Abstract P4-06-01: JAK2/STAT3 activity in inflammatory breast cancer supports the investigation of JAK2 therapeutic targeting

Abstract

Background: Inflammatory breast cancer (IBC) is a virulent subtype of locally advanced breast cancer that accounts for 1–5% of all breast cancers diagnosed in the United States. Conventional therapy for IBC (preoperative chemotherapy, mastectomy, radiation therapy) results in a median 5 year overall survival of 50%, which supports the need for investigation into the molecular distinctiveness of IBC, with the ultimate goal of developing effective therapeutic agents that target these molecular changes. Some of the distinctive molecular characteristics of IBC include the presence of a substantial proportion of CD44+/CD24- breast cancer cells that express stem cell-like characteristics, over-expression of E-cadherin, and extensive formation of tumor emboli. Examination of breast tumors and pre-clinical data suggests that the JAK2/STAT3 pathway is active in CD44+/CD24- breast cancer cells, and is stimulated by various mechanisms associated with IBC, such as high IL-6 levels. We investigated the role of JAK2/STAT3 activation in IBC as preclinical evidence to pursue JAK2 targeted therapy for IBC in a clinical setting. Methods: Using de-identified breast tissue specimens from both untreated and treated IBC patients obtained on a protocol approved by our institutional review board; we performed immunohistochemical (IHC) and multicolor immunofluorescence analysis to detect the presence of CD44+/CD24- cells and the fraction of activated phospho-STAT3 (pSTAT3). The number of cells positive for pSTAT3 was assessed pre and post-treatment. We also analyzed the status of CD44+/CD24- cells and pSTAT3 in SUM149 and SUM190 IBC cell lines, and an IBC xenograft model (IDC31) derived from primary tumor obtained from an IBC patient. We tested the efficacy of multiple different JAK2 inhibitors to inhibit the growth and viability of cell cultures and xenografts. Results: All IBCs were highly enriched in CD44+/CD24- cells, with approximately 80% of all cancer cells within tumors displaying this phenotype. About 85% of IBC cases show activation of pSTAT3, and a significant fraction (40%) of CD44+/CD24- cells were pSTAT3 positive. Interestingly, the fraction of pSTAT3+ cells was lower in the CD44+/CD24- cells in post treatment samples from triple negative but not from luminal tumors. JAK2 inhibition significantly decreased the proliferation of pSTAT3+ IBC cells lines in vitro and the growth of pSTAT3+ xenografts including the IBC model ICD31. Discussion: Specific molecular characteristics of IBC result in a unique and virulent disease course. Based upon a predominance of CD44+/CD24- breast cancer stem cells present in IBC, we investigated the JAK2/STAT3 pathway in IBC tissue specimens, cell lines and an IBC xenograft model. Our preclinical data demonstrates a highly active JAK2/STAT3 pathway in IBC which lends itself to exploration of the efficacy of a JAK2 inhibitor in the treatment of this disease. A phase I/II study is underway to evaluate combination ruxolitinib and chemotherapy for the primary treatment of triple negative IBC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-01.