DF/HCC Program Affiliation

Sarcoma
Gynecologic Cancer

Research Abstract

We have a longstanding interest in the mechanisms of multi-drug resistance in human cancer. In the last several years, we have focused on the generation and analysis of several drug resistant human cancer lines with the goal of identifying novel mechanisms of acquired resistance to taxane. Using a variety of research tools we have defined a number of novel genes associated with the paclitaxel resistance, including TRAG-3, IL-6, MM-TRAG, GBP1 and Stat3. I have cloned the novel genes TRAG-3 and MM-TRAG. Importantly, stable expression of a GBP1 transgene in the paclitaxel-sensitive ovarian cancer cell line was sufficient to confer moderate paclitaxel resistance. TRAG-3 appears to be an important immunogenic tumor antigen and is understudy by many investigators. Our data suggest that increased expression of GBP1 and MM-TRAG may play important roles in the development of multi-drug resistance.

Currently, the principle focus of our research is on the IL-6, Jak, Stat pathway and its role in supporting the drug resistant phenotype both in cell line work and in vitro. we have confirmed and extended our previous findings that a significant proportion of drug resistant cell lines as well as tumor specimens demonstrate activation and/ or over-expression Stat3 pathway. Furthermore, we have identified two new small molecules SD-1029 and SD-1008 as small molecule inhibitors of the Jak-Stat3 pathway. Another part of our current research is to define molecular mechanisms of acquired drug resistance in human ovarian cancer by functional screen. We will use the TRC lentiviral shRNA human kinase and preselected drug resistance associated genes library to screen targets for reversing drug resistance. The screen will be performed in established ovarian multi-drug resistant cell lines. Short-term ovarian cancer cultures are also available for validation and further study. Since the role of the majority of human kinases is still largely unknown it is anticipated that this screen will identify several new kinases that might serves as therapeutic targets.

Publications

• van Vlerken LE, Duan Z, Seiden MV, Amiji MM.Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer.Cancer Res 2007 May 15;67(10):4843-50.
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• Materna V, Surowiak P, Kaplenko I, Spaczynski M, Duan Z, Zabel M, Dietel M, Lage H.Taxol-resistance-associated gene-3 (TRAG-3/CSAG2) expression is predictive for clinical outcome in ovarian carcinoma patients.Virchows Arch 2007 Jan 10.
  17216190
• Duan Z, Bradner JE, Greenberg E, Levine R, Foster R, Mahoney J, Seiden MV.SD-1029 inhibits signal transducer and activator of transcription 3 nuclear translocation.Clin Cancer Res 2006 Nov 15;12(22):6844-52.
  17121906
• Duan Z, Foster R, Bell DA, Mahoney J, Wolak K, Vaidya A, Hampel C, Lee H, Seiden MV.Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer.Clin Cancer Res 2006 Sep 1;12(17):5055-63.
  16951221
• Duan Z, Foster R, Brakora KA, Yusuf RZ, Seiden MV.GBP1 overexpression is associated with a paclitaxel resistance phenotype.Cancer Chemother Pharmacol 2006 Jan;57(1):25-33.
  16028104
• Duan Z, Lamendola DE, Duan Y, Yusuf RZ, Seiden MV.Description of paclitaxel resistance-associated genes in ovarian and breast cancer cell lines.Cancer Chemother Pharmacol 2005 Mar;55(3):277-85.
  15565326
• Duan Z, Duan Y, Lamendola DE, Yusuf RZ, Naeem R, Penson RT, Seiden MV.Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicin-resistant human cancer cell lines.Clin Cancer Res 2003 Jul;9(7):2778-85.
  12855658
• Lamendola DE, Duan Z, Yusuf RZ, Seiden MV.Molecular description of evolving paclitaxel resistance in the SKOV-3 human ovarian carcinoma cell line.Cancer Res 2003 May 1;63(9):2200-5.
  12727840
• Duan Z, Feller AJ, Penson RT, Chabner BA, Seiden MV.Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-r
  10589757
• Duan Z, Feller AJ, Toh HC, Makastorsis T, Seiden MV.TRAG-3, a novel gene, isolated from a taxol-resistant ovarian carcinoma cell line.Gene 1999 Mar 18;229(1-2):75-81.
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