EUREKA PROJECT > 4184 TOBEFOUND
THE NETHERLANDS
Translational Biomarkers for Innovative Medicine Development
To identify and generate translational kinase biomarkers for non-small cell lung cancer in order to develop innovative medicines and to correlate and predict in-vitro and in-vivo drug effects.
Status > FINISHED - 16-Dec-2009 Technological Area Market Area Start Date > 30-Sep-2007 Duration > 24 Months Participating countries > THE NETHERLANDS, BELGIUM | Main contactPAMGENE Mr. Theo Van Der Leij > Chief Operations Officer Organisation type > SME |
Project Description
The pharmaceutical industry is continuously searching for novel and faster ways to discover and develop new medicines. A very promising and innovative methodology to improve the efficiency of the pharmaceutical process is the generation and use of translational biomarkers. Scientific research shows that various types of cancer entail the explicit expression of specific proteins and an over-activity of protein kinases. Tumour cells start to grow by the activation of protein kinases. Up to 30% of all proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in the transmission of signals within the cell. Protein kinases have profound effects on cell growth and deregulated kinase activity is a frequent cause of cancer. Protein kinases can serve as excellent biomarkers since kinases regulate many aspects that control cell growth. Researchers are now able to identify specific kinases that are expressed or modified differentially in samples from healthy persons (or controls) versus those from patients with disease. Drugs which inhibit specific kinases can then be developed to treat specific types of cancer. Translational biomarkers can mean a significant breakthrough in the pharmaceutical process, not only in the selection of relevant patients for clinical trials, but also in providing early and reliable diagnostic tests. The main objective of the EUREKA project TOBEFOUND is to generate translational kinase biomarkers for non-small cell lung cancer (NSCLC) which allow for the development of new medicines and the prediction of in-vitro and in-vivo drug effects. Lung cancer is the number one cause of death from cancer, largely due to late diagnosis, which makes effective treatment difficult. Non-small cell lung cancer (NSCLC) accounts for 75-80% of lung cancers and it is the type of lung cancer most often studied in clinical trials. The project partners have already carried out an initial feasibility study into the functioning of multiplex biomarkers for NSCLC, related to a wide spectrum of upstream kinase targets (tyrosine). The EUREKA project aims to further explore and investigate these biomarker profiles using cancer cell lines, xenografts (pseudo animal tests) and clinical samples (human tissues). For a more accurate and reliable prediction, more subtle effects need to be investigated. In order to allow for more subtle investigations of the kinase activity and effects, new biomarker tests (chip arrays and assays) will have to be designed and investigated, containing specific tyrosine kinase targets. In addition, in order to complete the understanding of the signalling pathways, downstream kinase targets (serine-threonine) will also be investigated. To achieve this, new biomarker tests will be set up and investigated, containing serine-threonine kinase targets. Furthermore, this EUREKA project aims to correlate the interplay between kinase targets and their genetic mutations, as they play a significant role in patient response prediction. To investigate the various kinase mutations, new tests will be generated, containing specific tyrosine kinase mutation targets. Summarising, translational multiplex biomarker profiles will be investigated for 3 targets: 1) Tyrosine kinase targets; 2) Serine-threonine kinase targets; 3) Tyrosine kinase mutation targets. If the definition phase is completed successfully, the project partners hope to obtain the following results: 1. Specific chip arrays and assays; 2. Translational multiplex kinase biomarker profiles; 3. A database with predictive in-vitro and in-vivo drug effects. These results will then allow the project partners to proceed to further drug development and to initiate the preparatory steps for the first clinical trials. Keywords: medical technology, translational, biomarkers.
Technological Development Envisaged
There are two main types of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC accounts for 75-80% of lung cancers. Thus, this is the type of lung cancer most often studied in clinical trials. There are different types of treatment for lung cancer: surgery, radiation therapy and chemotherapy or a combination of these treatments. Although chemotherapy remains the standard of care for lung cancer, new less toxic drugs are urgently needed. Translational biomarkers are becoming more widely used now in many aspects of drug discovery and drug development. Biomarkers are not only useful for drug development to partially curtail the expensive trials, but they can also serve to make critical decisions about whether or not a drug should be continued beyond the clinical stage of development. Additionally, biomarkers are increasingly being used for patient selection with respect to responses to targeted therapies, cancer research and research into various disease states. Scientific research shows that various types of cancer entail the explicit expression of specific proteins and an over-activity of protein kinases. As the cancer progresses, certain proteins are being produced. Tumour cells start to grow by the activation of protein kinases. Kinases are known to regulate the majority of cellular pathways and cell growth and deregulated kinase activity is a frequent cause of cancer. Protein kinases can serve as excellent biomarkers since kinases regulate many aspects that control cell growth. Tyrosine kinases are a subgroup of the larger class of protein kinases and a high level of tyrosine kinase activity is often related with tumour growth. It is therefore important not only to understand the tyrosine kinase actions, but also to understand and characterise the agents that inhibit (inhibitory agents) the tyrosine kinase activity. The EUREKA project TOBEFOUND aims to investigate translational multiplex biomarker profiles for 3 targets, being: 1. Tyrosine kinase targets; 2. Serine-threonine kinase targets; 3. Tyrosine kinase mutation targets. An exciting target is the human epidermal growth factor receptor (EGFR, i.e. HER1), and agents targeting this receptor, including gefitinib, cetuximab, and erlotinib (OSI-774; Tarceva(TM)), are being investigated. These agents have anti-tumour activity and are less toxic than most therapies. Patient characteristics may also affect outcome, and research is ongoing to identify predictive markers of response to enable patient selection and improve outcome. Recently identified mutations within the HER1/EGFR tyrosine kinase (TK) domain may provide insight into why some patients respond rapidly to HER1/EGFR tyrosine kinase inhibitors. Surrogate markers of efficacy are also being investigated, which could be used to monitor and optimise anti-tumour activity. Therefore, although more work is required, data indicate that HER1/EGFR inhibitors will play an important role in treating patients with NSCLC.
