hospital, London), outlined the main steps in the natural history of CML. The initial phase characterised by glucose-6phosphate dehydrogenase clonality is followed by a Ph’ chronic phase. Ras activation accompanies the accelerated phase which
p5 3 gene The human gene for ~53 is located on chromosome 17. Several mutations of ~53 are found at high frequency in most human cancers, including pancreatic, gastric, breast, brain, lung, colon, skin, bladder, uterine, ovarian and testicular cancers. In addition, germ-line mutations in the p53 gene are found in the Li-Fraumeni cancer family syndrome. Normal p53 protein probably acts as a negative regulator of cell growth whilst point mutations in ~53 may activate growth promoting activity. Monoclonal antibodies against ~53 can detect the protein in conventional histological specimens. David Lane (Dundee), the discoverer of ~53, found using immunohistology a high level of ~53 protein in approximately 60% of human cancers. High protein levels are caused by the ~53 mutations which result in a more stable protein than the normal counterpart which is undetectable histologically. Detectable levels ofp53 thus provide a marker of malignancy. Furthermore, the presence of ~53 immunoreactivity carries a worse prognosis for many cancers. I. Filipe (Guy’s Hospital, London) reported that p53-positive gastric cancers have a median survival of 13 months, whilst p53negative tumours have a median survival of 102 months. Mutant ~53 could act as a transcription factor or could have a more direct effect on DNA replication. Thus, mutant ~53 protein is a potential target for therapy because of its cancer specificity and wide spectrum of distribution. Potential immunogenic peptides from ~53 have been described by A. Hill and Sir Walter Bodmer’s ICRF group at Oxford. These may provide immunogenic epitopes for cytotoxic T cells against ~53 mutants. What the future holds
K. Sikora (Royal Postgraduate Medical School, Hammersmith Hospital) provided an exciting ‘crystal ball’ review
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News
of the potential future therapies arising from an improved understanding of the malignant process. Over the past 50 years there has been modest improvement in the long-term survival of many common cancers. Understanding the biology of carcinogenesis may have implications for therapeutic developments. The identification of genes involved in familial cancers will improve diagnostic accuracy and better knowledge of the function of normal and abnormal genes may provide specific and effective therapies. Cancer therapy is likely to include cytokines such as interferons and interleukins, stable oligonucleotides or ribozymes, modulators of tumour cell responsiveness molecules such as EGF, calmodulin or drugs such as verapamil which can make them more vulnerable to attack by chemotherapy, normal tissue protection by growth factors such as granulocyte colony stimulating factor or interleukins, specific antibody targetting of chemotherapy and eventually correction of mutant oncogenes and replacement of suppressor genes. Although in v&o experiments are promising, the area of gene therapy is far removed from clinical application. Finally, enzyme targets may be attractive in cancer therapy. Recently characterised enzymes that modify the ras C-terminus described at this conference provide the beginning of the development of chemical inhibitors. Other chemical blockers of enzyme activity described in the conference were bryostatin, a tetradecanoyl phorbol acetate analogue which is currently investigated for its activity against protein kinase C, and a new class of lipid-lowering drugs such as lovastatin that block hydroxymethylglutaryl coenzyme A reductase. These agents also block prenylation of rus, resulting in growth arrest of cells with increased mutant rus activity. Bryostatin, unfortunately, even at very low doses can cause platelet aggregation as shown in early clinical trials, conducted by A. Harris (ICRF, Oxford).
