89th Annual Meeting of the American Association for Cancer research (AACR)

CONFERENCE REPORT 89th Annual Meeting of the American Association for Cancer Research (AACR) New Orleans, LA, USA 28 March-I April 1998 Henk J. Broxterman', Nafsika H. Georgopapadakou 2 ~Dept. of Medical Oncology, Academm HospltaIVrqe Unlversltelt, Amsterdarn,The Netherlands 2DuPont Merck ResearchLabs,Wilmington, Delaware,USA

This international conference attracted over 12 000 delegates from academia and industry.. It covered in approximately 5000 oral presentations and posters in paraUel sessions, a variety of topics related to carcinogenesis, minor biolog%, experimental therapeutics and clinical research.We will slmlmarize here some of presentations relevant to tumor response to drugs, new targets and approaches to drug discovery, and new agents in preclinieal or clinical development. Cell cycle. Andrew Koff (Memorial Sloan Kettering Cancer Center, New York, USA) reviewed the mechanisms that control cell proliferation, a process with profound implications in tumor development and treatment. In his introduction, he reminded the audience that multiple genetic changes are required for tumorigenesis: uncontrolled proliferation, chromosomal rearrangements, genomic instability, suppression of apoptosis, mutations in DNA repair genes, and inability to differentiate. Cyclin-dependent kinases (CDKs) are central to the proliferation process.Three CDKs (CycD/DKC 4,6 and CyeE/CDK 2) drive proliferation

through G1 phase into S phase Activation of at least two pathways involving distinct CDKs (and the tumor suppressor Rb) is required for Sphase activity. Ronald de Pinho (Einstein College of Medicine, Bronx, NewYork, USA) expanded on the theme that multiple changes are required for tumorigenesis, focusing on three: the tumor suppressors Rb and p53 and the telomercs.While damage to Rb may cause unchecked proliferation, additional damage to p53 is needed to abrogate apoptosis, and telomere 'reactivation' to achieve immortality. In the same session, Neal Rosen (Memorial Sloan-Kettering Cancer Center, NewYork, USA), discussed chemotherapeutic agents in development that target the cell cycle: intrinsic cell cycle machinery (cyclin kinases and cyclins), upstream signal transduction pathways, and checkpoint machinery.An example of a cdk inhibitor is flavopiridol (ICs0eq0.4~tM) , currently in Phase I clinical trials. Intriguingly, farnesyl transferase inhibitors, of which three are in clinical development, inhibit II(though not K- or N-) Ras processing with typical Kis of 0.1 btM,but illhibit the growth of most cell lines independently of Ras status.At 0.5 btM, they synergize with taxol. He suggested that other targets related to the cell cycle may be responsible for the mechanism of action of these 'rationally designed" agents. Another agent, the natural product herbimycin A, down-regulates expression of Dtype cyclins at the mRNA level. He concluded that drug effects on tumors are complex and unpredictable, mutations of cell cycle regulatory genes in tumors adding another layer of complexity. C o m b i n a t o r i a l a p p r o a c h e s to d r u g discovery. Great expectations for the long-term development of new drugs are built on the use of combinatorial approaches for the discovery of tumor-specific targets. Combinatorial chemistry can be defined as the process whereby a very large number of compounds are evaluated for information about a target with a very low cost per data point (II. Mario Geysen, GlaxoWelcome). Several examples of approaches involving combinatorial

biology were reported.With the use of laser microdissection technology (10 000 cells minhlmm) and hybridization with 7-met probes the differential expression of genes in a tumor versus normal tissue is screened.Another example is the screening of high versus low metastatic colon cancer cell lines. Lewis TWilliams (Chiton Technologies) reported that in 3 months, 2600 n ew genes were discovered using these technologies. Another example is the theoretical possibility to create mutant enzymes for cancer gene therapy by applied molecular evolution.A portion of a gene is then replaced by a random sequence to obtain a more active or selective enzyme. Lawrence A. Loeb (University of Washington, Seattle USA) reported on the use of this technique to engineer Herpes Simplex thymidine kinase. One of the pioneers in the use of combinatorial libraries is Kit S. Lam (University of Arizona,Tucson,Arizona, USA) who uses solid phase chemistry to prepare so-called one bead one compound libraries for anticancer drug development.After mixing the beads with a target (cell or enzyme, e.g. a protein kinase) and selection for binding, the compound on the bead can be microsequenced because each bead contains 1013 molecules. Ira Pastan (NC1) reported the development of a bio-engineered immunotoxin against a mesothelioma antigen, which is in Phase 1 trial.The successful use of a phage display library to target the tumor endothelial cell component in vivo (because the virus particles are too large to rapidly pass the vessel wall) was reported by Erkki Ruoslahti (The Burnham Institute, La Jolla, California, USA): this innovative approach revealed many peptide motifs specific for tumor endothelial cells, now used to develop new therapeutic approaches. Such approaches, though promising, will need innovative clinical studies to define their therapeutic potential. A n t i v a s c u l a r t h e r a p y . The endothelial cell as target for antiangiogenic antieancer therapy was highlighted in several sessions. In part, the discussion is still on what models would predict antieaneer activity of antiangiogenie drugs and what would

