Isoforms of MUC16 activate oncogenic signaling through EGF receptors to enhance the progression of pancreatic cancer.

Aberrant expression of CA125/MUC16 is associated with pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. However, knowledge of the contribution of MUC16 to pancreatic tumorigenesis is limited. Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. MUC16 enhanced tumor malignancy through the activation of AKT and GSK3ß oncogenic signaling pathways. Activation of these oncogenic signaling pathways resulted in part from increased interactions between MUC16 and epidermal growth factor (EGF)-type receptors, which were enhanced for aberrant glycoforms of MUC16. Treatment of PDAC cells with monoclonal antibody (mAb) AR9.6 significantly reduced MUC16-induced oncogenic signaling. mAb AR9.6 binds to a unique conformational epitope on MUC16, which is influenced by O-glycosylation. Additionally, treatment of PDAC tumor-bearing mice with either mAb AR9.6 alone or in combination with gemcitabine significantly reduced tumor growth and metastasis. We conclude that the aberrant expression of MUC16 enhances PDAC progression to an aggressive phenotype by modulating oncogenic signaling through ErbB receptors. Anti-MUC16 mAb AR9.6 blocks oncogenic activities and tumor growth and could be a novel immunotherapeutic agent against MUC16-mediated PDAC tumor malignancy.

Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors.

A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5 + anti-PD-L1 + PolyICLC induced rejection of human MUC1 expressing tumors and provided a long-lasting, MUC1-specific cellular immune response, which could be adoptively transferred and shown to provide protection against tumor challenge in human MUC1 transgenic (MUC.Tg) mice. Furthermore, antibody depletion studies revealed that CD8 cells were effectors for the MUC1-specific immune response generated by the mAb-AR20.5 + anti-PD-L1 + PolyICLC combination. Multichromatic flow cytometry data analysis demonstrated a significant increase over time in circulating, activated CD8 T cells, CD3+CD4-CD8-(DN) T cells, and mature dendritic cells in mAb-AR20.5 + anti-PD-L1 + PolyICLC combination-treated, tumor-bearing mice, as compared to saline-treated control counterparts. Our study provides a proof of principle that an effective and long-lasting anti-tumor cellular immunity can be achieved in pancreatic tumor-bearing hosts against their own antigen (MUC1), which can be further potentiated using a vaccine adjuvant and an immune checkpoint inhibitor.

IgE-Based Therapeutic Combination Enhances Antitumor Response in Preclinical Models of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced immunosuppression attenuates the immunotherapy response in PDAC. To date, studies have focused on IgG-based therapeutic strategies in PDAC. With the recent interest in IgE-based therapies in multiple solid tumors, we explored the MUC1-targeted IgE potential against pancreatic cancer. Our study demonstrates the notable expression of FceRI (receptor for IgE antibody) in tumors from PDAC patients. Our study showed that administration of MUC1 targeted-IgE (mouse/human chimeric anti-MUC1.IgE) antibody at intermittent levels in combination with checkpoint inhibitor (anti-PD-L1) and TLR3 agonist (PolyICLC) induces a robust antitumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that the antigen specificity of the IgE antibody plays a vital role in executing the antitumor response as nonspecific IgE, induced by ovalbumin (OVA), failed to restrict tumor growth in pancreatic tumor-bearing mice. Utilizing the OVA-induced allergic asthma-PDAC model, we demonstrate that allergic phenotype induced by OVA cannot restrain pancreatic tumor growth in orthotopic tumor-bearing mice. Together, our data demonstrate the novel tumor protective benefits of tumor antigen-specific IgE-based therapeutics in a preclinical model of pancreatic cancer, which can open new avenues for future clinical interventions.

Development of copolymeric nanoparticles of hypocrellin B: Enhanced phototoxic effect and ocular distribution.

