Tumor penetrating nanomedicine targeting both an oncomiR and an oncogene in pancreatic cancer

Abstract

Developing new targeted therapy for pancreatic cancer is one of the major current challenges in cancer research. KRAS mutations and miRNA dysregulation (e.g. miR-21-5p oncomiR) play key roles in Pancreatic Ductal Adenocarcinoma (PDAC), leading to rapid progression of the disease. As the KRAS mutation is a main driver of PDAC, anti-KRAS strategies remain a major therapeutic approach for PDAC treatment. Previously, utilization of either siKRAS or small chemically modified single-stranded RNA molecules that specifically disable miR-21 (anti-miR-21) were effective in slowing PDAC tumor growth in various tumor models when packaged in an innovative delivery system (TPN) required for efficient drug delivery to the PDAC tumor site. Here we have tested the utility of targeting the KRAS pathway through multiple mechanisms and via dual targeting of a PDAC oncomiR and oncogene. Initially we found that miR-217, which has been shown to directly regulate KRAS expression, is downregulated in our PDAC samples, thus we tested the benefits of anti-miR-21, miR-217 mimic or siKRAS loaded into the tumor-penetrating nanoparticles (TPN) that we had previously shown to potently target the largely impenetrable PDAC tumors, and found an enhanced anti-tumoral response upon dual treatments in KRAS-mutated PDAC models.

Inhibition of miR-21 Regulates Mutant KRAS Effector Pathways and Intercepts Pancreatic Ductal Adenocarcinoma Development

“…Recently, interfering RNAs as a therapeutic approach to PDA have been explored using tumor-penetrating nanoparticles as a delivery modality that can penetrate the dense tumor stroma (17,18). This technique has demonstrated efficacy in xenograft murine models with dysregulated miRNAs, specifically when both miR-21 and KRAS were simultaneously targeted (18,19). Although miRNA expression in PDA has been reported, progressive profiling of dysregulated miRNAs with PanIN progression has been minimally studied.…”

microRNA‐based diagnostic and therapeutic applications in cancer medicine

“…For example, functionalization with EGFR or CD133 aptamers (instead of folate) enhances the delivery of anti‐miR‐21 AMO to the tumor site in an orthotopic mouse model of breast cancer (Shu et al, 2015 ; Yin et al, 2019 ). Treatment with nanocomplex loaded with MirVana® miR‐21 inhibitor and decorated with tumor‐ and cell‐penetrating tandem peptides suppresses tumor growth in immunocompetent and immunocompromised subcutaneously implanted mouse models of PDAC (Gilles et al, 2018 ; Gilles et al, 2019 ). Treatment with an unconjugated anti‐miR‐21 AMO in KRas‐driven p53‐mutated genetically engineered model of PDAC (variant KPC model) at a young age, when only precursor lesions (pancreatic intraepithelial neoplasia) have formed, prevents the development of more advanced and invasive lesions (Chu et al, 2020 ).…”

Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer

“…miRNA mimics require encapsulation in liposomal nanoparticles or complexing with polymers or other coated nanoparticles [18,128]. A double-stranded miR-217 mimic encapsulated in a PEGylated lipid nanoparticle, decorated with iRDG tumor penetrating-peptide, is effective at downregulating KRAS expression in vitro cell assays, but it may not be as effective as short interfering RNAs (siRNAs) against KRAS in an in vivo subcutaneous PDAC tumor model [129]. miR-34a is an excellent candidate for replenishing therapy in PDAC [130].…”