The
European Institute of Oncology A new cancer institute is being built in Milan, Italy. Sponsored by the main Italian merchant bank, Mediobanca, together with a group of companies (including Fiat, Pirelli and Ferruzzi), banks and insurance companies, the new cancer centre will be called the European Institute of Oncology. One of the major innovative elements of its statute is the article which states that “at least one third of the staff of the Institute will be non-Italian”. Even whilst construction is going on, some of the non-clinical departments are being set-up, locating them temporarily near the site of the new Institute. The first scientist to join the staff is the epidemiologist Peter Boyle, previously at International Agency for Research in Cancer (IARC) in Lyon and one of the editors of the European Journal of Cancer. The second innovative feature, at least from the Italian point of view, is that the Institute will be the first private cancer centre in the country (all the other Institutes are state-owned, belonging to the Ministry of Health) but, again by Statute, the income will be reinvested in research. Four major areas are described in the project: laboratory research, diagnosis, treatment and training. The European Institute is being built in the southern part of Milan on an area of 29,000 square metres, it will have 175 beds and is expected to be ready in February, 1994. The new centre is welcomed by the city, which already hosts the much larger Istituto Nazionale Tumori but is unable to satisfy the growing demand for cancer care required of it from patients all over the country. At any one time there are almost 1000 patients waiting for one of the 500 beds of the Istituto Nazionale Tumori and it is felt that a new centre will significantly increase the availability of oncological services in Northern Italy. The sponsors of the European Institute of Oncology have requested the advice of Umberto Veronesi who is expected to be appointed as director of the new centre when his mandate at his present Institution expires.
European Institute of Oncology (under construction).
Book Reviews/News
Critical requirements of successful photodynamic therapy include adequate means of light delivery and dosimetry. Several chapters address these points. The design of appropriate lasers, power and the wavelength of their outputs, the relation between wavelength of the laser light and tissue penetration, and techniques for measuring photodynamic dose are all covered in some depth. Ultimately, the success or failure of photodynamic therapy rests heavily on the ability to optimise drug and light dosage in the chosen treatment volume. This, in turn, must rest on sound knowledge of the pharmacokinetic behaviour of the photosensitisers. Much attention is paid by some authors to the study of drug transport and localisation, both in tissues and intra-cellularly, stability, and methods of drug delivery, particularly by carrier proteins. While inhomogeneity of distribution is an important factor, there is evidence that useful therapeutic differentials can be obtained in some situations, although there is no exclusivity of uptake in tumour cells. Tumour selectivity in treatment rests much more on the substantial degree of selectivity of light delivery that can be attained in some situations. Several papers address the question of skin sensitivity to photodynamic treatments. Exposure of porphyrins to light of appropriate wavelength leads to the generation of a variety of complement activation products which can, in turn, induce several various types of response in experimental mice. Mechanisms of therapeutic strategies involving treatment of pathological disorders, including psoriasis with photosensitisers and light, are also discussed. While photodynamic therapy of solid tumours is unlikely to have the widespread applicability of radiotherapy with highenergy beams of ionising radiation, evidence is accumulating that it will find a specialised place in the local treatment of some types of lesions. A survey of the use of photodynamic therapy with haematoporphyrin derivative has given encouraging results in the treatment of early stage lung cancer. Similarly, photodynamic therapy of some superficial bladder tumours that failed other primary treatments, have given encouraging results. Details of some ongoing studies of the response of brain tumours to photodynamic therapy are also reported with, as yet, few definitive results. The future scope of photodynamic therapy generally remains admittedly uncertain, but still has promise. Increasing evidence that damage to tumour vasculature is an important feature of the effect, lends support to the view that photodynamic therapy may find an increasing role as an adjunct to other methods of attacking tumour vasculature. Further, indications that morbidity of photodynamic therapy is not exacerbated by previous exposure of the tissue to therapy with ionising radiation is another plus. Overall, this book is a comprehensive introduction to the field of photodynamic therapy. It is informative to a degree in questions of detail without being too indigestible. The reports of the discussions are large enough to be useful, which is not always the case in publications of proceedings of conferences. The book is recommended reading to all participants in the field, as well as to educated outsiders. G.E. Adams MRC Radiobiology Unit Chilton Didcot Oxon OX 11 ORD U.K.
