Abstract 4288: Targeted therapy against aldehyde dehydrogenase in ovarian cancer

Abstract OBJECTIVE. Aldehyde dehydrogenase-1 (ALDH1) expression characterizes a subpopulation of cells with enhanced tumor initiating and differentiating properties in some cancers. We have examined the association of ALDH1 with chemoresistance and whether downregulation of ALDH1 sensitizes cells to chemotherapy in models of ovarian cancer. METHODS. Microarray profiling was performed on SKOV3ip1 and the taxane-resistant SKOV3TRip2 cell lines. Primary ovarian cancer xenografts with and without cisplatin exposure were examined for selection of ALDH1-positive cells. Small interfering RNA (siRNA) was used to downregulate ALDH1 in vitro, and in vivo by incorporation into neutral DOPC liposomes, for evaluation of chemosensitization in an orthotopic model of ovarian cancer. RESULTS. Microarray analysis found 29 genes upregulated and 18 genes downregulated by more than 10-fold when comparing the taxane-resistant SKOV3TRip2 ovarian cancer line compared to its parental SKOV3ip1 line. Included among these was a 92.7-fold higher ALDH1 signature. Increased expression and activity of ALDH1 was confirmed by Western blot and the ALDEFLUOR assay (58% of cells ALDH1-active). In primary ovarian cancer xenografts in NOD-Scid mice, cisplatin treatment resulted in an increase in ALDH1-positive cells, from a baseline of 1% to 38% with therapy (p<0.001). ALDH1-positive cells were not limited to perivascular, hypoxic, or advancing edge regions of the tumor. SiRNA constructs downregulating expression of ALDH1 were identified, and reduced viability of SKOV3TRip2 cells in vitro by 49% (p<0.001). ALDH1 targeting also reduced the docetaxel IC50 from 178nM to 82nM. In the A2780cp20 cell line (a cisplatin-resistant cell line derived from A2780), ALDH1 siRNA alone reduced growth by just 16%, but sensitized cells to cisplatin with a reduction in IC50 from 5.1 to 2.0μM. In an in vivo orthotopic model of ovarian cancer, we treated mice with control siRNA, ALDH1-siRNA incorporated into DOPC liposomes, chemotherapy, or combined chemo/ALDH1-siRNA-DOPC. ALDH1 alone or docetaxel alone had minimal effect on SKOV3TRip2 tumor growth, but ALDH1-siRNA-DOPC plus docetaxel reduced growth by 89.8% compared to docetaxel/control siRNA (p=0.003). Similarly, in the A2780cp20 model, ALDH1-siRNA-DOPC alone or cisplatin had a nonsignificant reduction, while ALDH1-siRNA-DOPC plus cisplatin reduced tumor growth by 73.4% compared to cisplatin/control siRNA (p=0.013). CONCLUSIONS. ALDH1 expression is associated with taxane and cisplatin chemoresistance in ovarian cancer cell lines. ALDH1 expression can be induced by cisplatin treatment in vivo, and targeting ALDH1 sensitizes resistant cell lines to chemotherapy. This enzyme may be important for identification and targeting the chemoresistant population in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4288.