Arcaro
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Onkologie, Abteilung » Prof. Dr. Felix Niggli » Arcaro
Completed research project
| Title / Titel | Cancer and Cell Biology | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | Common tumors in children include leukemia, brain tumors and neuroblastoma. Current treatments of childhood malignancies such as radiotherapy and chemotherapy are inefficient, due to the resistance of the tumor cells to apoptotic signals. Promising new therapies are, however, emerging, which are based on blocking receptor tyrosine kinase (RTK) signalling to some of their downstream signalling targets such as phosphoinositide 3-kinase (PI3K), protein kinase B (PKB) /Akt, the mammalian target of rapamycin (mTOR) or mitogen-activated extracellular signalregulated kinase activating kinase (MEK). We want to further study the potential of targeting PI3K signalling as a novel therapeutic approach for childhood malignancies. PI3Ks are a family of eight enzymes in humans, which are subdivided into 3 classes (I-III), based on sequence homology and substrate specificity. Class I and II PI3Ks transduce signals from RTKs, such as the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor (IGFR), that control cell growth and proliferation, survival and motility. The importance of PI3K signalling in the context of human glioblastoma and acute myeloid leukemia (AML) is underscored by the high frequency of mutations in the tumor suppressor gene phosphatase tensin homology (PTEN), which encodes a lipid phosphatase that antagonises the action of PI3K. Since class I and II PI3Ks are composed of 7 different isoforms, a precise knowledge of the expression pattern and regulation of these enzymes in childhood malignancies is a pre-requisite for the design of pharmacological approaches aimed at inhibiting PI3K signalling in the cancer cells. We will attempt to inhibit the function of distinct PI3K isoforms in AML, glioblastoma, and neuroblastoma cell lines, by transfecting dominant negative mutants or RNAi constructs, and study their impact on tumor cell responses such as growth, chemoresistance, radioresistance and motility. Together the planned studies will hopefully lead to the identification of novel targets for pharmacological inhibitors, leading in turn to the development of new drugs for childhood malignancies. |
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| Publications / Publikationen | Arcaro, A., Aubert, M., Espinosa del Hierro, M.E., Khanzada, U.K., Angelidou, S., Tetley, T.D., Bittermann, A.G., Frame, M.C., and Seckl, M.J. (2007). Critical role for lipid raft-associated Src kinases in activation of PI3K-Akt signaling. Cell. Signal., in press, doi: 10.1016/j. cellsig.2006.12.003 Guerreiro, A.S., Boller, D., Shalaby, T., Grotzer, M.A., and Arcaro, A. (2006). Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin-like growth factor receptor inhibition. Int. J. Cancer, 119, 2527-2538 Khanzada, U.K., Pardo, O.E., Meier, C., Downward, J., Seckl, M.J., and Arcaro, A. (2006). Potent inhibition of small cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling. Oncogene, 25, 877-887 Doepfner, K.T., Boller, D., De Laurentiis, A., Guerreiro, A.S., Marinov, M., and Arcaro, A. (2007). Recent Patents of Gene Sequences Relative to the Phosphatidylinositol 3-kinase / Akt Pathway and their Relevance to Drug Discovery. Recent Patents on DNA & Gene Sequences, 1, 9 Guerreiro, A.S., Boller, D., Doepfner, K., and Arcaro, A. (2006). IGF-IR: Potential Role in Antitumor Agents. Drug News & Perspectives, 19 (5), 261-272 Project 4417 Seite 1 Arcaro, A., Khanzada, U.K., Vanhaesebroeck, B., Tetley, T.D., Waterfield, M.D., and Seckl, M.J. (2002). Two distinct phosphoinositide 3-kinases mediate polypeptide growth factor-stimulated PKB activation. EMBO J., 21, 5097-5108 Arcaro, A., Zvelebil, M.J., Wallasch, C., Ullrich, A., Waterfield, M.D. and Domin, J. (2000). Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol. Cell. Biol., 20, 3817-3830 Arcaro, A., Volinia, S., Zvelebil, M.J., Stein, R., Gout, I., Layton, M.J., Ahmadi, K., Watton, S.J., Downward, J. and Waterfield, M.D. (1998). Human phosphoinositide 3-kinase C2beta, the role of calcium and the C2 domain in enzyme activity. J. Biol. Chem., 273, 33082-33090 |
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| Keywords / Suchbegriffe | Acute myeloid leukemia, glioblastoma, medulloblastoma, neuroblastoma, phosphoinositide 3¬kinase, protein kinase B/Akt, receptor tyrosine kinase, epidermal growth factor, apoptosis | ||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Other links to external web pages | http://www.kispi.uzh.ch/onkologie/ http://www.cnz.uzh.ch/arcaro.html | ||||
| Funding source(s) / Unterstützt durch |
Other Public Sources (e.g. Federal or Cantonal Agencies), Foundation Foundation Krebsliga Zürich, Oncosuisse, Stiftung zur Krebsbekämpfung, Fondation FORCE,Ida de Pottére-Leupold-Fonds zur Förderung der Krebsforschung, Novartis Stiftung für Medizinisch-Biologische Forschung, Stiftung für Molekularbiologische Tumorforschung |
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| In collaboration with / In Zusammenarbeit mit |
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| Duration of Project / Projektdauer | Jan 2007 to Dec 2009 |