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Oncogenomics and the development of new cancer therapies
Author: Robert L. Strausberg
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"insight review articles NATURE | VOL 429 | 27 MAY 2004 | www.nature.com/nature 469 C ancer can result from a multitude of genetic alterations. These range from point mutations to insertions and deletions to chromosomal translocations in the tumour cell?s DNA 1?3 . The completion of the human genome sequence 4,5 , rapid improvements in our understanding of the molecular basis of cancer, and the introduction of new technologies for assessing genomic, transcriptional and proteomic changes provide new opportunities for addressing the prac- tical challenges of cancer. In particular, prospects for the development of new therapeutics appear to be excellent. Important cancer-causing mutations, genomic rearrange- ments and transcriptional changes could be fully catalogued during the next decade, judging by the success of recent oncogenomics initiatives. Coordinated international research efforts analogous to the Human Genome Project (HGP) have the potential to produce an integrated database of cancer-causing mutations, and of the subsequent tran- scriptional and translational alterations. Such a database could directly identify targets for therapeutic agents. The clinical responses seen with the first generation of targeted therapeutic agents, such as the kinase inhibitor Gleevec 6 and the monoclonal antibodies Rituxan 7 , Her- ceptin 8 and Avastin 9 , have raised expectations that in future there will be an arsenal of targeted cancer therapies of high efficacy and specificity at our disposal 10,11 . Before us is an extraordinary opportunity to contribute to the development of new therapies, but how best to direct and coordinate our efforts is a question we need to investigate further and is the subject of this review. The importance of genomic technology The use of automated sequencing technology and the completion of the human genome have accelerated the identification of mutations and alterations in cancer genomes that might be ?targetable? by various therapies. The most easily ?banked? data ? and the most definitive of molecular biology data forms ? are DNA sequence infor- mation. But significant challenges remain: finding small alterations (often just a difference of a single base pair) in the genome is extremely difficult, as is making such studies comprehensive across the many types of cancer and ensur- ing that large amounts of data are reported in a meaningful fashion. Nevertheless, we are optimistic that a comprehensive mutational database is possible for most human cancers. Many parts of the genome are now being resequenced to identify somatic alterations in exons, and several important cancer mutations have been identified using this strategy 12?14 . Furthermore, advances in DNA sequencing technologies may further reduce the cost and increase the efficiency of obtaining cancer genome sequences. The availability of the human genome sequence has made alterations such as chromosomal aberrations, transloca- tions, deletions, amplifications and methylation easier to locate 2,15?20 . The new sequence-based approaches, such as digital karyotyping 21,22 , a method for detecting DNA copy number on a genomic scale, allow sequence amplifications and deletions to be discovered in a high-throughput manner. And the recently introduced bacterial artificial chromosome (BAC)-end sequencing 23 identifies chromosomal breakpoints in a comprehensive, high-resolution manner. The challenge is to gain the best from each technology so that an efficient and comprehensive analysis of each cancer can be achieved. Although much effort is focused on individual cancer types, the sequence-based nature of many approaches, with the genome as a point of reference, allows ready data- base compilation. Databases have already been established for mutations in individual genes such as p53 (ref. 24). Such initiatives could eventually serve as a focal point or model for coordinated community-wide compilations of cancer-related mutations 12,13,25 and the prospect of a more comprehensive approach. It is not just genomic technology that has improved ? methods for detecting messenger RNA have too. Micro- arrays make major contributions to this because they provide a cost-effective means of assessing and comparing mRNA levels in multiple samples 26?29 . Indeed, studies using this technology have suggested that transcription profiles allow the molecular classification of cancers, as well as insight into the biology of tumour progression 30?32 . This raises the possibility of novel approaches for diagnosing cancers and for predicting response to therapy. In addition, sequence-based approaches for gene tagging ? for exam- ple, serial analysis of gene expression (SAGE) 33?35 , massively parallel signature sequencing 36 and expressed sequence tags (including ORESTES) 37 ? provide data sets that facilitate and complement the microarray approaches. The large-scale transcript sequencing