Main contactPAMGENE Mr. Theo Van Der Leij > Chief Operations Officer Organisation type > SME |
Contribution to project
The organisation's 3 dimensional flow-through micro-array technology offers alternative, new approaches to drug discovery, clinical diagnostics and basic research. PAMGENE provides detailed and unique information for intelligent compound selection in the preclinical research phase to pharmaceutical and biotechnology companies. Together with industrial and academic partners PAMGENE has developed a technology platform for working out protein kinase pathways. The data generated by PAMGENE are generated in real-time, therefore IC50, Ki and mechanism of action information can all be determined in only a few hours. The main advantage of the PAMGENE array technology is that side-effects from potential drug compounds, normally detectable only at the clinical trial stage, can be detected very early in the pre-clinical phase. The clinical research phase is often the most critical phase and determines the introduction of the compounds in the market. The discrimination between different patient groups and the ability to predict possible efficacy of compounds is being increasingly demanded by the authorities. The 'fingerprints' generated with Tyrosine Kinase and Serine/Threonine Kinase PamChip(R) Micro-arrays kinase chips are helpful tools in the stratification of patients and can serve as biomarkers or even diagnostic markers to comply with the increasing demand for more 'personalised medicines'. In order to investigate the translational biomarker profiles PAMGENE will use its PamStation96. This fully automated integrated system is designed for processing PamChip(R) 96 plates. It is ideal for high throughput micro-array-based screening-applications. Up to 96 arrays can be analysed at one time and up to 48 plates can be processed per day. It is possible to alter the temperature on-line (20 degrees Celsius - 80 degrees Celsius) and watch experiment progress in real-time; ideal for generating melting curves. The real-time detection of the PamStation96 offers a unique capability of generating kinetic data on enzyme/substrate interactions. PAMGENE will be responsible for the following project activities: * Tyrosine biomarker profiles; * Serine-threonine biomarker profiles; * Correlation kinase and mutation targets. Furthermore, PAMGENE will be responsible for the overall project management.
Expertise
The organisation (PAMGENE, www.pamgene.com) is a small (36 people) and young (2000) post-genomics company, translating its unique micro-array technologies, with the theme of fast multi-marker testing, into complete products for both diagnostics and pharmaceutical laboratories. PAMGENE is anchored in science and business through the support of an array of international well-known scientists and universities as well as through commercial relations with first class companies such as OLYMPUS (www.olympus.co.jp) and INNOGENETICS (www.innogenetics.com). This gives PAMGENE a unique position to have the insights into healthcare from both academia and industry. Its 3-dimensional flow-through micro-array technology is used for analysis of both proteins and nucleic acids. PAMGENE supports drug discovery in areas including compound profiling in diseases concerning, amongst others, kinases. Selectivity and potency data, quickly and easily generated on PAMGENE's PamStation(TM) instruments, enables pharmaceutical companies to select compounds with improved chances of success in drug development.
Main contactJANSSEN PHARMACEUTICA N.V.
Mr. Henk Sipma > Assistant director Drug Discovery Contracts http://www.janssenpharmaceutica.be Organisation type > Large company |
Contribution to project
JOHNSON & JOHNSON and PAMGENE have carried out an initial exploration into the development of multiplex biomarkers for non-small cell lung cancer, related to a wide spectrum of upstream kinase targets (tyrosine). The EUREKA project aims to further explore and investigate these biomarker profiles using cancer cell lines, xenografts (pseudo animal tests) and clinical samples (human tissues). The EUREKA project has the ambition to correlate in-vitro and in-vivo drug effects. For a more accurate and reliable prediction, more subtle effects need to be investigated. For this, new biomarker tests (chip arrays and assays) will be designed by PAMGENE and tested by JOHNSON & JOHNSON (J&J). Where PAMGENE has the chip and micro-array expertise, J&J has the compound know-how and pharmaceutical expertise to carry out pre-clinical tests. To complete the understanding of the signalling pathways, downstream kinase targets (serine-threonine) and kinase-related-off-targets will be investigated. To accomplish this, new biomarker tests will be set up and investigated, containing serine-threonine kinase targets. The specific tasks of J&J are: 1. To generate specific biomarker profiles (including off-target effects) with J&J owned compounds and reference compounds. 2. To translate profiles from compound related J&J owned cell-lines to ex-vivo (patient) material. 3. To prepare all biological material, including cell-lines, xenografts and ex-vivo materials. 4. To execute complementary experiments to further scientifically prove/investigate generated hypotheses on pathways and mechanism-of-action.
