Therapeutic Strategy For Pancreatic Cancer Research Articles

ITGA2 induces STING expression in pancreatic cancer by inducing DNMT1 degradation.

Integrin alpha 2 (ITGA2, also known as CD49b or VLA-2) is the alpha subunit of a transmembrane receptor for collagens and related proteins. Previously, we found that ITGA2 may regulate immune cell infiltration in pancreatic cancer by inducing PD-L1 expression. As yet, however, whether ITGA2 regulates immune cell infiltration in pancreatic cancer by other mechanisms remains unclear. RNA sequencing was performed to identify differentially expressed genes in ITGA2-silenced pancreatic cancer cells. Protein-protein interactions were detected via co-immunoprecipitation. The infiltration level of immune cells was assessed using an immunofluorescence staining assay. We found that ITGA2 can activate the cytosolic DNA-sensing pathway and promote STING expression in pancreatic cancer cells. In addition, we found that ITGA2 induces DNMT1 degradation by disrupting the interaction between DNMT1 and Kindlin2 in pancreatic cancer cells. As a DNA methyltransferase, we found that DNMT1 overexpression induced by ITGA2 silencing significantly up-regulated the methylation level of the STING gene promoter. Finally, ITGA2 silencing combined with DNMT1 inhibitor treatment induced immune cell infiltration in pancreatic cancer. Our data indicate that ITGA2 induces STING expression by interacting with DNMT1 and inducing the degradation of DNMT1. ITGA2 silencing combined with DNMT1 inhibitor treatment may be a novel therapeutic strategy for pancreatic cancer.

Nanoparticle-based immunotherapy of pancreatic cancer.

Pancreatic cancer (PC) has a complex and unique tumor microenvironment (TME). Due to the physical barrier formed by the desmoplastic stroma, the delivery of drugs to the tumor tissue is limited. The TME also contributes to resistance to various immunotherapies such as cancer vaccines, chimeric antigen receptor T cell therapy and immune checkpoint inhibitors. Overcoming and/or modulating the TME is therefore one of the greatest challenges in developing new therapeutic strategies for PC. Nanoparticles have been successfully used as drug carriers and delivery systems in cancer therapy. Recent experimental and engineering developments in nanotechnology have resulted in increased drug delivery and improved immunotherapy for PC. In this review we discuss and analyze the current nanoparticle-based immunotherapy approaches that are at the verge of clinical application. Particularly, we focus on nanoparticle-based delivery systems that improve the effectiveness of PC immunotherapy. We also highlight current clinical research that will help to develop new therapeutic strategies for PC and especially targeted immunotherapies based on immune checkpoint inhibitors.

Abstract 5824: Fully-humanized, bioengineered miR-1291 modulates key nutrient transport and metabolism to control tumor metabolism

Abstract Tumor progression is accompanied by metabolic reprogramming to allow carcinoma cells to access essential nutrients under the tumor microenvironment. To meet energetic and material needs for high-rate proliferation and tumorigenesis, cancer cells generally rely more heavily on vital nutrients (e.g., glucose, amino acids, and vitamins) than normal cells. Therefore, controlling nutrient transport and metabolism in cancer cells is a promising therapeutic strategy. Our previous studies have suggested that microRNA-1291-5p (miR-1291-5p or miR-1291) is downregulated in pancreatic cancer (PC) cells and acts as a tumor suppressor. The current study is to delineate the role of miR-1291 in the control of PC cell metabolism and develop miR-1291 therapy. We first employed our newly-invented RNA bioengineering technology to achieve high-level and large-scale, in vivo fermentation production of a fully-humanized biologic miR-1291 agent at a high degree of homogeneity (> 4 mg BioRNA per liter of culture and > 97% purity). RNA sequencing studies revealed that BioRNA/miR-1291 was selectively processed to target miR-1291-5p to modulate the transcriptome in PC cells. Proteomics study showed that a number of proteins were reduced remarkably in AsPC-1 cells by biologic miR-1291-5p, among which PNPO, an enzyme that mediates the synthesis of essential nutrient vitamin B6 (VB6), was revealed as a leading target of miR-1291-5p. Besides PNPO and the previously-reported glucose transporter SLC2A1/GLUT1, amino acid transporter SLC7A5/LAT1 was verified as a direct target for miR-1291-5p. Downregulation of PNPO, LAT1, GLUT1 protein expression by biological miR-1291 led to sharp alteration of homeostasis of glucose, amino acids, and VB6 in human PC cells, and subsequent suppression of glycolysis capacity and mitochondrial function as well as the increase of oxidative stress. Combination treatment with bioengineered miR-1291 and 5-FU exerted strong synergism in the inhibition of PC cell and organoid proliferation in vitro. In addition, miR-1291 mono- and combination therapy were effective to control tumor growth in pancreatic cancer patient-derived xenograft (PDX) mouse models. These results demonstrate a critical role for miR-1291 in the regulation of PC cell metabolism which provides insight in developing new therapeutic strategies for PC. Citation Format: Mei-Juan Tu, Frank J. Gonzalez, Ai-Ming Yu. Fully-humanized, bioengineered miR-1291 modulates key nutrient transport and metabolism to control tumor metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5824.