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Conference report be the end-points in clinical trials in this field. Classically, what one wants to see is tumor shrinkage; however, it is not yet k n o w n w h e t h e r cytostasis and 'tumor dormancy' induced by inhibitors of tumor vessel growth are clinically meaningful end-points (J.M. Pluda, NCI).The theoretical advantage is that endothelial cells might not b e c o m e resistant to treatment since they lack the genetic variability present in tumors. Many drugs are in preclinical or Phase I development such as VEGF tyrosine kinase antagonists (SU5416), av~3 integrin antagonists (SD983) as well as metailoproteinase inhibitors (Marimastat, in Phase 11I trials) and compounds such as the tubulinbinding agent combretastatin-A (D.J. Chaplin, Middlesex, UK).The clinical evaluation of the efficacy of most of these agents has only started. Nevertheless, it is unlikely that antivascular drugs will be useful as single agents in advanced disease. Instead, synergy with other anticancer therapies is what is h o p e d for (J.M. Pluda, NCI). Oncogene-based drug targeting. The promise of many gene therapyrelated approaches is that specific gene mutations in cancer cells may be corrected with no effects on normal, untransformed cells. Possible targets w e r e reviewed by Bert Vogelstein

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(Johns Hopkins Univ, Baltimore, MD, USA) in his lecture on 'gatekeepers' and 'caretakers' in cancer genetics. 'Gatekeepers' are genes that control cell progression through the cell cycle.While the classical tumor suppressor gene in colon epithelium is the APC gene, the gatekeeper involved in most c o m m o n cancers is not yet identified.' Caretakers" are genes that do not directly affect cell birth or death rate but maintain genetic stability.While the great majority of colon cancers do not have increased mismatch repair or mutation rate, they may have defective mitotic checkpoint genes leading to c h r o m o s o m e instability.These defects may be responsible for sensitivity of tumor cells to chemotherapy.A widely pursued target for gene therapy is the P53 tumor suppressor protein (for example, ONYX-15; Phase ID, w h i c h is k n o w n to be involved in a form of resistance to chemotherapy-induced apoptosis.The challenge n o w is to detect those downstream effects of P53 w h i c h can be targeted in order to find specific cancer therapies (Arnold J. Levine, Princeton University, Princeton, N e w Jersey, USA).At least 18 genes appear to be regulated by P53; one is MDM2, w h i c h stabilizes P53. Conditions such as vectors, routes of administration etc. are being explored by a number of groups.The

Drug Resistance Updates (1998) I, 151-152 © 1998 Harcourt Brace & Co. Ltd

biological effect aimed at by reintroduction of wild-type P53 itseff in P53-deleted cancer is inhibition of tumor growth and/or potentiation of standard chemotherapy. Other gene therapy approaches reported on w e r e the introduction of the E1A gene (Phase I trial in patients with advanced breast and ovarian cancer; G.N. Hortobagyi, MD Anderson, Houston, Texas, USA) and exposure to the enzyme cytosine deaminase in combination with 5-fluorocytosine to enhance intracellular delivery of 5fluorouracil, e.g. to purge breast cancer cells from leukaphetesis material (Albert B. Deisseroth,Yale University. N e w Haven, CT USA).These reports, as well as reports on other agents (anti-EGFR, anti-mutant RAS), s h o w the complexity of the n e w target-based approaches (Robert S. Kerbel, Sunnybrook Health Science Center, Toronto, Canada) and, though perhaps not directly leading to successffil treatment in the near future, they may be the h o p e for n e w cancer therapies in the next century. Correspondence to: Dr H.J BroxZerman,Dept. of

Medical Oncology,Academic Hospital Vrije Universiteit, P.O.Box 7057, 1007 MB Amsterdam.The NetherlandsTel:~731 20 444 2607, Fax:4 3t 20 444 3844, E-mail: [email protected]