Expertise
The organisation is part of the world's largest healthcare company, JOHNSON & JOHNSON, and enjoys an international reputation for pharmaceutical innovation and quality. JANSSEN PHARMACEUTICA benefits significantly from the expertise of the prestigious global R&D company, Johnson & Johnson Pharmaceutical Research & Development (PRD). They are committed to providing innovative, cost effective, knowledge-based products which improve health and the quality of life, through encouraging decentralised, entrepreneurial efforts and active partnerships with companies inside and outside the organisation. Innovation is placed at the centre of their culture, and they reward it, create structures to maximise it and fund significant internal and external research. In the tradition of functional autonomy, they are motivated by an entrepreneurial spirit. JOHNSON & JOHNSON has a decentralised approach to R&D: experience has taught them they are much better off having small groups of dedicated scientists working with as little bureaucracy as possible and a sense of ownership and accountability for business. Let them do their own thing and good things will happen. This decentralised approach to R&D gives the companies freedom, flexibility and resources to define their own priorities and to collaborate as needed. They are all bound together by guiding principles of the Credo, the statement of shared values. Flat, flexible structures eliminate hierarchical barriers and facilitate critical team-based activities throughout the drug development process. Teams and individuals are truly empowered. For example, when a PRD drug reaches the development stage, it becomes the responsibility of a Global Product Team (GPT), a new structure created to drive drug development through the entire product life cycle. Operating entrepreneurially as integrated business units, these teams move decision making to a more horizontal process, thereby facilitating a faster delivery of results and a more efficient use of resources. In the fashion of a virtual company, each team is charged with making the critical decisions to support global development needs and move its product through the pipeline. JANSSEN PHARMACEUTICA maintains active partnerships with the companies who market their products. They also work closely with major centres of clinical development through local operating companies worldwide. The R&D technology infrastructure is being enhanced to maximise all aspects of global research and development. Common systems are being developed for business critical processes, including those supporting clinical research and development, regulations, pharmacovigilance and the provision of electronic dossiers to regulatory authorities. They also develop valued partnerships with other pharmaceutical and biotechnology companies, academic institutions and technology vendors, combining centres of excellence to our mutual benefit. Based in BELGIUM, JANSSEN PHARMACEUTICA was established in 1953 by a young medical doctor, Dr. Paul Janssen. Unlike most pharmaceutical companies, it was created not as a subsidiary of a chemical factory, but solely with the aim of conducting pharmacological research. One objective of the company has always been the continuous development of better drugs to improve the quality of life. In 1961 JANSSEN PHARMACEUTICA joined the JOHNSON & JOHNSON GROUP of companies. With more than 80 drugs to its name, JANSSEN is one of the most innovative pharmaceutical companies in the world and its products have found major applications in human medicine. In BELGIUM alone, the company employs over 3,700 people, more than a third of whom are graduates. No fewer than five JANSSEN drugs are on the current World Health Organisation's List of Essential Drugs. JANSSEN PHARMACEUTICA is part of the world's largest healthcare company, JOHNSON & JOHNSON, and enjoys an international reputation for pharmaceutical innovation and quality. The medicines discovered and developed by the R&D organisations of JANSSEN PHARMACEUTICA are marketed predominantly by their own sales and marketing forces, which are respected by members of the medical community throughout the world. The early foundations of this international network were laid by CILAG (1936) and JANSSEN PHARMACEUTICA (1953). Both companies established medical marketing and sales operations in various countries to support the medicines discovered in their laboratories. When, in the early 1990s, healthcare systems around the world underwent massive changes, it was decided to combine these local operations under a single name, Janssen-Cilag, in countries where both had a presence. This unified structure allows increased flexibility and customer responsiveness, and ensures the optimum use of resources. The local companies are responsible for registration, clinical development, medical information and sales in the local markets. The strength lies in what they value: customers, innovation, integrity, people and performance. The company's worldwide research and development centre, Johnson & Johnson Pharmaceutical Research & Development is conducting research and development into a wide range of human disorders, including mental illness, neurological disorders, anaesthesia and analgesia, gastrointestinal disorders, fungal infection, allergies and cancer. In almost no other industry are the products and production processes subjected to such thorough checks as in the pharmaceutical industry. The ultimate goal of all this effort is the manufacture of pure and safe drugs, which each and every patient is entitled to expect. To satisfy such stringent criteria, Janssen-Cilag is committed to permanent effort and substantial investments in manpower and equipment for its chemical and pharmaceutical production facilities.