Abstract 943: Insulin-like growth factor-2 a potential target for screening and treatment in patients with triple negative breast cancer
Authors: Nalo M. Hamilton, Diana Marquez-Garban, David Austin, Neda Moatamed, Lorena P. Burton, David Elashoff, Begonya Comin-Anduix, Tristan Grogan, Madhuri Wadehra, Helena Chang, Adrienne Martinez, Mary-Lynn Brecht, Isabel Jabara, Richard Pietras, Yahya Elshimali, Jaydutt Vadgama, Michael Jung
Journal: Cancer Research (2021)

Abstract Triple-negative breast cancer (TNBC) affects only about 10-15% of women with breast cancer (BC) but accounts for almost 50% of all BC deaths. At this time, development of targeted treatments for TNBC are urgently needed. Insulin-like growth factor-2 (IGF2) is highly expressed in TNBCs and mediates its proliferative effects via two hormone receptors, insulin-like growth factor -1 receptor (IGF1R) and insulin receptor (IR). Using a TNBC tissue microarray (TMA) consisting of 159 archival clinical samples, we confirm that IGF2 is highly expressed in tumor tissue as compared to nearby normal tissue (P&amp;lt;0.001). In addition, evaluation of a second breast cancer TMA that included archival TNBC samples from African American and Latino women, IGF2 expression was similarly higher in these samples than in samples from Caucasian women (P&amp;lt;0.02). Since enrichment of IGF1R and IR are detected in TNBC and are known to allow signaling crosstalk, the effects of BMS-754807, a dual IGF1R/IR antagonist, were assessed on TNBC progression in vitro and in vivo with human and murine models. To determine the effects of BMS-754807 in vitro, we used cell viability assays with TNBC cell lines, MDA-MB-231 and HCC1806. BMS-754807 significantly reduced cell viability after 48 and 72 hours (P&amp;lt; 0.01), and a similar effect was observed in the murine TNBC cell line 4T1 (P&amp;lt; 0.01). In vivo, BMS-754807 inhibited tumor growth of human TNBC as well as mouse 4T1 xenografts (P&amp;lt; 0.05). Further, in studies of immune cell populations using syngeneic 4T1 tumor xenografts, BMS-754807 significantly decreased myeloid derived suppressor cells (P &amp;lt;0.05) in the tumor microenvironment (TME) and in the spleen of BALC/c mice. Additionally, there was an increase in T effector CD8+ and CD4+ tumor infiltrating lymphocytes (P&amp;lt; 0.05), particularly of spleen T central memory cells (P&amp;lt;0.01). Notably, conversion of CD8+ from T central memory to a T effector memory phenotype that is fully active against tumors can confer long term immunity against recurrence. This data suggest that IGF2 is a potential biological marker for breast cancer disparities and that targeting receptors of IGF2 with drugs such as BMS-754807 could provide additional treatment options in combination with current therapies, thus reducing TNBC progression and ultimately improving patient outcomes. [Funded by NIH U54 143931 Cancer Center Partnership and CBCRP] Citation Format: Nalo M. Hamilton, Diana Marquez-Garban, David Austin, Neda Moatamed, Lorena P. Burton, David Elashoff, Begonya Comin-Anduix, Tristan Grogan, Madhuri Wadehra, Helena Chang, Adrienne Martinez, Mary-Lynn Brecht, Isabel Jabara, Richard Pietras, Yahya Elshimali, Jaydutt Vadgama, Michael Jung. Insulin-like growth factor-2 a potential target for screening and treatment in patients with triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 943.