The overall aim of CHEMORES is to improve the outcome of cancer chemotherapy by developing novel tools to predict tumour response to treatment as well as individual toxicity to chemotherapy. It is not our intention to develop new cancer drugs, but rather to examine treatment failure in currently used chemotherapy regimens. The project focuses on melanoma and lung cancer, two diseases exhibiting a high degree of intrinsic and/or acquired resistance to chemotherapy. CHEMORES is a collaborative effort involving 27 research groups and companies with the ambition to integrate clinical scientists with leading preclinical research groups in the field, and also with state-of-the-art technology platforms and bioinformatics resources. Our hope is that investigation of large sets of patient tissue samples coming from several European countries, concomitant with the availability of clinical and biochemical data will allow for major breakthroughs in the field of personalized medicine, regarding the detection of novel tumour-associated biomarkers and their utility for clinical management.
The work plan for CHEMORES spans over five years, with a total budget of 8.7 million Euros, and consists of the following six main activities:
1. Identification of candidate genes of intrinsic and acquired chemotherapy resistance in large series of melanoma and lung cancer tissue specimens and serum obtained before and after chemotherapy. These studies will be performed on sequentially taken fresh frozen tumour samples and serum/plasma samples obtained from paired patients. Patient materials are derived from large clinical trials and we will use several integrated platforms for bioresources, genomics, proteomics and biostatistics that are already established by the consortium.
2. Identification of candidate genes of intrinsic and acquired chemotherapy resistance in preclinical model systems. The preclinical model systems include cultured tumour cell lines, tumour stem cells and animal models. Thus, the initial clinical and preclinical investigations (activities 1-2) are aimed at generating improved knowledge about tumour-associated genes linked to chemoresistance mechanisms and pathways.
3. Validation of chemotherapy resistance mechanisms and pathways associated with the identified genes of chemoresistance, using large series of clinical samples. Key mechanisms and pathways will be studied further in large numbers of clinical samples using high-throughput technologies, both at the genomic level and at the protein level.
4. Functional validation of potential molecular mechanisms of chemotherapy resistance using preclinical models. State-of-the-art technologies such as RNAinterference and mouse tumour models will be used in these investigations to deepen the understanding of the biological mechanisms and pathways involved in chemoresistance in melanoma and lung cancer.
5. Identification and initial preclinical development of potential novel modulators of drug resistance based on validated molecular mechanisms. The efficiency of potential modulators will be explored following definition of key mechanisms/pathways, mainly in studies using preclinical systems such as mouse tumour models and cultured cell lines.
6. Identification and validation of predictive markers of individual toxicity associated with chemotherapy. Toxicity data and biological samples (i.e. DNA) from patients participating in large clinical trials will be analysed. Detailed data on individual chemotherapy-associated toxicity will be collected, as well as pharmacokinetic data. These clinical parameters will be compared to individual biological characteristics, obtained mainly by large-scale analyses of single nuclotide polymorphisms (SNPs) in selected candidate genes. The expected outcome is a limited set of SNPs that may predict toxicity to a defined drug and can be further developed into tools to be used for prediction of individual toxicity.
The CHEMORES project is sponsored by the 6th Framework of Research and Technological Development of the EU, Priority Life sciences, genomics and biotechnology for health.
Contract number: LSHC-CT-2007-037665
Project duration: 2007-02-01 – 2012-01-31
Project coordinator: Johan Hansson (Karolinska Institutet)
Project manager: Christine Chang (Karolinska Institutet)
Project administrator: Evelyn Goransson (Karolinska Institutet)
Scientific officer: Flemming Nielsen (European Commission)