News
PET in Early Clinical Trials The EORTC in collaboration with the UK Cancer Research Campaign has, over the past 10 years, developed a new initiative for the selection, preclinical toxicology and early clinical trials of new anticancer agents. The preclinical development is based on a simple subacute toxicology protocol which only uses rodents combined with pharmacokinetic studies. The system is so rapid and inexpensive that it has enabled 50 new chemicals to be assessed during the period the scheme has been in operation. There are already indications that some of these new chemicals, for example, 4-hydroxyandrostenedione, the anthrapyrazolones and temozolomide, may become established clinically. A major problem in early clinical trials is that methods used to measure tumour response are insensitive and many potentially new classes of chemical may have been lost in the past because their small but important antitumour properties were not detected. Had they been, they would then have been studied further in the laboratory and more effective analogues would have been developed. Position emission tomography (PET) provides the opportunity to measure the regional tissue content and kinetics of antitumour agents labelled with such radionuclides as carbon 11 and fluorine 18. With the availability of suitably labelled methionine, fluorodeoxyglucose, water and thymidine, PET scanning allows small changes in protein synthesis, glucose utilisation, perfusion and DNA synthesis induced in tumours by therapy to be monitored. It has already been shown in some investigations that PET scanning with these chemical tracers can accurately predict the sensitivity of some cancers to treatment. At a meeting between EORTC clinical triallists and the EC Concerted Action group on PET on 14 November 1991 at the Cancer Research Campaign headquarters in London, the two groups reviewed their experience with phase I/II clinical trials and the use of PET in oncology. Various ways in which early clinical trials could be integrated with PET were discussed. Some chemicals at present on clinical trial can be labelled with positron emitters and used for tumour and normal tissue pharmacokinetic studies. Besides using PET to measure early response to treatment and changes in metabolic status induced by therapy, it may also be possible to use PET to measure the therapy resistant fraction of tumours, tumour hypoxia, the multidrug resistance status of tumours and their 06-alkyltransferase content. Further thought is to be given to formulating specific PET projects that could be carried out in parallel with current and future phase I/II trials. In addition, mechanisms for financing such initiatives need to be identified. To this end it was agreed that a workshop should be held in late 1992 to discuss further the use of PET in early clinical trials. Anybody interested in obtaining further details should contact Professor T.A. Connors, MRC Toxicology Unit, Woodmansterne Road, Carshalton, Surrey SMS 4EF, U.K.
News
1285
The European School of Oncology
10th ANNIVERSARY EVENTS 15th - 16th October, 1992 Milan, Italy Bioethics in Oncology Chairpersons: J. Holland (US), M. Slevin (GB) Faculty: Aaronson (NL), Cazzullo (IT)),Fiorentino (IT), Koinuma (JP), Lederherg (US), McDonnell (ICE),Olweny (US), Rothman (US), Vemafridda (IT), Veronesi (IT), Weil (FR) Truth telling in the Western European context; Changing patterns in Japan; Medicine and government; Ethical issues
in developing countries; Euthanasia and other media favorites; Terminal care and ethics in the developing countries; Planning a global research and educational agenda in bioethics. I..
Chemoprevention of Cancer Chairpersons: M. Sporn (US), P Boyle (IT) Faculty:CraigJordan (US), Cuzick (GB), Ki Hong (US), McVie (GB), Moon (US), Powles (GB), Schroeder (NL), Vernnesi (IT), Walker (US), Willett (US)
I-II
Tobacco Carcinogenesis and Control
Chart-persons. P Boyle (IT), M. Peckham (GB), W. Zatonski (PL), H. Zur Hausen (DE)
Faculty: Bartsch (FR), La Vecchia (IT), Mattin-Momno (ES), Maynard (GB), Schwab (DE), Walker (US), Wood (GB)
The epidemiological evidence of cigars, pipes and cigarette smoking and risk of cancer; Differences in the effect of black and blond tobacco on cancer risk; Chemical carcinogenesis and mechanisms;Preventive strategies and their efficacy;Introduction of “European Oncologists Against Tobacco”. .*.
