Abstract 428: Dual E-selectin and CXCR4 inhibition reduces tumor growth and increases the sensitivity to docetaxel in experimental bone metastases of prostate cancer

Abstract

Abstract Prostate cancers preferentially metastasize to the skeleton where the bone microenvironment can stimulate excessive tumor cell growth and spread, and promote the emergence of clinically-resistant disease. An improved understanding of the complex relationship between prostate carcinoma (PCa) cells and the bone microenvironment has created a powerful opportunity to develop novel therapies. PCa cells preferentially roll and adhere on bone marrow vascular endothelial cells, where constitutive E-selectin expression and abundant stromal cell-derived factor-1α (SDF-1α) are expressed and interact with E-selectin ligands and CXCR4 present on PCa cells. These molecular interactions initiate a cascade of activation events that lead to the development of treatment resistant metastases. This suggests that agents able to antagonize these molecular interactions may be used as pharmacological treatments of bone metastatic disease. In the current studies we investigate if a dual E-selectin/CXCR4 inhibitor (GMI-1359) could impact the intraosseous growth of the metastatic, androgen-independent PC3M cell line and affect chemosensitivity to docetaxel. PCa cells, including PC3M, selected for increased visceral and bone metastatic potential express high levels of E-selectin ligands and CXCR4 as compared to nonmetastatic PCa cell lines. We evaluated the ability of GMI-1359 administered alone or in combination with docetaxel to inhibit the growth and metastasis of intratibially implanted luciferase-transfected PC-3M cells. Approximately two weeks post tumor cell implantation, mice were treated by intraperitoneal injection for 2 weeks with either saline twice daily; 40 mg/kg GMI-1359 twice daily, 5 mg/kg docetaxel once weekly or a combination of GMI-1359 and docetaxel. Thirty-five days after initiation of treatment, the percentage of tibiae positive by X-ray and the size of osteolytic lesions was impacted by treatment with GMI-1359 alone or in combination with docetaxel. Docetaxel alone had only a modest impact on intraosseous lesions. Lytic units were reduced by 38%, 78% and 88% in mice treated with docetaxel alone, GMI-1359 alone, or GMI-1359 in combination with docetaxel, respectively. The significantly reduced intraosseous growth of PC3M cells correlated with decreased serum levels of both mTRAP and type I collagen fragments. Our data provides a clear biologic rationale for the use of a dual E-selectin/CXCR4 inhibitor as an adjuvant to taxane-based chemotherapy in men with high-risk prostate cancer to prevent bone metastases. Given its complementary mechanism of action to traditional chemotherapy, GMI-1359 warrants further development not only in prostate carcinoma, but also in other malignancies where tumor cells are likely to spread to bone. Citation Format: Giovanni L. Gravina, Andrea Mancini, Alessandro Colapietro, Simona D. Monache, Adriano Angelucci, Alessia Calgani, William E. Fogler, John L. Magnani, Claudio Festuccia. Dual E-selectin and CXCR4 inhibition reduces tumor growth and increases the sensitivity to docetaxel in experimental bone metastases 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 428. doi:10.1158/1538-7445.AM2015-428