In the present work, we have developed a photosensitizer hypocrellin B (HB) and nano silver loaded PLGA-TPGS nanoparticles with improved singlet oxygen production for enhanced photodynamic effect for the efficient treatment of age related macular degeneration. Random copolymer (PLGA-TPGS) synthesized by ring opening and bulk polymerization was characterized by IR, 1H NMR and TGA analysis. HBS-CP-NPs prepared by nanoprecipitation techniques were spherical shaped 89.6-753.6nm size particles with negative zeta potential. The average encapsulation efficiency was 84.06±11.43% and HB release from the HBS-CP-NPs was found to be biphasic with a slow release of 1.41% in the first 8h and 48.91% during 3days as measured by RP-HPLC. DSC thermograms indicate that HB was dispersed as amorphous form in HBS-CP-NPs. The ROS generation level of HBS-CP-NPs was significantly higher than that of HB/HB-CP-NPs. The production of 1O2 of HBS-CP-NPs has been assessed using EPR spectrometer. The 1O2 generating efficiency follows the order of nano silver>HB-CP-NPs>HBS-CP-NPs>pure HB drug solution. The superior phototoxic effect of HBS-CP-NPs (85.5% at 50µM) was attained at 2h irradiation in A549 cells. Significant anti angiogenic effect of HBS-CP-NPs was observed in treated CAM embryos. Following intravenous injection of HBS-CP-NPs to rabbits, the maximum amount of HB was found in retina (3h), iris (9h), aqueous humour (9h) and vitreous humour (9h).

Antitumor efficacy of photodynamic therapy using novel nanoformulations of hypocrellin photosensitizer SL052.

Recent preclinical and clinical testing of hypocrellin-based photosensitizer SL052 for use in photodynamic therapy (PDT) of cancer has shown encouraging results. Further optimization of its formulation for delivery could considerably extend the therapeutic efficiency of this drug. A nanoformulation encapsulating SL052 into biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) was developed using a single-emulsion solvent evaporation technique and characterized in terms of particle size and loading of the photosensitizing agent. This nanoformulation, SL052-PLGA-nanoparticles (NPs), was compared with recently created nanoformulation based on polyvinylpyrrolidone (SL052-PVP-NPs) and standard liposomal SL052 preparation in terms of efficacy when used for PDT treatment of squamous cell carcinomas SCCVII growing subcutaneously in syngeneic mice. The therapeutic effect of PDT using these three different SL052 formulations was tested for both 1 and 4 h intervals between drug injection and tumor light exposure. The longer time interval produced higher tumor cure rates with all SL052 preparations. With both drug-light intervals, PDT based on SL052-PLGA-NPs produced superior therapeutic benefit compared with the other two SL052 formulations.

Water-soluble and biocompatible sono/photosensitizer nanoparticles for enhanced cancer therapy.

AIMS: Most sono/photosensitizers of cancer sonodynamic/photodynamic therapy (SDT/PDT), such as hypocrellin SL052, are water-insoluble, therefore restricting their clinical applications. In this article, we present a water-soluble nanocarrier to load the SDT/PDT sensitizer SL052 with improved pharmacokinetics and therapeutic efficacy. MATERIALS & METHODS: Nanoclusters of polyvinylpyrrolidones with SL052 formed water-soluble nanoparticles (SL052-NPs) while retaining the chemical structure of SL052. RESULTS: The experimental results show that SL052-NPs improve the drug's physicochemical properties and significantly enhance the efficacy of SL052 in terms of pharmacokinetics and cancer killing. Water-soluble SL052-NPs can be used to deliver the drug to deep cancer tissues. A potential benefit of SL052-NPs is that polyvinylpyrrolidones can help SL052 evade the reticuloendothelial system, thereby increasing circulation half-life and improving drug biodistribution. CONCLUSION: SL052-NPs greatly improved the physicochemical properties of SL052 without modifying its chemical structure, allowing for deep-site cancer drug delivery, imaging for diagnosis, and ultrasound or photocontrolled localized cancer therapy.