A Novel miR-544 Targeting Small Molecule as an Adjuvant Therapy for Preventing Breast Cancer Metastasis and Relapse
Abstract
Background: Breast cancer remains the most common malignancy among women, and despite advances in diagnosis and treatment, existing front-line therapies are limited in effectiveness due to their lack of specificity and severe toxicity. It is now well established that most solid tumors, including breast cancers, are exposed to periods of hypoxic stress within the tumor microenvironment and adaptation to such stress selects for drug-resistant and metastatic phenotypes, hallmarks of advanced disease that account for most breast cancer-related deaths. Numerous studies have also identified a unique class of microRNAs (miRNAs) that are upregulated in tumor cells in response to hypoxia (hypoxamiRs) and whose expression correlate with poor patient outcomes. Although these miRNAs represent novel therapeutic targets, most RNA-targeting therapies employed to date are limited in their effectiveness. Therefore, an opportunity exists to develop novel hypoxamiR-targeting drugs and test their spectrum of activity for treating breast cancer. BCRP Overarching Challenge: This research proposal addresses efforts to revolutionize existing treatment regimens for breast cancer patients by replacing drugs that have life-threatening toxicities with safe, effective interventions. and eliminate mortality associated with metastatic breast cancer. Hypothesis and Objectives: The long-term objective of this proposal is to develop miRNA-targeting small molecules as adjuvant therapies that reduce the incidence of tumor metastasis and relapse in patients with advanced breast cancer. Published and preliminary studies from our lab have identified miR-544 as a hypoxamiR that drives metabolic adaptation of triple-negative breast cancer (TNBC) cells to hypoxic stress thereby promoting tumorigenesis. Using a novel drug discovery platform, we identified small molecules that selectively inhibit miR-544 biogenesis/maturation with high selectivity and specificity and showed that one molecule (1: 1,8-diamino-3,6-di(pyrrolidin-1-yl)-2,7-naphthyridine-4-carbonitrile) sensitized TNBC cells to killing by hypoxia and 5-fluorouracil in vitro and impeded growth of TNBC cell line-derived xenografts (CDXs) in vivo. To advance these discoveries, this proposal aims to evaluate the spectrum of molecule 1 activity by quantifying dose dependent effects on tumor progression and metastasis of CDXs representing different TNBC subtypes and correlating outcomes with miR-544 levels/activity directly in tumors. The ability of molecule 1 to sensitize tumor cells to killing by chemotherapeutics and prevent tumor relapse will also be conducted in a treatment naïve TNBC patient-derived xenograft (PDX). Lastly, molecule 1’s impact on the cellular composition and molecular evolution of the PDX will be interrogated by single cell RNA-sequencing and results correlated with animal outcomes to validate molecule 1’s mode of action in tumors. Specific Aims Specific Aim 1: Evaluate the spectrum of activity and therapeutic potential of a novel miR-544 targeting small molecule 1 in preclinical animal models of TNBC. Specific Aim 2: Evaluate the mode of action and potential toxicity of molecule 1 in TNBC PDXs using a genomics-based approach. Study Design: In the proposed studies, we will interrogate the full spectrum of molecule 1 activity in TNBC by quantifying dose-dependent impacts on tumor progression and metastasis of CDXs representing different TNBC molecular subtypes, and correlating outcomes with miR-544 levels/activity in tumors. An optimized dose of molecule 1 will then be tested for its ability to block growth and metastasis of a treatment naïve TNBC PDX, which better models the complex tumor heterogeneity of patient tumors and the role of the tumor microenvironment in disease progression. Mice harboring the treatment naïve PDX will also be administered various front-line chemotherapeutics alone or in combination with molecule 1 to assess impacts of the small molecule on
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210795
Entities
People
- Donald G Phinney
Organizations
- United States Army
- University of Florida