MicroRNAs (miRNAs) are emerging as potential cancer therapeutics, but effective delivery mechanisms to tumor sites are a roadblock to utility. Here we show that systemically delivered, synthetic miRNA mimics in complex with a novel neutral lipid emulsion are preferentially targeted to lung tumors and show therapeutic benefit in mouse models of lung cancer. Therapeutic delivery was demonstrated using mimics of the tumor suppressors, microRNA-34a (miR-34a) and let-7, both of which are often down regulated or lost in lung cancer. Systemic treatment of a Kras-activated autochthonous mouse model of non-small cell lung cancer (NSCLC) led to a significant decrease in tumor burden. Specifically, mice treated with miR-34a displayed a 60% reduction in tumor area compared to mice treated with a miRNA control. Similar results were obtained with the let-7 mimic. These findings provide direct evidence that synthetic miRNA mimics can be systemically delivered to the mammalian lung and support the promise of miRNAs as a future targeted therapy for lung cancer.
miR34a is a tumor-suppressor miRNA that functions within the p53 pathway to regulate cell-cycle progression and apoptosis. With apparent roles in metastasis and cancer stem cell development, miR34a provides an interesting opportunity for therapeutic development. A mimic of miR34a was complexed with an amphoteric liposomal formulation and tested in two different orthotopic models of liver cancer. Systemic dosing of the formulated miR34a mimic increased the levels of miR34a in tumors by approximately 1,000-fold and caused statistically significant decreases in the mRNA levels of several miR34a targets. The administration of the formulated miR34a mimic caused significant tumor growth inhibition in both models of liver cancer, and tumor regression was observed in more than one third of the animals. The antitumor activity was observed in the absence of any immunostimulatory effects or dose-limiting toxicities. Accumulation of the formulated miR34a mimic was also noted in the spleen, lung, and kidney, suggesting the potential for therapeutic use in other cancers. Mol Cancer Ther; 13(10); 2352-60. Ó2014 AACR.
Metabolic dysregulation is a hallmark of cancer. Many tumors exhibit auxotrophy for various amino acids, such as arginine, because they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase-1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase-1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct antitumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments antitumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Tumor-bearing mice (CT26, MC38, and MCA-205) receiving pegzilarginase in combination with anti–PD-L1 or agonist anti-OX40 experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust antitumor immunity characterized by increased intratumoral effector CD8+ T cells and M1 polarization of tumor-associated macrophages. Our data suggest potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both antigen-presenting cells and tumor cells, and increased presence of M1-like antitumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer.
MicroRNA (miRNA) mimics have emerged as a novel class of therapeutics with promising anti-oncogenic activity. These mimics are modeled after naturally occurring tumor suppressor miRNAs that are ubiquitously expressed in normal cells but frequently show a loss-of-function in human malignancies. The premise for the strong inhibitory activity is based on the observation these endogenous miRNAs control multiple oncogenic pathways commonly deregulated in cancer. Therefore, “miRNA replacement therapy” acts in accordance with our current understanding of cancer as a pathway disease that can only be successfully treated when intervening with multiple cancer pathways. We have identified a series of key tumor suppressor miRNAs, including miR-34, and validated the therapeutic potential in cultured cancer cells and mouse models of cancer. The translation of this potential into future medicines, however, was hampered by the lack of a robust clinically relevant delivery system. To facilitate a rapid route to the clinic, we have screened a panel of external delivery systems that are in pre-clinical development or have already reached the clinic featuring another oligonucleotide. Here, we present the pharmacologic and pharmacodynamic parameters of miRNA mimics complexed in ionizable NOV340 liposomes (SMARTICLEs, Marina Biotech, Bothell, WA) in an orthotopic tumor model of hepatocellular carcinoma. Treatment of mice carrying existing tumors mimics led to significant tumor regression, prolonged survival and lacked notable drug-related side effects. Some of the mice appeared to be tumor-free. The data demonstrate the therapeutic utility of the NOV340/miRNA formulation and support the initiation of IND-enabling studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5636. doi:1538-7445.AM2012-5636
Tumors unable to synthesize L-Arginine (arginine) due to decreased expression of enzymes of the arginine biosynthetic pathway show increased sensitivity to arginine depletion. Pegzilarginase (AEB1102) is a bioengineered human PEGylated arginase 1 with enhanced pharmacological properties that enables marked depletion of arginine in plasma and slows tumor growth in pre-clinical in vivo models. Extracellular depletion of arginine directly affects tumor cells, increasing protein turnover, inhibiting proliferation, inducing apoptosis, and increasing autophagy (PMID:27109103); however, the impact of arginine availability on tumor immunogenicity has not been clearly established. Depletion of extracellular arginine induces autophagy, and given the known relationship between autophagy and antigen processing for MHC presentation (PMID:29058602) we hypothesized that pegzilarginase could trigger an enhanced recruitment of immune cells to the tumor microenvironment. Pegzilarginase, both as monotherapy or in combination with anti-PD-L1 mAb (10F.9G2), was administered to Balb/c mice bearing palpable, syngeneic, subcutaneous CT26 tumors. At pre-determined time points, tumor measurements were taken and tumor cell viability and immunophenotyping were assessed via flow cytometry. Treatment with both pegzilarginase or anti-PD-L1 mAb alone slowed tumor growth compared to control. Combination treatment of pegzilarginase and anti-PD-L1 mAb resulted in an enhancement of anti-tumor activity with 12.5% complete response (CR) observed in the anti-PD-L1 mAb monotherapy group and 25% CR observed in the combination therapy group. All mice with CR were re-challenged with fresh CT26 cells and failed to develop new tumors, consistent with induction of an immune memory response. We observed a decrease in tumor cell viability in all treatment groups on days 7 and 17, with the combination treatment group showing the greatest reduction in viable cells and tumor volume at day 17. The observed anti-tumor activity in monotherapy and combination therapy groups was accompanied by an increase in CD45+ tumor-infiltrating cells, with the combination therapy group showing the highest proportion of CD45+ tumor-infiltrating cells, including total T cells, macrophages and dendritic cells, and an increase in serum IFN-γ. Combination of pegzilarginase and anti-PD-L1 mAb results in synergistically greater anti-tumor activity than either monotherapy, and is accompanied by an increase in tumor-infiltrating immune cells. The enhanced infiltration of immune cells into tumor following depletion of arginine with pegzilarginase monotherapy and combination therapy challenges some of the prevailing theories on the role of arginine in immune cell signaling and cancer biology. Citation Format: Giulia Agnello, Mark D. Badeaux, Danlee Enzler, Leslie Priddy, Jason F. Wiggins, Christopher L. Daige, Scott W. Rowlinson. Depletion of blood arginine with pegzilarginase (AEB1102) in combination with anti-PD-L1 increases tumor infiltration by immune cells and enhances antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 869.
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