Abstract 4476: Targeting Wnt5a and STAT3 pathways for the treatment of prostate cancer

Abstract

Abstract Background and Aims Wnt5a protein levels are upregulated in prostate cancer (PCa) compared to benign tissue and patients with high Wnt5a protein levels have a better outcome after radical prostatectomy compared to patients with low Wnt5a levels (Syed Khaja AS, 2011; 2012). Thus, the reconstitution of the Wnt5a signaling pathway could be a promising therapeutic approach in PCa, as already shown in breast cancer (Säfholm A, 2008). Constitutively active STAT3 (pSTAT3) has been correlated to PCa progression and disruption of its signaling pathway could represent a promising strategy for the treatment of patients with advanced PCa (Hellsten R, 2008). We have analyzed the expression of Wnt5a and pSTAT3 in a cohort of patients with metastatic Castration Resistant Prostate Cancer (mCRPC). Using in vitro and in vivo techniques we have explored the effect of the Wnt5a-mimicking peptide FOXY5 for the reconstitution of the Wnt5a pathway in PCa, and we have studied the effect of the STAT3 inhibitor Galiellalactone (GL) on PCa cell viability, apoptosis, invasion, tumor growth and metastases. Methods Wnt5a and pSTAT3 protein expression was analyzed by IHC on a TMA construct with duplicate cores of malignant tissues from 38 patients with mCRPC. Statistical and correlation analyses were performed using the SPSS version 21. Cell viability was determined by MTT assay; apoptotic cells were visualized with M30 CytoDeath antibody 24h after treatment with FOXY5 or GL. Cell invasion was analyzed using matrigel pre-coated cell culture inserts in the presence or absence of FOXY5 or GL. For the animal study, NMRI nude mice were injected orthotopically with 1×106 DU145-Luc cells, and treated IP with GL every day or with FOXY5 every second day. Primary tumor growth and metastatic spread were evaluated weekly by in vivo luminescence using the IVIS Lumina II system. 9 weeks after injection animals were sacrificed and organs were analyzed for the presence of metastases. Results IHC analyses of TMA showed high pSTAT3 and low Wnt5a expression in CRPC patients, with a small but significant correlation (r = 0.4646; p = 0.0038). Our results show that GL inhibits viability and induces apoptosis of DU145-Luc cells in vitro, and that it reduces tumor growth and metastatic spread to lymph nodes in vivo. FOXY5 treatment has no effects on cell viability or on primary tumor growth, but it significantly reduces cell invasion in vitro and metastatic spread to lymph nodes in vivo. Conclusions Our results confirm that the reconstitution of the Wnt5a pathway and the inhibition of the STAT3 pathway are a promising therapeutic approach for the treatment of mCRPC. We found that GL and FOXY5 are good candidates for the treatment of mCRPC, as they inhibit tumor growth and metastatic spread to lymph nodes. Since these two compounds act through different mechanisms, our future studies will explore the possibility of a combination of GL and FOXY5 for the treatment of PCa. Citation Format: Giacomo Canesin, Susan Evans-Axelsson, Rebecka Hellsten, Nicholas Don-Doncow, Tommy Andersson, Anders Bjartell. Targeting Wnt5a and STAT3 pathways for the treatment of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4476. doi:10.1158/1538-7445.AM2015-4476