Abstract C043: SHIP-1: Therapeutic target to reduce health disparities in African Americans with pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and African Americans (AA) have higher mortality rates compared to European Americans (EA) due to heighten inflammation which is known to be regulated by Src-homology inositol phosphatase-1 (SHIP-1). SHIP-1 is a master regulator of macrophage development and function which impacts tumor immunity and thus can be a therapeutic target that may explain treatment failure, which contributes to health disparity associated with AA vs. EA with PDAC. We reported that SHIP-1 expression is vital for the expansion of tumoricidal M1 macrophages, which in turn corresponds to an increase in anti-tumor responses in PDAC models. Our preliminary clinical data shows a significant increase in PDAC biomarker microRNA (miR-155) gene expression and a corresponding decrease in SHIP-1 gene and protein expression in the blood of healthy AA vs. EA individuals, significant increases in the percentages of inflammatory M2 macrophages with a reduction of tumoricidal M1 macrophages. Also, AA PDAC patients have significantly higher levels of inflammatory cytokines IL-6 and IL-8 in their serum, that correspond with the expansion of M2 Macrophages compared to EA PDAC patients. Our preliminary data suggests that SHIP-1 enhancers can reprogram M2 into M1 macrophages in the presence of serum from AA but not EA PDAC patients. Therefore, we hypothesize that AA PDAC patients compared to EA PDAC patients have reduced SHIP-1 expression which in turn leads to the expansion of M2 Macrophages that corresponds with dampened anti-tumor immune responses that are associated with treatment failure, and that this process can be reversed using SHIP-1 enhancers. We propose the following Specific Aims: Aim 1. To identify the cellular mechanism(s) by which SHIP-1 controls the development of monocytes into tumoricidal macrophages. Aim 2. To evaluate SHIP-1 molecular signatures required for tumoricidal macrophages and its impact on anti-tumor responses in tumor microenvironment (TME) of 3D patient-specific PDAC cultures and Aim 3. To evaluate the sensitivity of SHIP-1 stratified 3D patient-derived PDAC cultures response to checkpoint immunotherapy. We will use AA and EA PDAC clinical specimens and state-of-the-art technologies to address the aims of this study. We expect to validate SHIP-1 as a therapeutic target to treat all PDAC patients and reduce the health disparity gap for African Americans. Citation Format: Krystal Villalobos-Ayala, Valentina Laverde, Jennifer Permuth, William Kerr, Mokenge Malafa, Clayton Yates, Tomar Ghansah. SHIP-1: Therapeutic target to reduce health disparities in African Americans with pancreatic cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C043.