projects, such as those of the United States and Brazil, have resulted in the establishment of and presentation of data on the Cancer Oncogenomics and the development of new cancer therapies Robert L. Strausberg 1 , Andrew J. G. Simpson 2 , Lloyd J. Old 2 & Gregory J. Riggins 3 1 Department of Mammalian Genomics, The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, Maryland 2085, USA (e-mail: RLS@tigr.org) 2 Ludwig Institute for Cancer Research, 605 Third Avenue, New York, New York 10158, USA 3 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA Scientists have sequenced the human genome and identified most of its genes. Now it is time to use these genomic data, and the high-throughput technology developed to generate them, to tackle major health problems such as cancer. To accelerate our understanding of this disease and to produce targeted therapies, further basic mutational and functional genomic information is required. A systematic and coordinated approach, with the results freely available, should speed up progress. This will best be accomplished through an international academic and pharmaceutical oncogenomics initiative. STRAUSBERG new 19/5/04 1:48 pm Page 469 � 2004 Nature Publishing Group insight review articles 470 NATURE | VOL 429 | 27 MAY 2004 | www.nature.com/nature Genome Anatomy Project website (http://cgap.nci.nih.gov), a key reference for the definition of human gene expression in normal tis- sues and tumours 38 . Although sequence-based approaches such as SAGE are currently less well suited to the analysis of large numbers of samples, sequencing facilitates the discovery of new genes, thereby serving as a platform for the design of microarrays. In addition, the precise digital nature of DNA sequencing is particularly well suited to transcript quantification and the development of community- wide databases 34,38 . The continued improvements in DNA sequencing have increased the cost-effectiveness of transcript tagging, and have made it easier to obtain more information about rarer transcripts. In addition, the use of longer SAGE tags has improved the linkage of tags to specific genes and within the genome 39 . Although still expensive, full-length complementary DNA sequencing remains the ?gold standard? for both gene identification and the definition of gene structure 40,41 . Full-length cDNA sequences will be crucial for the eventual compre- hensive documentation of alternative splice forms 42?44 in cancer, and for the discovery of their biological roles in the initiation and progres- sion of the disease. Although efforts have begun 42 , these transcripts have not been comprehensively catalogued in normal cells and cancer cells, and a complete picture has yet to emerge. Increasing emphasis on full-length cDNA sequencing promises to greatly increase our knowledge of splice variants in cancer and offers the potential to identify new cancer-specific targets. An important goal for oncogenomics is the integration of com- plete genome analyses and transcriptome analyses so that accurate models of the molecular basis of cancer can be built. This step will depend first and foremost on the further decrease in cost and increase in scale of the analytical technologies. But it will also depend on how well these activities are organized: the new databases and analytical tools must be aimed at providing integrated views of the changes in cancer within cells and across diverse cancers. The need for enhanced informatics tools Database development and analysis tools were vital for the HGP. They will be equally important for the development and population of a database of the molecular biology of cancer. The goal is to incor- porate various types of genomic data (such as mutations, transcrip- tional changes and cytogenetic events) in a common database with standard terms (for example, using a common scheme for tumour classification). Already, cancer genome projects have been established that provide a starting point for this 12,34,38,45 . Given the existing template provided by the human genome sequence, it is feasible to display diverse data sets (especially those with sequence-based information) in a common framework that is accessible to all. To provide a complete view of cancer, it is important that the database contains not only information about molecular changes in cancers, but also data documenting the absence of changes in cancer, such as resequenced genes in cell lines or tumours that are found to be wild type. This will provide a more complete view of tumours and will help to avoid duplication of resequencing efforts. Similar to the HGP, the cancer genome project would need a set of standards for the data. Discovering cancer targets Central to expectations of accelerated target discovery is the percep- tion that genome, transcriptome and proteome analyses will lead to the identification of molecules against which cancer therapeutics might be targeted (Fig.1). Among many possible approaches, the three that are currently receiving the most attention are: (1) small-molecule inhibitors of oncogenic signals, (2) antibodies