Abstract 549: Sensitization to chemotherapy by inhibition of cathepsin proteases in a mouse model of metastatic breast cancer

Abstract

Abstract A growing body of evidence supports the role of the tumor microenvironment in promoting malignant progression and modulating the response to anti-cancer therapy. Tumor associated macrophages (TAMs) have been established as an important component of the tumor microenvironment, contributing to angiogenesis, matrix remodeling, invasion and metastasis. We and others have identified cysteine cathepsin proteases as key effectors of these pro-tumorigenic functions of TAMs. These same processes, which are integral to tumor progression, may also aid tumors in recovering from cytotoxic insults, thereby blunting our therapeutic efforts. There is thus a strong rationale for combinatorial targeting of both the tumor and the supporting stroma. We have uncovered such a phenomenon in a mouse model of metastatic mammary carcinogenesis (MMTV-PyMT). Following maximum tolerated dose paclitaxel treatment (TaxMTD), we observed an elevation in levels of circulating cathepsin-activity+ myeloid cells and a subsequent increase in macrophages and cathepsin activity levels in the tumor. In co-cultures, cathepsin-activity+ macrophages reduced paclitaxel-induced tumor cell death. Furthermore, the use of primary macrophages from various cathepsin null genetic backgrounds identified cathepsins B and S as mediators of this effect. To determine whether cathepsin inhibition could therefore enhance the effects of chemotherapy, we treated MMTV-PyMT mice with both TaxMTD and a pan-cathepsin inhibitor, JPM. While JPM alone had no effect on mammary tumor burden, it significantly impaired tumor growth when combined with TaxMTD, demonstrating that the TaxMTD-induced elevation in tumor cathepsin activity is functionally relevant. To further our goal of simultaneous targeting of tumor and stroma, we added a low-dose cyclophosphamide regimen, which has been shown to have both anti-angiogenic and immune-stimulatory properties. This triple combination treatment was substantially more effective than any double or single drug combination. Importantly, metastatic burden was also significantly reduced in triple-treated mice as compared to controls, and long-term survival was improved. These studies suggest cathepsin+ macrophages are recruited to the tumor after TaxMTD treatment to promote tumor survival and recovery. The efficacy of combining cathepsin inhibition with paclitaxel highlights both the importance of integrated therapeutic targeting of tumor and stroma, as well as the role of TAMs in modulating resistance to chemotherapy. The addition of cysteine cathepsin inhibition to chemotherapeutic regimens thus holds considerable promise for clinical translation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 549. doi:10.1158/1538-7445.AM2011-549