The CXCR1 Axis: A Putative Therapeutic Cancer Stem Cell-Like Marker in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest survival rates of all cancers in the United States. Not only is PDAC found at the late stages, but patients also present with or develop chemotherapy resistance at an elevated frequency. Left with limited options for treatment, researchers are investigating new options for these patients. One major area of interest is the sub-population of cells in the tumor called cancer stem cells (CSCs). These cells are known for having high resistance to chemotherapy, along with propagating and re-building the tumor after most non-CSCs have been therapeutically targeted. Previous studies have determined CXCR4, ALDH1, CD24, CD44, and CD133 as markers for CSC-like PDAC cells. In the present study, we investigate the closely related CXCR1 as another possible marker and therapeutic target for PDAC CSCs. CXCR1 is known for its role in inflammation and wound healing. The CXCR1 axis includes the ligands CXCL6 and IL-8, both of which promote the progression of cancer. Previously, Ginesteir et al. has shown targeting the CXCR1 axis in triple negative breast cancer reduced CSC-like phenotypes in vitro and in vivo. Investigations of CXCR1 in PDAC demonstrate IL-8 induces increased tumorsphere formation in vitro (Chen et al.), leading us to investigating CXCR1 in PDAC CSCs. We hypothesize that PDAC cells with high CXCR1 activity also exhibit increased CSC-like characteristics and targeting CXCR1 will reduce those characteristics. To investigate the role of CXCR1 in CSC-like phenotype of PDAC, we used the PDAC cell line CD18, along with its gemcitabine resistant (GemR) counterpart. We used the CXCR1/2 antagonist Navarixin at high enough concentrations to inhibit CXCR1. Using the previously found gemcitabine and navarixin IC50 concentrations for each parent cell line, we treated cells for 72 hours. Post-treatment, we analyzed the expression of several known CSC markers, CXCR1, and IL-8 through qRT-PCR and ELISA. We expected to see higher expression and activity of CXCR1 in cells with higher known CSC marker expression. We also anticipated that gemcitabine treatment would induce higher expression of CSC markers, whereas navarixin would exhibit lower expression. From our results, we see the beginning trends of gemcitabine treated cells having increased expression of the CSC markers and navarixin decreasing or not changing the expression levels. These results differ for IL-8, which undergoes an increase in expression when treated with both gemcitabine and navarixin, which may warrant further exploration into the role of ligands in CSC-like phenotypes. One possible explanation for this difference would be the regulation of IL-8 expression based on CXCR1 activity, as IL-8 interacts with CXCR1.https://digitalcommons.unmc.edu/surp2021/1040/thumbnail.jp

Polymer delivery systems for long-acting antiretroviral drugs

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients’ needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence.</p

Delivery of gene editing therapeutics

For the past decades, gene editing demonstrated the potential to attenuate each of the root causes of genetic, infectious, immune, cancerous, and degenerative disorders. More recently, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9 (CRISPR-Cas9) editing proved effective for editing genomic, cancerous, or microbial DNA to limit disease onset or spread. However, the strategies to deliver CRISPR-Cas9 cargos and elicit protective immune responses requires safe delivery to disease targeted cells and tissues. While viral vector-based systems and viral particles demonstrate high efficiency and stable transgene expression, each are limited in their packaging capacities and secondary untoward immune responses. In contrast, the nonviral vector lipid nanoparticles were successfully used for as vaccine and therapeutic deliverables. Herein, we highlight each available gene delivery systems for treating and preventing a broad range of infectious, inflammatory, genetic, and degenerative diseases. Statement of significance: CRISPR-Cas9 gene editing for disease treatment and prevention is an emerging field that can change the outcome of many chronic debilitating disorders.</p