to surface compo- nents and intercellular communicating factors, and (3) molecularly defined vaccines. For the first of these options, obvious targets are oncogenes, such as kinases 46,47 , because of their causal involvement in tumorigenesis. The development of targeted chemical and biological agents that reduce their oncogenic function has been successful 48,49 . Oncogenes can be putatively identified by the amplification of the gene that encodes them, the over-representation of their transcript or protein in tumours, chromosomal translocation, and/or the cancer-related occurrence of activating missense mutations in their gene sequences 2 . The best example of a targeted, small-molecule oncogene inhibitor that interrupts a crucial signalling pathway is imatinib (better known by its commercial name, Gleevec), which is already in clinical use. Figure 1 Types of target identified through comprehensive genome and transcriptome analysis of cancer cells. Most genetic targets will result from a ?gain of expression?, as in the case of genes that are activated by either a point mutation or a chromosomal rearrangement that creates a new protein sequence. Targets can also be proteins with a normal sequence that are pathologically overexpressed by genomic amplifications, promoter mutations or upstream pathway activation. An example is the discovery of epidermal growth factor receptor (EGFR) genomic amplification, leading to its overexpression and increased kinase activity, which can be targeted by small molecules. Designing compounds that are toxic to cells on the basis of ?loss of expression? might be an alternative way to target cancer cells; this approach could be adopted in the case of missing tumour-suppressor proteins, a genetic event that is common in tumour development. Oncogene amplified or rearranged in genome Oncogene activated by point mutation Other oncogenic or signalling proteins with cancer-restricted overexpression Tumour-endothelium-expressed proteins Loss of tumour suppressor Loss of gene(s) in deleted region of chromosome Loss of expression of downstream gene Vital function in tumour Small molecules, biologics siRNA, ribozymes, etc. Tumour-specific and immunogenic Tumour vaccine development Monoclonal antibodies, aptamers Chemical synthetic lethal screen Lost protein is widely expressed in normal cells Cell-surface expression Target characteristics (revealed by further analysis) Therapeutic approach Loss of expression Possible targets for therapy Gain of expression STRAUSBERG new 19/5/04 1:48 pm Page 470 � 2004 Nature Publishing Group insight review articles NATURE | VOL 429 | 27 MAY 2004 | www.nature.com/nature 471 It was the observation of a ubiquitous chromosomal transloca- tion in chronic myelogenous leukaemia that first prompted the development of Gleevec. Although Gleevec was initially developed as an inhibitor of the bcr-abl kinase 6 , it is now known to inhibit a select family of tyrosine kinases, including KIT and PDGFR, in a variety of tumour types 50 . The application of Gleevec to a specific, oncogene- dependent form of sarcoma, known as gastrointestinal stromal tumour (GIST), had spectacular anti-tumour effects and provided proof that both haematopoietic and solid tumours are amenable to targeted therapy 51,52 . The frequency of relapse because of resistance currently limits the effectiveness of this treatment. The need for other treatments is stim- ulating the search for similarly effective molecules that might be simultaneously applied, as in the anti-HIV cocktail 53,54 . Part of the success of Gleevec can be attributed to the intensity and productivity of the academia?industry interaction that took place throughout its development as an anti-cancer agent. This new and effective cancer treatment would not be available today without this cooperative interaction 6,52 , nor would its wider application to include the treatment of the solid tumour GIST have been achieved 55,56 . Furthermore, the first treatment for Gleevec-resistant patients is now emerging from a similar academia?industry interaction with the development of the multi-kinase inhibitor SU11248 (ref. 57). Transcriptome and genome data also identify targets that are potentially suitable for immunotherapeutic intervention. Among the genes that are most actively sought are those that have their expres- sion restricted to one or more non-essential tissues or cells, such as the breast, the prostate or melanocytes, irrespective of disease state 58?61 . These genes are potential targets for vaccines or antibodies, because the targeted destruction of the remnants of an organ, such as the prostate, following its surgical removal is clinically acceptable irre- spective of the disease state of the individual cells. As potential targets, these molecules have the great advantage of typically being present at high levels in tumours. In addition, new genes are being discovered that are expressed in a range of tumours but are restricted in their normal expression to one or more non-essential or embryonic tissues distinct from that in which the tumour is found. A