The CanCure Research Plan

Main goals

The purpose of this project is to substantially improve opportunities to evaluate molecular effects during treatment of colorectal cancer (CRC), leading to progress in drug discovery and in clinical practice. We will establish tools and resources that can assist the development of novel therapies targeting specific mutated oncogenes or oncogenic cancer pathways, as well as prediction of responses to such agents. First, we will build on our own and public knowledge of mutated genes and pathways in CRC to generate isogenic cell lines with defined genetic lesions in these genes and pathways. Second, we will further develop a set of molecular tools, originated by the partners, that will allow us to determine activities of these genes and pathways in scalable formats, suitable for multiplex high-throughput screening. Third, these resources will be combined in a high-content screening demonstrator to determine the effects of established and experimental drugs, both in cell lines and in patient samples. The three scientific workpackages of the project will bring together research groups with complementary technical, biological and clinical expertise, and we will work closely with companies with interests in research tools, laboratory tests and drug development. The project will exploit a valuable set of resources available to the partners.

 

 

The problem

Cancer is, in essence, a genetic disease caused by the accumulation of mutations in genes in specific molecular pathways controlling cellular growth and spread. Recent genomewide mutational analyses by a partner in this application and others have uncovered several hundred novel candidate cancer genes in breast and colorectal cancers. A modest number of genes are mutated in tumors from a large fraction of patients, while a substantial number of genes are mutated in 1-5% of tumors. Despite the genelevel complexity, many mutated genes align in a limited number of molecular pathways frequently altered in cancer, e.g. the KRAS, TP53, TGFB, EGFR, and PIK3CA pathways. The recent introduction of several new, targeted drugs has expanded treatment options in cancer. Nevertheless, only minor progress has been achieved in adult oncology over the past few decades, with an overall reduction in mortality rate of only ~10%. The medical treatment regimens are currently administered to unselected patient populations; in general it is not possible to identify individual tumors likely to respond to specific therapies. This lack of predictors of response applies to all medical antitumor treatments - conventional cytotoxic drugs as well as more recently introduced targeted drugs. Thus, two linked areas in dire need of development are 1) discovery of novel cancer drugs; and 2) development of positive predictors of tumor response. Present knowledge about the performance of cancer drugs targeting oncogene products suggests that successful therapeutic concepts should simultaneously target several different pathways for enhanced therapeutic efficacy and to limit the emergence of compensatory mutations. However, methods have been lacking to simultaneously assess the activities of multiple genes and pathways in drug discovery. Accordingly, the screening for new promising lead compounds for therapy, as well as diagnostic, prognostic and predictive testing in cancer will require clinically relevant tumor models and scalable, cost-effective, and high-performance methods to assess the status of proteins and nucleic acids in affected pathways in cell lines and in patient samples. In combination, such new tools and markers could guide the development and clinical use of targeted cancer therapies, thereby fundamentally influencing drug development, as well as clinical genetics, pathology, and oncology.

The opportunity

Uppsala presently holds a critical combination of expertise in the form of preclinical and clinical research groups, infrastructure, and biotech companies, together providing opportunities to create and to apply radically improved tools for cancer drug development and diagnostics. Techniques beyond state-of-the-art for analysis of protein and nucleic acid markers, a world-leading resource of protein-binding antibodies and information about their tissue reactivity, a nationally leading center for next generation DNA sequencing, state-of-the-art expression profiling, high-throughput screening and bioinformatics, together with advanced clinical expertise and large biobanks from patients with CRC, jointly offer valuable opportunities to establish tools for drug development and new predictive tests, using CRC as a model cancer type. This proposal aims to address the need for improved drug development and therapy selection for individual patients generally, by building on our recent discoveries in cancer genomics and proteomics and our high-performance molecular technologies and reagent resources, to create and analyze stringent genetic model systems and collections of patient samples. The work will be conducted in the course of three interlinked scientific workpackages.