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2009 © Institute for Molecular Medicine Finland FIMM

Group Kallioniemi

Professor Olli Kallioniemi, MD, PhD, director of FIMM, is the head of the Medical Systems Biology, one of the three main research areas of FIMM. In collaboration between FIMM and the VTT Technical Research Centre of Finland our group is carrying out genome-scale cancer biology research in order to facilitate our understanding of the key steps in cancer progression and the identification of novel translational opportunities. The research focusses on breast and prostate cancer, the two most common hormonally regulated cancers. International cancer genomics consortia are now undertaking large-scale genomic, transcriptomic and epigenetic analyses of cancer. These studies are producing more and more accurate descriptions of the genomic and molecular portraits of human cancers. This provides an excellent opportunity to leverage this information to explore the functions of these genes in living cancer cell models as well as to develop diagnostic and therapeutic applications. While progress in genomic profiling technologies has been extraordinarily rapid, new methods and significant additional work is required to understand which of the genetic changes are functionally significant and which ones would have direct relevance to diagnosis and therapy.

We have developed a new technology to carry out genome-wide gene silencing in a miniaturized cell array format. Our efforts have led to an optimized platform, where up to 20,000 siRNA constructs are reverse-transfected to living cells in an array format (Mousses et al., 2003, Rantala et al., 2010). This provides a whole-genome, multi-parametric, high-content readout of the impact of genes on essential cancer cell functions. This assay is miniaturized to take place on a single microplate, hence increasing throughput and reducing cost by 100-300-fold as compared to current technologies based on 384 well plates.

We are using the new genomic and genome-scal biology tools to investigate genomic rearrangements in breast and prostate cancers, including DNA amplifications and fusion genes found by next-gen sequencing. For example, we have identified genes that are required for the survival of prostate cancer cells under androgen deprivation and have investigated micro-RNAs that regulate estrogen receptor signaling in breast cancer and androgen receptor signaling in prostate cancer. These studies are illuminating novel pathways or novel members of previously known pathways that contribute to these cancers.

We are also exploring the responses of cancer cells to commonly used drugs as a mean of identifying unexpected and novel therapeutic opportunities. In our pilot project on prostate cancer, we identified the antabus-drug Disulfiram as an effective inhibitor of prostate cancer growth at nanomolar concentrations. Molecular and genomic studies have then illuminated the potential mechanisms of the response. The combination of chemical and genetic/RNAi screens may in the future play a major role in the identification of optimal treatments for individual patients, and it will be necessary to apply the tools directly in personalized medicine. This is what we will undertake together with professors Jonathan K. C. Knowles, Kari Alitalo, Leif Andersson and Heikki Joensuu.

Selected publications:

1. Mousses S, Caplen NJ, Cornelison R, Weaver D, Basik M, Hautaniemi S, Elkahloun AG, Lotufo RA, Choudary A, Dougherty ER, Suh E, Kallioniemi O. RNAi Microarray Analysis in Cultured Mammalian Cells. Genome Res. 13: 2341-2347, 2003.
2. Kilpinen S; Autio R; Ojala K; Iljin K; Bucher E; Sara H; Pisto T; Saarela M; Skotheim R; Björkman M; Mpindi JP; Haapa-Paananen S; Vainio P; Edgren H; Wolf M; Astola J; Nees M; Hautaniemi S; Kallioniemi O. 2008. Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues. Genome Biology, vol. 9:R139, 2008.
3. Varjosalo M, Björklund M, Cheng F, Syvänen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He, W-W, Ojala P, Taipale J. Application of Active and Kinase-Deficient Kinome Collection for Identification of Kinases Regulating Hedgehog Signaling. Cell 133, 537 – 548, 2008.
4. Leivonen SK, Mäkelä R, Ostling P, Kohonen P, Haapa-Paananen S, Kleivi K, Enerly E, Aakula A, Hellström K, Sahlberg N, Kristensen VN, Børresen-Dale AL, Saviranta P, Perälä M, Kallioniemi O. Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines. Oncogene. Aug 17, 2009.
5. Iljin K, Ketola K, Vainio P, Halonen P, Kohonen P, Fey V, Grafström RC, Perälä M, Kallioniemi O. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res. Oct 1;15(19):6070-8, 2009

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