particularly strik- ing example is the growing number of cancer genes in the testis that are expressed only in tumours and in human gametes 62?64 . Although the contribution of these genes to the process of tumorigenesis is not yet known, they are important targets of potential cancer vaccines 65 . There are not, as yet, any molecular, therapeutic cancer vaccines for clinical use, although clinical trials are underway 66,67 . However, antibodies are already making a substantial contribution to therapy 68?70 . The monoclonal antibody Herceptin, for example, is targeted to the epidermal-growth-factor-like receptor encoded by the HER-2/neu gene, which is overexpressed in 20?30% of breast cancer patients. Rituxan is targeted to CD20 (which is selectively expressed on B cells) and is used for the treatment of patients with non-Hodgkin?s lymphoma both as single-agent therapy and in combination with chemotherapy 71 . Providing further optimism for the application of antibodies to cancer intervention is the recent introduction of Avastin 9 , the first targeted anti-angiogenesis agent, now approved as a treatment for metastatic colon cancer 72 . Herceptin, Rituxan and Avastin all function as naked antibodies. But antibodies can also be used to deliver toxic compounds to the tumour. Examples of this approach have already reached the clinic. Zevalin, a derivative of Rituxan ligated to the radioisotope 90 Y, is the first radio- labelled monoclonal antibody to be approved for the treatment of cancer 73 . Another example is Mylotarg, a monoclonal antibody used for the treatment of acute myeloid leukaemia. It targets CD33 and is coupled to the toxin calicheamicin, which initiates apoptosis 74 . From genomic discovery to clinical utility Mutations in certain tumour suppressors, such as p53 and APC, occur in many cancer types at high frequency. This information has raised hopes that targeted therapies could work on a broad spectrum of tumours. Although exploitation of these targets has proved to be quite challenging, several creative approaches are being explored, such as the use of selective replication of viruses in cancer cells, RNA interference or ribozymes 75?78 . For example, viruses have been engineered that selectively replicate in cells that have a loss of p53 function 75 . In the meantime, the most commonly used treatment involves the targeting of oncogenes, in particular kinases. But alterations in specific kinase genes are seen only in a subset of tumours. For example, colon cancer has a broad spectrum of low-frequency mutations in kinases, each of which could be a potential target 13,14 . This molecular hetero- geneity complicates the development of universally applicable therapies. The development of vaccines and antibody therapy against an array of cancers is similarly hampered by potential targets being found only in subsets of any tumour type. An individual tar- get is rarely present in as many as half of the tumours that arise in a given tissue 62 . Although a piecemeal approach to therapy may be unavoidable at present, a comprehensive genomic approach to the discovery of molecular alterations may identify unifying features that could result in broader-range therapies. Such common features could provide a means of targeting rare tumours or tumours more common in distinct geographical areas in a cost-effective manner. For example, in the case of kinase mutations in colon cancer, although no single mutation has been found in all of these cancers, a high proportion of cancers do have a kinase mutation, sometimes at the corresponding amino-acid position in different genes ? for example, in the autoinhibitory activation loop 13 . It is highly likely that targetable mutations (or other molecular changes) common to many cancers will be found and will open the way for the targeting of different types of tumour (including rare tumours that otherwise might not receive sufficient attention) that can be inhibited by the same agent, as in the case of Gleevec. A key to progress in this area is the establishment of assays that can indicate potential success in the clinic. Tools and assays for targeting molecular changes in cancer To discover useful small-molecule inhibitors once mutations or other alterations have been identified in cancers, several approaches (Fig. 2) are available. One clever strategy is to use two cell lines that are identical (isogenic) except for a single cancer-causing mutation for screening. For example, Kinzler and colleagues, who developed this approach, compared cells with and without a K-ras mutation 79 . The two cell lines were labelled with different fluorescent markers, then mixed together and allowed to grow in the presence of small-molecule libraries. The relative growth rates of the cells were monitored using fluorescence spectroscopy. If any of the small molecules added inhibited the growth of the cancer-causing cell line, but not the other line, then its properties were explored further. To be able to screen for inhibitors, scientists in research laborato- ries of even moderate size need to have access to