Abstract 5870: CPSI-1306: A novel macrophage migration inhibitory factor inhibitor against aggressive breast cancer
Authors: Subhadip Das, Nabanita Chatterjee, Sanjay Mishra, Dinesh K. Ahirwar, Sanjay Varikuti, Kirti Kaul, Rajni K. Shukla, Abhay R. Satoskar, Ramesh K. Ganju
Journal: Cancer Research (2018)

Abstract Breast cancer is the leading cause of mortality in women, accounting for 23% of all cancer deaths, and one in eight women will develop invasive breast cancer over the course of her life. Although there are therapies available, most tumors develop resistance. In addition, certain types of breast cancers, including high-grade metastatic and triple-negative breast cancer, have limited therapeutic options available. Thus, novel targeted therapeutic strategies are required for prevention of disease progression. Inflammation of breast tumors is a major confounding factor involved in tumor progression and metastasis. Therefore, targeting inflammatory microenvironment could be a major strategy to targets breast tumor progression. Macrophage migration inhibitory factor (MIF) induces severe proinflammatory responses through tautomerase and also functions as a chemokine that mediates the recruitment of inflammatory cells. It has been shown that overexpression of MIF helps in recruiting macrophages to the tumor microenvironment (TME). We are evaluating the clinical efficacy of CPSI-1306, a small-molecular inhibitor of MIF, using in vitro and in vivo assays. Previous reports show that CPSI-1306 specifically inhibits keto-enol tautomerase activity of MIF. In silico analysis of publicly available data showed that higher expression of MIF negatively correlates with breast cancer patient overall, distant metastasis and relapse-free survival. Next, we analyzed the effect of CPSI-1306 on breast cancer in vitro and found that CPSI-1306 significantly induces apoptosis and reduces the viability of metastatic breast cancer MDA-MB 468 and MDA-MB 231 cells in a dose- and time-dependent manner. Mechanistic studies showed that CPSI-1306 induced apoptosis by reducing mitochondrial membrane potential by increasing apoptogenic signals, including apoptosis induction factor (AIF) and Cytochrome-C. Further analysis revealed that CPSI-1306 inhibits activation of cell proliferation marker AKT in metastatic breast cancer cells. We further analyzed the clinical efficacy of CPSI-1306 in vivo, using preclinical MVT-1 mammary tumor orthotopic syngeneic mouse model, and observed that CPSI-1306 significantly reduces tumor growth and metastasis to the lungs. Histologic analysis revealed reduced number of Ki67-positive proliferative cells and CD31-positive blood vessels in CPSI-1306-treated tumors. Our studies revealed that CPSI-1306 could be used as a novel therapeutic agent against aggressive breast cancer. Citation Format: Subhadip Das, Nabanita Chatterjee, Sanjay Mishra, Dinesh K. Ahirwar, Sanjay Varikuti, Kirti Kaul, Rajni K. Shukla, Abhay R. Satoskar, Ramesh K. Ganju. CPSI-1306: A novel macrophage migration inhibitory factor inhibitor against aggressive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5870.