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Project B4

RNAi Screening for Synthetic Lethalities and Treatment Response Modifiers of Targeted Therapies in Hepatocellular Carcinoma

Principal Investigators: Dr. med. Lars Zender, Dr. rer. nat. Robert Geffers

 

 

Short Summary

Hepatocellular carcinoma (HCC) is a highly chemoresistant tumor with limited treatment options. The first systemic therapy for advanced cases has only recently been introduced with the multikinase inhibitor Sorafenib. However, the gain in survival under this therapy is only marginal. Here, we propose to harness multiplex RNAi screening to i) identify synthetic lethalities profiles in hepatocellular carcinoma in order to pinpoint new innovative therapeutic targets for HCC treatment and ii) to screen for genetic determinants of sensitivity or resistance towards Sorafenib.

 

List of relevant publications

  1. Zender L, Xue W, Zuber J, Semighini CP, Krasnitz A, Ma B, Zender P, Kubicka S,Luk JM, Schirmacher P, Richard McCombie W, Wigler M, Hicks J, Hannon GJ, Powers S, Lowe SW (2008) An Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer. Cell 135:852-64.
  2. Xue W*, Zender L*, Miething C, Dickins R, Hernando E, Krizhanovsky V, Cordon Cardo C, Lowe SW (2007) P53 Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 445:656-60. (* both authors contributed equally to this work) [See also News & Views in the same issue].
  3. Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S, Lowe SW (2006) Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125:1253-67 (see Editorial on page 1230).
  4. Zender L, Xue W, Cordon-Cardo C, Hannon GJ, Lucito R, Powers S, Flemming P, Spector MS, Lowe SW (2005) Generation and analysis of genetically defined liver carcinomas derived from bipotential liver progenitors. Cold Spring Harb Symp Quant Biol 70:251-61.
  5. Krizhanovsky V, Yon, M,  Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657-67.
  6. Ross A. Dickins, Katherine McJunkin, Eva Hernando, Prem K. Premsrirut, Valery Krizhanovsky, Darren J Burgess, Sang Yong Kim, Carlos Cordon-Cardo, Lars Zender, Gregory J. Hannon and Scott W. Lowe. (2007) Tissue specific and reversible RNAi in transgenic mice. Nature Genetics 39:914-21.
  7. Trehanpati N, Geffers R, Hissar S, Riese P, Toepfer T, Buer J, Kumar M, Guzman CAm and Sarin, SK (2008) Gene expression signatures of peripheral CD4+ T cells clearly discriminate between patients with acute and chronic hepatitis B infection. Hepatology.
  8. Nickeleit I, Zender S, Sasse F, Geffers R, Brandes G, Sorensen I, Steinmetz H, Kubicka S, Carlomagno T, Menche D, Gutgemann I, Buer J, Gossler A, Manns MP, Kalesse M, Frank R, and Malek NP (2008) Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition. Cancer Cel 14:23-35.
  9. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schaffer AA, Rathinam C, Taub N, Teis D, Zeidler C, Dewey RA, Geffers R, Buer J, Huber LA, Welte K, Grimbacher B, and Klein CA (2007) novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med 13:38-45.
  10. Pfoertner S, Jeron A, Probst-Kepper M, Guzman CA, Hansen W, Westendorf AM, Toepfer T, Schrader A J, Franzke A, Buer J, and Geffers R (2006) Signatures of human regulatory T cells: an encounter with old friends and new players. Genome Biol 7:R54.
  11. Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J, Krammer P, Linderkamp O, and Suri-Payer, E (2006) Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood 108:3371-78.
  12. Lamle J, Marhenke S, Borlak J, von Wasielewski R, Eriksson CJ, Geffers R, Manns MP, Yamamoto M, and Vogel A (2008) Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 134:1159-1168.
  13. Marhenke S, Lamle J, Buitrago-Molina LE, Canon JM, Geffers R, Finegold M, Sporn M, Yamamoto M, Manns MP, Grompe M, and Vogel A (2008) Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development. Hepatology 48:487-496.
  14. Rathinam C, Geffers R, Yucel R, Buer J, Welte K, Moroy T, and Klein C (2005) The transcriptional repressor Gfi1 controls STAT3-dependent dendritic cell development and function. Immunity 22:717-728.
  15. Westendorf AM, Templin M, Geffers R, Deppenmeier S, Gruber AD, Probst-Kepper M, Hansen W, Liblau RS, Gunzer F, Bruder D, and Buer J (2005) CD4+ T cell mediated intestinal immunity: chronic inflammation versus immune regulation. Gut 54:60-69.
  16. Quentmeier H, Geffers R, Jost E, Macleod RA, Nagel S, Rohrs S, Romani J, Scherr M, Zaborski M, and Drexler HG (2008) SOCS2: inhibitor of JAK2V617F-mediated signal transduction. Leukemia.
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