Abstract 4726: Identification of efficacy biomarkers for therapies targeting miR-10b

Abstract

Abstract Breast cancer stemness is one of the drivers of metastatic spread and presents a key target in the battle against metastatic disease, especially in triple-negative breast cancer (TNBC). Existing treatment options for TNBC are limited due to recurrence and resistance, representing a major unmet clinical need. MicroRNA-10b (miR-10b) is one of the major drivers of breast cancer cell migration and invasion. In our earlier studies, we discovered that miR-10b is also responsible for metastatic cell viability. With the goal of translation of this finding to the clinic, we developed a novel therapeutic, or “nanodrug,” that targets miR-10b, consisting of antisense anti-miR-10b oligonucleotides conjugated to magnetic nanoparticles (MN) that serve as delivery vehicles. Administration of the nanodrug in mice bearing metastatic MDA-MB-231 TNBC tumors prevents the development of metastases and stops the growth of pre-existing metastases. Additionally, combination treatment with adjuvant doxorubicin induced a stable regression of metastases in immunocompromised and immunocompetent mouse models of metastatic TNBC. A limitation of our previous studies is the lack of understanding of the molecular basis for the therapeutic effect of MN-anti-miR10b. To address this gap in knowledge, we performed RNA sequencing on MDA-MB-231 cells treated with the nanodrug or controls. Functional enrichment analysis of differentially expressed genes (DEGs) between cells treated with the nanodrug versus controls (PBS or bare MN) identified a significant overrepresentation of genes associated with cell differentiation. It has been suggested that miR-10b confers stem cell-like properties such as self-renewal and drug resistance onto cancer cells. Our RNA sequencing findings led us to hypothesize that MN-anti-miR10b functions by inhibiting these stem-like cancer cell (CSC) features that are critical to cancer survival. Here, we present preliminary data showing that miR-10b is overexpressed in MDA-MB-231 cells expressing a CSC-associated surface marker phenotype (CD44+/CD24-, compared to CD44-/CD24- cells) and that this trend is not universal among other miRNAs. Furthermore, we found that the nanodrug interferes with the ability of cells to assemble as spheroids, a property associated with CSCs. With our recent observation that the nanodrug inhibits miR-10b in metastases in vivo in as little as one dose after 72 hours, our next steps are to determine whether the cell differentiation-associated DEGs identified in RNA sequencing results can be used as biomarkers of nanodrug efficacy in vivo. Understanding the changes in gene expression induced by MN-anti-miR10b as a function of time will be critical for guiding treatment regimens in future preclinical and clinical trials. Citation Format: Alan Halim, Nasreen Al-Qadi, Sujan K. Mondal, Elizabeth Kenyon, N. Anna Savan, Hussein Mackie, Anna Moore. Identification of efficacy biomarkers for therapies targeting miR-10b [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4726.