materials such as diverse small-molecule libraries both for drug development and for the analysis of gene function in model systems or cell lines (Fig. 3). Although at an early stage, ways of accessing chemical libraries are being introduced, and there are strong indications that this process will continue. One such programme is the National Cancer Institute (NCI) Initiative for Chemical Genetics (ICG), which includes support for ChemBank (http://chembank.med.harvard.edu) 80 . This pro- gramme aims to systematically identify perturbational small mole- cules for each cancer-related protein coded in the human genome. This should help to better define regulatory pathway networks in cancer, thereby providing valuable information for the develop- ment of cancer treatments 81 . Coupled with the National Institutes of Health (NIH) newly announced goal ? part of its Roadmap initia- tive (http://nihroadmap.nih.gov) ? to apply small-molecule drug discovery on a genome scale 82 , as well as the increasing role of the National Human Genome Research Institute in translational STRAUSBERG new 19/5/04 1:48 pm Page 471 � 2004 Nature Publishing Group insight review articles 472 NATURE | VOL 429 | 27 MAY 2004 | www.nature.com/nature research 83 , the prospects of greater access to molecules for screening look good. Other established efforts, such as the NCI?s Rapid Access to Investigational Drugs (RAID) pro- gramme (http://dtp.nci.nih.gov/docs/raid/ raid_index.html), are providing opportuni- ties for academic (and industrial) researchers to have an active role in clinical develop- ment. Moreover, the NIH Roadmap initiative is now strongly advocating major academic participation in many areas of translational research. Although much of the emphasis has been placed by researchers on the screening of synthetic molecules created by combinator- ial chemistry, it should be remembered that the majority of clinically successful small molecules for the treatment of cancer are based on natural compounds 84 . Most of the world?s biodiversity exists in developing countries, which highlights the need to work internationally to improve cancer therapy 85 . The availability of small-molecule libraries is only a starting point. Functional data are needed for each target, testing in rele- vant animal models is required, and potential treatments (leads) have to be improved, re- tested and refined by medicinal chemists. Thereafter, the problems of good manufac- turing practice (GMP) production and regulatory approval have to be addressed before beginning to negotiate issues such as toxicology, pharmokinetics and access to tumour tissue. Similar difficulties need to be overcome for therapeutic antibodies and vaccines to be developed. For either form of immuno- therapy, the distribution of the potential target protein throughout the body will need to be determined, and for this, mono- clonal antibodies will be used as investiga- tive reagents. Although such antibodies can be raised using DNA or peptides, the use of whole protein has historically proved to be most reliable. But this requires the routine production of at least small quantities of such proteins, a process that is currently low throughput, although projects aimed at the large-scale generation (within the academic domain) of comprehensive sets of human proteins have been planned (FLEXGene) 86 . In addition, the analysis of naturally occurring immune responses to the poten- tial cancer-causing targets is important in identifying those that are most likely to be immunogenic and protective. Even after the suitability of a target has been confirmed, further challenges lie ahead: the availability of experimental therapeutic reagents, in the form of antibodies or recombinant proteins, is even more limited than it is for small-molecule inhibitors. At present, antibodies are produced in mice and then adapted for human use (?humanized?). Alternative strategies include the use of phage display libraries for antibody generation 87,88 , as well as selectively binding peptides 89,90 . The production of the quantity (grams) required for initial human trials is a major undertaking. And the production of gram quantities of highly purified recombinant proteins for vaccines, under GMP conditions, can at present only be pursued on a one-by-one basis in purpose-built facilities. For much of the academic research community, the barriers preventing the development of immunotherapy reagents are for- midable. However, they are not insurmountable. For example, the Ludwig Institute for Cancer Research has taken several potentially therapeutic antibodies, discovered by its own scientists, into clinical trials using reagents produced either in collaboration with industry or within its own biological production facilities 91?93 . Moreover, numerous vaccine trials have been undertaken by the Institute on the basis of two important and widely expressed antigens, MAGE and NY-ESO-1, both of which were first discovered by scientists at the institute 94,95 . Very recently, St Jude Children?s Research Hospital announced the construction of a