Cutaneous Melanoma Chairperson: N. Cascinelli (IT) Faculty: Anichini (IT), Bajetta (IT), Belli (IT), Cook (GB), Coulie (NL), Giannoui (IT), Illeni (IT), Kirkwood (US), Mackie (GB), Mihm (US), Natali (IT), Parmiani (IT), Rilke (IT), Rovini (IT), Santinami (IT), Soyer (AT), Vaglini (IT), Zunida (IT)
Tamoxifen and prevention of breast cancer, Ongoing studies on tamoxifen in the US, the UK and Italy; Retinoids and cancer prevention; The Milan cancer chemoprevention programme; EUROSCAN; Prevention of prostate cancer; Methodology. 1..
at the Istituto Nazionale Tumori (Milan); Immunological research. ***
Immunodiagnosis of ‘Ibmours
Prostate Cancer 2000
Chairperson:
S. von Kleist
(DE)
Diagnosis of cutaneous melanoma; Utility and limits of prevention campaigns in melanoma; Therapeutic ptngramming
Chairpersons: L. Denis (BE), G. Murphy (US)
Faculty: Bradwell (GB), Buraggi (IT), Denk (AT), Gion (IT), Hertel (DE), Hor (DE), Noujaim (CA), Schwartz (US), Wittekind (DE)
Faculty: Bagshaw (US), Boyle (IT), Coffey (US), Di Silverio (IT), Griffiths (GB). Pagan0 (IT), Scher (US), Schroeder (NL), Walsh (US)
In vitro procedures for immunodiagnosis; New serological marker substances; Immunohistology - a new diagnostical dimension;In vivo technologies for immunodiagnosis;Radioimmunodetection as a model for biologically targeted radio-
Epidemiology of prostate cancer, Prevention; Biology of prostate cancer, Endocrinology of prostate cancer, Radical prostatectomy; Radiotherapy; Endocrine therapy; Chemotherapy; Future considerations.
therapy. I
For further information contact: The Secretariat, European School of Oncology, Via Venezian 18, 20133 Milan, Italy Tel: (+39 2)70835923-2364283 Fax: (39 2)2664662
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EORTC Breast Cancer Cooperative Group-Manual and Fellowship A manual for clinical research in breast cancer* was published by the EORTC Breast Cancer Cooperative Group on the occasion of the 5th EORTC Breast Cancer Working Conference in Leuven, September 1991. The manual is now used as the principal source of reference for designing and running the group’s trials. It sets out standards for the assessment of patients, acquisition of clinical information and for undertaking investigation including mammography and steroid receptor analyses. Histopathological examination, tissue sampling and reporting are dealt with in detail. Standards are also described for good practice in surgery, radiotherapy and adjuvant systemic treatment for early disease for which the end-points of recurrence and cosmesis are also defined. Similarly, standards for the systemic treatment of metastatic disease are detailed together with criteria for determining response, physical toxicity and evaluating quality of life. The manual concludes with guidelines for the design of clinical trials and the processes for running, monitoring and analysing the results. The group has now organised five major working conferences on breast cancer since 1975, which have been the main European forum for discussions on all aspects of breast cancer. So far, the conferences have been held every 4 years, but it is now planned for the next one to be held in 1994 and every 2 years thereafter. This will ensure a more satisfactory frequency for this important disease and that better continuity is maintained from one conference to the next. A further initiative of the group has been to establish a research fellowship in the Data Center. Fellows will be qualified medical practitioners undergoing specialist training in either surgery, radiotherapy or medical oncology. They will be assigned to work on those studies of the group most related to their own research interests and they will act as the principal link between the trial coordinators, participating centres and the Data Center. The fellowships will provide an unrivalled opportunity for experience in clinical trial methodology and analysis, for participation in authorship of the group’s publications and to work towards a thesis for a higher doctorate. Enquiries should be addressed to the Chairman of the group, Professor R.D. Rubens, Guy’s Hospital, London SE1 9RT, U.K. * Order forms for the manual for clinical research in breast cancer can be obtained from the Administrative Secretariat, EORTC Breast Group, LJZ St Rafael, Gezwelziekten, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
Mutant Oncogenes: Targets for Therapy? This conference brought together clinicians and scientists to review new data on normal and abnormal oncogenes and to discuss potential therapies with mutant oncogenes and their products as targets in specific cancer therapy. Oncogenes are normal genes which when mutated could cause important events in carcinogenesis. Dominant oncogenes may be involved with growth control suppressor or recessive oncogenes which under normal circumstances can suppress cancer growth, but when mutated or deleted allow the development of cancer. The international conference entitled ‘Mutant Oncogenes: Targets for Therapy?’ held in September 1991 at the Royal College of Obstetricians and Gynaecologists attempted to translate laboratory developments into potential clinical application.
