Countless trials of chemotherapy and/or targeted agent combinations have failed to produce substantial gains in survival for patients with pancreatic ductal adenocarcinoma. Recent studies have demonstrated exciting potential of RNA medicine approaches to therapeutically target microRNAs (miRNA, small non-coding RNAs) either by inhibiting tumor promoting miRNAs (onco-miRs) or enriching tumor suppressor miRNAs. Here we use co-culture and murine models to show that photodynamic therapy (PDT) using verteporfin both improves delivery and synergizes mechanistically with tumor suppressive effects of miR-146a-5p. These results indicate promise RNA medicine strategies for PDAC and could have broader applicability in therapeutic delivery of RNA medicine to solid tumors.
Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal of human malignancies. The failure of myriad trials evaluating chemotherapy and/or targeted agent combinations to produce substantial gains in survival continues to motivate the investigation of new therapeutic strategies. Recent studies have demonstrated exciting potential of RNA medicine approaches to therapeutically target microRNAs (miRNA, small non-coding RNAs) which have been shown to regulate PDAC growth, survival and chemoresistance. However, while various miRNA therapies have been discussed for the past decade, challenges with delivery to most disease tissues have restricted their therapeutic use to liver and kidney disease. Here we explore the combination with photodynamic therapy (PDT) to enhance delivery of nanoparticles carrying RNA medicine agents through fibrotic PDAC stroma, and mechanistically synergize with depletion or enrichment of target miRNAs. Using transfection of miRNA mimics and inhibitors in PDAC cells we have evaluated a small panel of miRNAs that could serve as promising targets for either depletion or enrichment. In cell culture studies we find that PDT using verteporfin can enhance RNA medicine efficacy both through depletion of PDAC stroma (previously reported) to significantly enhance delivery to target tissue, and by synergizing mechanistically at the molecular level. In ongoing studies we are now examining the most promising combinations in murine xenografts. Taken together with clinical studies by others establishing the feasibility of PDT for PDAC these results indicate further promise of leveraging PDT to synergistically enhance emerging RNA medicine approaches.
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human malignancies. PDAC is characterized by dense fibrous stroma which obstructs drug delivery and plays complex tumor-promoting roles through paracrine crosstalk. Photodynamic Therapy (PDT) is a light-based modality which has been demonstrated to be clinically feasible and effective for tumors of the pancreas. Here, we use in vitro heterocellular 3D co-culture models in conjunction with imaging, bulk rheology and microrheology methods to investigate the impact of verteporfin-based PDT on non-cellular (ECM) components of PDAC stroma. By measuring the rheology of ECM before and after PDT we find that softening of ECM is concomitant with an increase in transport of nanoparticles (NPs). At the same time, as shown previously, photodestruction of stromal fibroblasts, leads to enhanced tumor response to PDT. Collectively these results in 3D tumor models suggest that photodynamic stromal depletion (PSD) could be used to enhance subsequent drug delivery and improve tumor response to treatment.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease marked by poor response to virtually all available treatments. Clinical trials of chemo, targeted therapies, and radiation, have resulted in minimal advances, and survival after diagnosis is generally less than a year. In the pursuit of new avenues for therapeutic development for this lethal disease, a number of studies have implicated the role of tumor-promoting microRNAs with altered expression PDAC tissues. Here, using in vitro 3D organoids we explore the strategy of combining photodynamic therapy (PDT) with a novel microRNA therapeutic platform to target miR21, an established onco-miR that targets multiple tumor suppressors. This approach is motivated by recent clinical studies establishing the technical feasibility of light delivery to the pancreas, combined by evidence that PDT may disrupt or loosen stroma and potentially increase delivery of anti-miR agents. To evaluate this hypothesis, we use in vitro co-culture models of PDAC cells and stromal fibroblasts that recapitulate the dense fibrotic stroma of PDAC tumors to evaluate response to treatment in verteporfin PDT and anti-miR combination and monotherapy treatment arms. Using stably-transfected miR-21 sponge expressing we also perform mechanistic studies to investigate the role of miR 21 in response to PDT and chemotherapy in 3D cultures with and without stromal partners.
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