large in-house production facility 1 Traditional toxicity screen Multiple cancer cell lines are grown in different small- molecule-containing media Growth arrest and cell death are markers of toxicity 2 Screening using cancer bio- markers and transcriptional assays Cells are genetically engineered to express the luciferase reporter gene under the control of an oncogenic transcription factor Small- molecule library added Oncogenic transcription factor 4 Functional screen A decrease in luciferase activity indicates molecules that inhibit transcription 3 Screening for targets for a specific mutation alteration Two genetically identical cell lines except for one cancer-causing mutation are fluorescently tagged then mixed together Cell 1 + BFP Cell 2 + YFP Small- molecule library added Small- molecule library added Small- molecule library added A reduced level of activity indicates small molecules that may be toxic Growth arrest or cell death, detected by fluorescent spectroscopy indicate toxicity Proteins with known functions ? for example, kinase activity ? are used Kinase Promoter Luciferase reporter gene Luciferase activity P P + Time Spectr oscopy Time Figure 2 Examples of general drug-screening approaches. Recently developed screens (shown in panels 2?4) take advantage of the knowledge generated by oncogenomics and move beyond the traditional toxicity screens portrayed in panel 1. Known mutations can be used to develop a controlled screen for a single alteration within isogenic cell lines 79 . BFP, blue fluorescent protein; YFP, yellow fluorescent protein. Pathways or profiles of malignant transcription can be used as biomarkers for transcriptional screens 97 . Defined oncogenic mutations can form the basis of functional screens. STRAUSBERG new 19/5/04 1:48 pm Page 472 � 2004 Nature Publishing Group insight review articles NATURE | VOL 429 | 27 MAY 2004 | www.nature.com/nature 473 for generating novel therapeutic agents, and its own staff will take forward any leads into clinical trials. Involving the entire research community Over the past few decades, the complexity and difficulty in develop- ing cancer interventions has become increasingly apparent. One informative indication of this challenge is the recent estimate that the total cost to develop a novel therapeutic is over US$800 million ? and much of this figure is accounted for by the number of failed leads 96 . It is hoped that increased industry?academia collaboration in the early assessment of potential therapeutics will significantly reduce the number of failures, and thus improve the rate of develop- ment and bring down costs. Among the important advances of the HGP is a change in thinking about research organization based on the establishment of international teams of academic and industrial scientists. We think that such collaborations will be vital for the generation of cancer therapeutics. For this to occur, academic researchers will need to adopt a more prominent role in the leadership of early-stage clinical trials (Fig. 3). We are at a crossroads where the community as a whole is accepting the responsibility for taking forward the advances that have been made in basic genomics, not only into their focused application in identifying new therapeutic targets, but also in the development of new therapies. The range of talent, approaches and organizational structures that this will bring together will certainly increase the probability of significant successes and justify the hopes that launched the HGP when it was first initiated some 15 years ago. Indeed, it is only when we can convincingly argue that the cancer victim is the real beneficiary of this endeavour that success can be claimed. a73 doi:10.1038/nature02627 1. Vogelstein, B. & Kinzler, K. W. The Genetic Basis of Human Cancer (McGraw-Hill, New York, 2002). 2. Balmain, A., Gray, J. & Ponder, B. The genetics and genomics of cancer. Nature Genet. 33 (suppl.), 238?244 (2003). 3. Popescu, N. C. Comprehensive genetic analysis of cancer cells. J. Cell. 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Recent changes Production and marketing of successful compounds Genomic and high- throughput approaches to defining new altertions Enhanced intellectual property protection resources for early non-profit research Molecular classification of tumours Novel screens based on molecular targeting Additional NIH- and foundation- funded core resources Additional NIH- and foundation- sponsored clinical trials Diverse small-molecule libraries with wide availabillity and innovation of other inhibitors Identification of mutations by single-gene approaches Intellectual property protection mainly for corporations Organ-based and historical classification of tumours Limited small- molecule libraries Cancer cell line growth screens Limited access to medicinal chemistry, toxicity screening and animal testing Drug-company- sponsored clinical trials Traditional drug discovery pipeline Figure 3 A comparison of how cancer drug development has occurred traditionally and more recently. 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