The conference started with a discussion of cytoplasmic oncogenes by N. Lemoine (Imperial Cancer Research Fund, Hammersmith Hospital). Ras oncogenes are some of the most frequently activated of the dominant acting oncogenes in human cancers. Activating point mutations can occur at an early stage in some tumours and may represent initiating events, whilst in others, they occur late in the disease and may be related to metastasis. Different tumour types may have different patterns of rus and clearly mutant rus is a potential target for molecular and designer drug therapy. Novel therapies against rus were highlighted by J. Hancock, (Royal Free Hospital, London) who discussed blocking posttranslational modifications and by I. Gibson (University of East Anglia) who discussed the potential of antisense oligodeoxynucleotides and ribozymes against rus. Rus proteins must undergo post-translational modifications in order to be translocated from their site of synthesis in the cytosol and their site of action in the cell membrane. These include farnesylation of a C-terminal cysteine, C-terminal proteolysis and methyl esterilication. It may be possible to develop inhibitors to block the expression and activity of the mutated form of the rus oncogene. Lovostatin, a new drug currently tested for its lipid lowering capabilities, could block farnelysation of rus and cause growth arrest. Another approach described was that ofinhibiting methyl transferase, inhibition of which should be more active against cells containing dominant negative rus proteins rather than normal rus. Chemically synthesised oligonucleotides can potentially inhibit prokaryotic and eukaryotic cells. Natural oligonucleotides are rapidly degraded in the serum or after entry into cells and considerable effort is now directed towards making oligonucleotides more stable in viva. Although inhibition of tumour growth has been demonstrated in nude mice by the use of antisense oligonucleotides, these effects have been of short duration. I. Gibson suggested that in some systems there was rapid uptake of the oligonucleotides by the cell, possibly due to specific receptor binding. More recently, ribozymes have been developed; these are catalytic RNA sequences that can form triplexes (triple strand helixes with RNA and DNA molecules) and even inactivate the gene. The potential therapeutic use of antisense oligonucleotides and ribozymes will continue to provoke interest. Immunotherupy M. Ritter (Royal Postgraduate Medical School) described the
mechanisms for normal immune surveillance and traffic of intracellular antigens as a basis for designing an effective immune response against mutated oncogenes. Immune surveillance entails the patrolling of the body by the recirculating pool of lymphocytes that are functionally mature and tolerant to cells. Encounter with non-self antigens can lead to clonal expansion of antigen-specific lymphocytes and destruction of the target by a variety of mechanisms. The nature of the antigen determines the nature of the response. For intracellular antigens there are two main routes by which they can reach the immune system; they can be released from dying cells and as free molecules can directly activate B cells. Also, free molecules can be endocytosed by antigen presenting cells (APC; macrophages, dendritic cells) processed to produce peptide fragments and following association with host cells MHC class II molecules, be presented as exogenous antigen on the antigen presenting cell surface to
News activate CD-4 positive cytokine-secreting T cells. Alternatively, intracellular protein antigens can be processed endogenously, to produce peptides that associate with MHC class I molecules. These, when at the cell surface, can activate the CD-8 positive T cells leading to lysis of the presenting cell. For intracellular oncogene products, immunogenicity will be determined by factors such as the nature and degree of difference between them and the normal proto-oncogene product, the ability of cells to process the mutant oncogene to appropriate peptides and the individual major histocompatibility complex peptide interaction. H. Stauss, from the ICRF, addressed whether mutant rus proteins can function as tumour antigens that can be recognised by helper and cytotoxic T cells. He showed that peptides corresponding to sequences of normal or mutant rus stimulate CD-4 positive MHC class II restricted helper T cells. These cells were either strictly specific for the mutant peptides or showed some cross-reaction with normal rus peptides. Peptide immunisation can therefore stimulate cytotoxic T cells. These, however, were unable to distinguish between mutant and normal rus peptides. The potential immunogenicity of peptides was explored further by the use of poliovirus as a vaccination system. Viral chimeras expressing a variety of epitopes from pathogens including HIV, HPV-16, Chlumydiu zruchomatis or cancer antigens, led to immune responses in model systems. This provided a great deal of encouragement for the future development of cancer vaccines.
