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Integrated Chemical synthesis and Screening in patient Cells

Final ReportSummary - ICSC (Integrated Chemical synthesis and Screening in patient Cells)

The ICSC project has successfully developed a technology that uniquely is capable of identifying novel drug candidates showing efficacy in cancer cells from tumour tissue isolated from individual colorectal cancer patients. Very importantly the ICSC project was developed in direct interaction with the end-users: hospitals and academic institutions. This has led to an exciting expansion of the ICSC technology where we go from cell functional testing of individual compounds to testing of compounds in combination. We have thus been able to combine up to four different polymer-coated micro particles each carrying a drug molecule, which structure is dictated by an optical code on each micro particle. To expand the use of the technology from drug discovery to patient treatment, we have included registered drugs on the particles that are used in the adjuvant treatment of colorectal cancer patients. The technology will therefore in its finally developed form be applicable for optimization of the chemotherapeutic treatment of patients by identifying the combination of drugs that show efficacy and lack of resistance in the individual patient.

In the ICSC project, we have developed prototypes of the arrays that are to be used in future clinical testing.

Project context

The ICSC project is a 'research for small and medium-sized enterprises (SMEs)' focused project that is to develop an integrated high throughput chemical synthesis and cell-based screening platform for the development of efficacious novel drug candidates without the need for chemical- nor cell biological infrastructure. The technology will put early drug discovery into the hands of institutions that have a comprehensive knowledge of disease mechanisms and management of patients.

The technological core of the ICSC project is a newly developed high-throughput drug discovery technology, ChemoCellomics®, which integrates chemical synthesis and high throughput cell-based screening in a micro-format that allows the screening to be conducted directly in primary cells from patients. ChemoCellomics® is the first technology that merges chemical synthesis and cell-based screening. This is accomplished using a proprietary polymer with dual functionalities for chemical synthesis and cell attachment and growth. The polymer is optimised for synthesis of peptides, peptidomimetic compounds and a large panel of drug-like small molecules. The basic polymeric structure is the same used for human tissue engineering, and constitutes optimal environment for cell attachment and growth. The ChemoCellomics® technology has already proven successful in identifying novel, in-vivo efficacious compounds that through modulation of a family of intracellular protein-protein interactions show efficacy in colon cancer. The technology is presently formatted as polymer beads (300 - 400 µm in diameter) where biologically active compounds are identified by isolating beads showing the desired biological activity followed by mass spectrometry-based identification of the bead-associated compounds.

In the ICSC project, the beads are replaced by polymer-coated micro particles (250 µm round sheets) that are optically encoded. The encoding represents the synthetic history of the individual compounds, and thereby replaces the previously used highly expertise- and infrastructure demanding mass spectrometry. The small form factor of the micro carriers further allows high throughput screening to be conducted directly in primary cells isolated from patients.

It is expected that the ICSC technology will have a major impact on multiple areas within life sciences in particular drug discovery. Early drug discovery including synthesis of large chemical libraries and high throughput cell-based screening have previously been reserved pharmaceutical- and major biotechnology companies with comprehensive chemistry- and cell biological infrastructure. The philosophy behind the development of the ICSC technology is to provide institutions (hospitals, academia and small biotechnology companies) possessing detailed knowledge about disease mechanisms and patient treatment, a capability to exploit this knowledge in early drug discovery.

The project is scientifically supported by world-class researchers in the fields of chemical synthesis and modification of polymer resins and in the design and encoding of micro carriers. The SMEs will during the subsequent commercialization provide essential components of the final product. These include production of encoded micro carriers, supply of cell-specific antibodies, and preparation of final array of micro carriers including chemical library ready for cell attachment and high throughput screening.

The ICSC proto type will support the market for development of drugs against solid tumours; additionally, the technology is adaptable to most areas of human and veterinary drug discovery. The ICSC technology is not replacing an existing technology, but is providing a paradigm shift in drug discovery. It is therefore expected that the commercial impact will be considerable.

Project objectives

The main strategic goal of the ICSC project is to develop a technology that allows institutions like hospitals, universities and small biotechnology companies that are devoid of comprehensive chemistry and cell biological infrastructure to conduct early drug discovery including high throughput screening of large chemical libraries to identify novel drug candidates.

To reach this goal, we have the following science and technology objectives:

1) develop optically encoded particles where measurement of biological activity and compound decoding can be done in a DNA microarray reader;
2) establish procedures for chemical library synthesis and cell attachment on optically encoded particles;
3) successful testing of prototype including high throughput cell-based screening on defined cancerous cells from patients and identification of active compounds.

During the project period, it became apparent, after scientific discussions with end-users at the hospitals, that the ICSC technology could be applied to direct identification of the combination therapy being effective in the individual colorectal cancer patient. Such application would immediately benefit patients, and would provide a value product for the SMEs.

Medical treatment of colorectal cancer in Europe and United States (US) includes 10 individual drugs given in combinations of 3 - 4 drugs. In ICSC, we have made polymer coated microparticles holding eight of these drugs: leucovorin, irinotecan (SN38), 5-fluorouracil, oxaliplatin, doxorubicin, cisplatin, cetuximab and panitumumab. Combining these eight types of microparticles in combinations of three at three different concentrations provides more than 2000 individual treatment regimens. The microparticles are combined in wells of microarrays produced in the ICSC project by MLD. The microarrays have been designed to be read in a standard DNA microarray reader. The system produces robust and quantifiable results.

The drugs composing the efficacious combination treatment is identified by reading the optical code (described in deliverable D 2.3).

The ICSC concept has been tested on a number of cell lines as well as on primary tumour cells from patients. In all cases, cells were challenged with a combination of either three compounds or three concentrations of the same compound. The testing has reviled significant differences between patients with regard to their sensitivity against the most commonly used chemotherapeutic combinations.

Potential impact:

It is expected that the ICSC technology will have a major impact on multiple areas within life sciences in particular drug discovery. Early drug discovery including synthesis of large chemical libraries and high throughput cell-based screening have previously been reserved pharmaceutical- and major biotechnology companies with comprehensive chemistry- and cell biological infrastructure. The philosophy behind the development of the ICSC technology is to provide institutions (hospitals, academia and small biotechnology companies) possessing detailed knowledge about disease mechanisms and patient treatment, a capability to exploit this knowledge in early drug discovery.

The ICSC project has had immediate impact and is expected to have a major impact longer term.

Immediate impact:

- A comprehensive technology has been developed that opens for screening of large chemical libraries against primary cells from cancer patients.
- An easy-to-use technology has been developed that allows screening of combination libraries against primary cancer cells from individual patients (extension of the original project).
- Hospitals in Denmark (University Hospital Bispebjerg and University Hospital Rigshospitalet) and in US (University of Colorado Cancer Center) have approved to conduct clinical testing of above mentioned easy-to-use technology. Launch expected in beginning of 2012.
- The SME 2cureX has received funding from financial investors.
- 2cureX and the University Hospital Bispebjerg have received funding from the Danish Council for Strategic Research.
- Two papers accepted in international, peer reviewed journals.

Longer-term impact:

- Use of the technology at hospitals to design the combination therapy that is matched to the individual colorectal cancer patient. Such technology will both improve treatment quality and raise the cost efficiency providing a positive impact on the health care systems.
- Further, we see a huge potential in identifying novel drug candidates that in combination with established cancer treatment regimens will improve patient outcome.
- Roll-out of the technology to other cancer types than colorectal cancer.

Project website:
http://www. icsc-fp7.eu

Contact details:
Ole Thastrup
E-mail: ot@2curex.com
Tel: +45-221-15399