Project: The development of a novel platform for “Next Generation Kinome Profiling”.

The aim of this project is to develop a novel protein kinase assay that allows a rapid identification of the activity of complete sets of protein kinases in a single patient sample. The proposed diagnostic assay developed using this technology can be used to determine the most optimal combination of kinase inhibitors for targeted and personalized treatment of patients, and to monitor treatment response. _x000D__x000D_Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. Kinases are particularly prominent in signal transduction and co-ordination of complex functions such as the cell cycle. To date over 518 distinct kinases have been identified in humans (1). A detailed explanation on the functioning of protein kinases in cellular processes can be found in the Annex. As key regulators of most cellular pathways, protein kinases are frequently associated with diseases, including multiple types of cancer, cardiovascular disease, neurodegenerative disease, diabetes, immune disease and others. As such, protein kinases are also considered important targets for therapeutic intervention._x000D__x000D_In fact, several kinase inhibitors have been approved for treatment for cancer and inflammatory diseases. Many more are under development or in clinical trials. Kinase inhibitors are one of the largest classes of new cancer drugs. More than 10,000 patent applications for kinase inhibitors have been filed since 2001 in the United States alone (2). This interest has been fuelled by the realization that kinases are intimately involved in cancer cell growth, proliferation and survival. Indeed, kinases and their direct regulators are among the most frequently mutated oncogenes and tumor suppressors. Several new cancer treatments are designed to inhibit aberrantly activated kinases within cancer cells in an effort to prevent cell division. _x000D__x000D_In general cancer cell growth is usually influenced by multiple kinases. Therefore, inhibition of a single kinase is often ineffective. Consequently the simultaneous administration of a cocktail of highly selective kinase is probably much more efficient (3) or alternatively the using of single drugs that bind to multiple proteins (4). Which kinase inhibitor combination is most effective strongly depends on the identity of the affected kinases in the tumor. The challenge is how to identify patients that are most likely to respond to a specific kinase inhibitor, predict the best combinations of targets and to prioritize those combinations for clinical testing. This is a daunting task, because the number of possible target combinations is almost limitless, but clinical trials are slow and expensive._x000D__x000D_There is an urgent need for tools that can predict which kinases inhibitors are effective and if it is necessary to inhibit multiple kinases. Kinome profiling is a powerful tool to measure the activity of cellular kinases. Unfortunately, current methods in kinome profiling are still complex, time-consuming, unreliable and inaccurate. Technical shortcomings prevent the use of kinome profiling for clinical diagnostic applications, but also hamper the identification of novel drug targets and the development of improved kinase inhibitors. Therefore, there is an urgent need for a novel rapid kinome profiling method that provides an accurate snapshot (diagnosis) of all kinase activity in a patient sample and is capable of determining which kinase inhibitor cocktail will be most effective in the individual patient and to monitor the treatment response (personalized medicine). This project will develop such a method (fig. 3 & 4). _x000D__x000D_Three expert SME companies (Pepscope BV, PEPperPRINT GmbH and PubGene AS) and one academic P (Erasmus Medical Center) will join forces to develop a “Next Generation Kinome Profiling” assay that is appropriate for such applications. To validate the prototype assay, the consortium will use colorectal cancer as a model. Despite recent advances in the field of cancer, this disease is a leading cause of death worldwide with 7.6 million casualties in 2008 (5). For colorectal cancer, several kinase inhibitors have been identified (6). Some are already approved for clinical use and others are in phase II/III clinical phases. If successful, this platform technology will also be suitable to determine kinase activity profiles in other types of cancer samples, and other diseases related to altered kinase activity. This tool will support and inform decision-making throughout the kinase drug development continuum._x000D_

Acronym KINOPRO (Reference Number: 7820)
Duration 01/03/2013 - 29/02/2016
Project Topic In this project, the consortium will develop a “Next Generation Kinome Profiling” assay. The proposed technology will be significantly superior to existing alternatives. Kinome profiling of patients will facilitate a more personalized treatment approach for diseases such as cancer
Network Eurostars
Call Eurostars Cut-Off 9

Project partner

Number Name Role Country
4 Erasmus Medical Center Partner Netherlands
4 PEPperPRINT GmbH Partner Germany
4 Pepscope BV Coordinator Netherlands
4 PubGene A/S Partner Norway