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quickly develops into blast crisis with Ph’ chromosomes. Survival following blast crisis is very short only lasting on average l-2 months. B. Young described experiments in which antisense oligonucleotides introduced into cells inhibited the production of a novel CML-related fusion protein. This approach promises to be valuable for treating CML bone marrow cells ex viva. It may eventually be possible to deliver antisense oligonucleotides in viva for systemic treatment of CML. Tumour suppression genes
Tumour suppression genes were in the forefront at the conference. Work on the retinoblastoma (RBl gene) was reviewed. J. Yandel (Harvard, USA) described germ line mutations of RBI gene associated with a hereditary predisposition to retinoblastoma and other tumours. Somatic mutations have also been found in many common tumours other than retinoblastoma including sarcomas and breast, bladder, prostate and lung cancers. Chromosome 17
Abnormalities on chromosome 17 have been implicated in many cancers, particularly involving breast cancer. c-erb-2 is significant as an independent poor prognosis marker in breast cancer. On this chromosome also lies the nm23 metastasis suppressor gene. Allelic deletion or reduced expression of the gene can allow expression of a metastatic phenotype in several common cancers. Although the ~53 gene on 17p and the c-erb-2 gene on 17q have excited great interest, there are other genes on chromosome 17 which merit further examination.
Epidermal growth factor (EGF) receptor
The c-&-l proto-oncogene encodes a receptor tyrosine kinase (the EGF receptor) which appears to play a central role in the pathogenesis of many human cancers. The fact that the epidermal growth factor receptor is expressed on the outside of the cell surface membrane of cancer cells is attractive for the design of monoclonal antibody-directed therapy. Experiments were described by J. Park (Genentech, California) that provide a basis for immunotherapy of human cancers expressing high levels of EGF receptors. It is already known that the c-erb-2 oncogene which is amplified and overexpressed in many adenocarcinomas is a marker of poor prognosis in breast cancer. Because of its relative tumour specificity, it is a good target for immunotherapy. Several monoclonal antibodies have recently been described which can be used therapeutically. Preclinical studies of radiolabelled antibody have already shown successful localisation in tumour xenografts. Furthermore, bispecific antibodies have also been constructed which combine an anti-c-crb-2 specificity with an anti-CD3 specificity to enhance T cell mediated cytotoxicity. Chronic myelogenous leuhuemiu (CML)
The ABL proto-oncogene is implicated in the cause of leukaemias that carry the Philadelphia chromosome (PH). Abnormal cells usually have two altered chromosome translocations in chromosomes 9 and 22, designated T (9;22). In CML, breaks on chromosomes 22 are restricted to a small region of DNA. This restricted location is termed the break point cluster region (BCR). B. Young, (ICRF Molecular Oncology Unit, St Bartholomew’s Hospital, London), outlined the main steps in the natural history of CML. The initial phase characterised by glucose-6phosphate dehydrogenase clonality is followed by a Ph’ chronic phase. Ras activation accompanies the accelerated phase which
p5 3 gene The human gene for ~53 is located on chromosome 17. Several mutations of ~53 are found at high frequency in most human cancers, including pancreatic, gastric, breast, brain, lung, colon, skin, bladder, uterine, ovarian and testicular cancers. In addition, germ-line mutations in the p53 gene are found in the Li-Fraumeni cancer family syndrome. Normal p53 protein probably acts as a negative regulator of cell growth whilst point mutations in ~53 may activate growth promoting activity. Monoclonal antibodies against ~53 can detect the protein in conventional histological specimens. David Lane (Dundee), the discoverer of ~53, found using immunohistology a high level of ~53 protein in approximately 60% of human cancers. High protein levels are caused by the ~53 mutations which result in a more stable protein than the normal counterpart which is undetectable histologically. Detectable levels ofp53 thus provide a marker of malignancy. Furthermore, the presence of ~53 immunoreactivity carries a worse prognosis for many cancers. I. Filipe (Guy’s Hospital, London) reported that p53-positive gastric cancers have a median survival of 13 months, whilst p53negative tumours have a median survival of 102 months. Mutant ~53 could act as a transcription factor or could have a more direct effect on DNA replication. Thus, mutant ~53 protein is a potential target for therapy because of its cancer specificity and wide spectrum of distribution. Potential immunogenic peptides from ~53 have been described by A. Hill and Sir Walter Bodmer’s ICRF group at Oxford. These may provide immunogenic epitopes for cytotoxic T cells against ~53 mutants. What the future holds
