CAST - Cancer Stem Cell Innovation Center

SUMMARY SFI-CAST has been established by the Research Council of Norway with the aim of using knowledge about stem cell biology to improve our understanding of cancer, and to develop new therapeutic tools. SFI-CAST was hosted by the Oslo University Hospital (OUS) with the University of Oslo (UiO) as research partner. The Centre?s research activities were carried out at the OUS Radiumhospital, OUS Rikshospital, OUS Ullevål, the Oslo Science Park (Forskningsparken), Domus Medica, and the department of Chemistry at University of Oslo. SFI-CAST was headed by Prof. Stefan Krauss (director) and Prof. Ola Myklebost (co-director). The core company partners of SFI-CAST were Affitech Research AS, PCI-Biotech AS and Odin Therapeutics AS. Central academic partners were Prof. Harald Stenmark (Dept. of Biochemistry, OUS), Prof. Iver A. Langmoen (Dept. of Neurosurgery, OUS), Prof. Elsa Lundanes, Prof. Tyge Greibrokk and Dr. Steven Wilson (Dept. of Chemistry, UiO), Prof. Gunhild M. Mælandsmo, (Dept. of Tumor Biology, OUS), Dr. Therese Sørlie (Dept. of Genetics, OUS) and Prof. Ragnhild A. Lothe and Dr. Rolf I. Skotheim (Dept. of Molecular Oncology, OUS), Prof. Joel Glover (Dept. of Physiology, UiO) and Prof. Gustav Gaudernack (Dept. of Immunology, OUS). The three scientific focus areas of SFI-CAST were: (i) Development of a benchmark inhibitor of the cancer relevant WNT signalling cascade; (ii) Biomarkers in cancer stem cell programming and (iii) Stem cell based immunotargets and immunotherapy in cancer. Pathway inhibitor program WNT signalling is central in stem cell biology and is frequently de-regulated in cancer. Despite the importance of this pathway, no therapeutic substance that can block specifically the WNT signalling pathway has reached patient care. SFI-CAST has developed and extensively validated a first of its class small molecular WNT inhibitor that shows therapeutic promise in the cancer arena. The inhibitor was patented and licensed to Merck/Millipore as a research tool and work is ongoing to further advance the inhibitor towards clinical testing. In April 2013, the SFI-CAST WNT inhibitor program was featured as the cover story of Sci-Bx, a weekly publication of Nature/ BioCentury. Biomarker program Early recognition of cancer is a central requirement for therapeutic success. Therefore, an extensive international effort is ongoing for identifying therapeutic markers. Oxysterols are implied in a number of tumours, including breast cancer. SFI-CAST has developed a protocol for reliably identifying oxysterols in small samples. Furthermore, using cutting edge genome technologies such as exon microarrays and whole-transcriptome RNA-sequencing SFI-CAST researchers have identified and validated a novel biomarker, TCF7L2, that is a fusion partner to the WNT effector TCF4. In a third development, SFI-CAST researchers have analyzed key factors conferring stem-like properties to cancer cells, such as the role of HMGA2 and microRNA let-7. Immunotargets, antibodies and immunotherapy program Cancer can, by many parameters, be seen as a failure of the immune system to eliminate abnormal cells. Restoring the capability of the immune system to eliminate cancer cells is seen as a promising strategy in cancer therapy. SFI-CAST researchers have developed a unique strategy to train the immune system of patients with glioblasoma multiforme - a very severe brain cancer with high mortality - to recognize cancer cells. The protocol is based on exposing the immune system ex vivo to cancer cells that are grown under stem cell conditions. The program is at current tested in an exploratory clinical trial at the Oslo University Hospital and shows promise. Inven2, the technical transfer office of the Oslo University Hospital, is developing a commercialization program for the immunotherapy protocol. Furthermore, addressing specific cancer cells through surface molecules has been a core focus of SFI-CAST and a fruitful interaction with the industry partners PCI Biotech AS and Affitech Research AS. In particular enhanced delivery of drugs (antibody or ligand-toxin-based) targeting CD133, CD44, EpCAM and CSPG4 has been obtained. During its operational period, the SFI-CAST researchers and industry partners have published 359 peer reviewed articles showing the extensive and interactive research of the centre. SFI-CAST scientists have contributed with valuable new findings to our understanding on the role of stem cell biology in cancer. New analytical tools were identified, novel biomarkers were found, novel therapeutic compounds that address the central WNT signalling stem cell pathway in cancer were developed, and advanced concepts for immunotherapy based on stem cell properties in cancer were brought to patients. The achieved results comprise a valuable asset for the next steps on the path towards personalized medicine in the cancer arena.

The overall aim of the present project is to shift the focus in cancer research and cancer treatment from the tumor as a whole to an entity called the "tumor stem cell". Bearing in mind that with few exceptions most of our knowledge about cancer and its t reatment today is based on the characteristics of the bulk of tumors rather than that small fraction of cells with stem cell character, a shift of focus may have significant consequences. It is the firm conviction of the members of this consortium that th is will change the way we understand and treat cancer in the near future, and that it is within our reach to contribute to such a change by bringing together basic scientists from several disciplines, clinicians and partners in Norwegian biotech industry. The proposed research activities will have three main goals: 1)To characterize with innovative approaches tumor stem cells and provide methods for identifying, visualizing, isolating and targeting tumor stem cells. 2) To create a concerted action betwe en key players of the Norwegian biotechnology industry and academic researchers to use the gained knowledge for advancing tumor stem cell based diagnosis and therapy. For these goals, an integrated center will be established that allows a high mobility of researchers between the academic laboratories and the industry research facility, and between the Norwegian center and international partner laboratories. 3) Finally, by being hosted by Rikshospitalet-Radiumhospitalet, the time from laboratory discovery to actual medical diagnosis and early clinical trials will be dramatically reduced, giving the industrial partners and the hospital a much needed competitive edge.