K. Sikora (Royal Postgraduate Medical School, Hammersmith Hospital) provided an exciting ‘crystal ball’ review
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of the potential future therapies arising from an improved understanding of the malignant process. Over the past 50 years there has been modest improvement in the long-term survival of many common cancers. Understanding the biology of carcinogenesis may have implications for therapeutic developments. The identification of genes involved in familial cancers will improve diagnostic accuracy and better knowledge of the function of normal and abnormal genes may provide specific and effective therapies. Cancer therapy is likely to include cytokines such as interferons and interleukins, stable oligonucleotides or ribozymes, modulators of tumour cell responsiveness molecules such as EGF, calmodulin or drugs such as verapamil which can make them more vulnerable to attack by chemotherapy, normal tissue protection by growth factors such as granulocyte colony stimulating factor or interleukins, specific antibody targetting of chemotherapy and eventually correction of mutant oncogenes and replacement of suppressor genes. Although in v&o experiments are promising, the area of gene therapy is far removed from clinical application. Finally, enzyme targets may be attractive in cancer therapy. Recently characterised enzymes that modify the ras C-terminus described at this conference provide the beginning of the development of chemical inhibitors. Other chemical blockers of enzyme activity described in the conference were bryostatin, a tetradecanoyl phorbol acetate analogue which is currently investigated for its activity against protein kinase C, and a new class of lipid-lowering drugs such as lovastatin that block hydroxymethylglutaryl coenzyme A reductase. These agents also block prenylation of rus, resulting in growth arrest of cells with increased mutant rus activity. Bryostatin, unfortunately, even at very low doses can cause platelet aggregation as shown in early clinical trials, conducted by A. Harris (ICRF, Oxford).
The
European Institute of Oncology A new cancer institute is being built in Milan, Italy. Sponsored by the main Italian merchant bank, Mediobanca, together with a group of companies (including Fiat, Pirelli and Ferruzzi), banks and insurance companies, the new cancer centre will be called the European Institute of Oncology. One of the major innovative elements of its statute is the article which states that “at least one third of the staff of the Institute will be non-Italian”. Even whilst construction is going on, some of the non-clinical departments are being set-up, locating them temporarily near the site of the new Institute. The first scientist to join the staff is the epidemiologist Peter Boyle, previously at International Agency for Research in Cancer (IARC) in Lyon and one of the editors of the European Journal of Cancer. The second innovative feature, at least from the Italian point of view, is that the Institute will be the first private cancer centre in the country (all the other Institutes are state-owned, belonging to the Ministry of Health) but, again by Statute, the income will be reinvested in research. Four major areas are described in the project: laboratory research, diagnosis, treatment and training. The European Institute is being built in the southern part of Milan on an area of 29,000 square metres, it will have 175 beds and is expected to be ready in February, 1994. The new centre is welcomed by the city, which already hosts the much larger Istituto Nazionale Tumori but is unable to satisfy the growing demand for cancer care required of it from patients all over the country. At any one time there are almost 1000 patients waiting for one of the 500 beds of the Istituto Nazionale Tumori and it is felt that a new centre will significantly increase the availability of oncological services in Northern Italy. The sponsors of the European Institute of Oncology have requested the advice of Umberto Veronesi who is expected to be appointed as director of the new centre when his mandate at his present Institution expires.
European Institute of Oncology (under construction).