Future therapies for pancreatic carcinoma: Insights into cancer precision medicine.

Pancreatic carcinoma (PC) has one of the highest rates of cancer-related death worldwide. Except for surgery, adjuvant chemotherapy, chemoradiotherapy, and immunotherapy have shown various efficacies depending on the stage of the patient. We read the review “Current and emerging therapeutic strategies in pancreatic cancer: Challenges and opportunities” and offer some opinions that may improve its precision and completeness. This review presents a map of appropriate therapies for PC at different stages. Based on the clinical trial outcomes mentioned in the review, we evaluated the potential therapeutic options for PC and helped explain the contradictory efficacy between different programmed cell death protein 1/programmed cell death ligand 1 clinical trials, which may have resulted from the unique features of PC. Although R0 resection and adjuvant chemotherapy are still the gold standards for PC, new modalities, with or without clinical validation, are needed to establish more specific and precise treatments for PC.

NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells

Pancreatic cancer is one of the most lethal human neoplasms, and despite advances in the understanding of the molecular complexity involved in the development and progression of this disease, little of this new information has been translated into improvements in therapy and prognosis. Ezrin (EZR) is a protein that regulates multiple cellular functions, including cell proliferation, survival, morphogenesis, adhesion, and motility. In pancreatic cancer, EZR is highly expressed and reflects an unfavorable prognosis, whereas EZR silencing ameliorates the malignant phenotype of pancreatic cancer cells. NSC305787 was identified as a pharmacological EZR inhibitor with favorable pharmacokinetics and antineoplastic activity. Here, we endeavored to investigate the impact of EZR expression on survival outcomes and its associations with molecular and biological characteristics in The Cancer Genome Atlas pancreatic adenocarcinoma cohort. We also assessed the potential antineoplastic effects of NSC305787 in pancreatic cancer cell lines. High EZR expression was an independent predictor of worse survival outcomes. Functional genomics analysis indicated that EZR contributes to multiple cancer-related pathways, including PI3K/AKT/mTOR signaling, NOTCH signaling, estrogen-mediated signaling, and apoptosis. In pancreatic cells, NSC305787 reduced cell viability, clonal growth, and migration. Our exploratory molecular studies identified that NSC305787 modulates the expression and activation of key regulators of the cell cycle, proliferation, DNA damage, and apoptosis, favoring a tumor-suppressive molecular network. In conclusion, EZR expression is an independent prognosis marker in pancreatic cancer. Our study identifies a novel molecular axis underlying the antineoplastic activity of NSC305787 and provides insights into the development of therapeutic strategies for pancreatic cancer.

Rutin Promotes Pancreatic Cancer Cell Apoptosis by Upregulating miRNA-877-3p Expression.

(1) Background: pancreatic cancer is one of the most serious cancers due to its rapid and inevitable fatality, which has been proved very difficult to treat, compared with many other common cancers. Thus, developing an effective therapeutic strategy, especially searching for potential drugs, is the focus of current research. The exact mechanism of rutin in pancreatic cancer remains unknown. (2) Method: three pancreatic cancer cell lines were used to study the anti-pancreatic cancer effect of rutin. The potent anti-proliferative, anti-migration and pro-apoptotic properties of rutin were uncovered by cell viability, a wound-healing migration assay, and a cell apoptosis assay. High-throughput sequencing technology was used to detect the change of miRNAs expression. Immunoblotting analysis was used to detect the expression of apoptotic proteins. (3) Results: CCK-8 and EDU assays revealed that rutin significantly inhibited pancreatic cancer cells’ proliferation (p < 0.05). A wound-healing assay showed that rutin significantly suppressed pancreatic cancer cells’ migration (p < 0.05). A flow cytometric assay showed that rutin could promote pancreatic cancer cells’ apoptosis. Intriguingly, rutin significantly upregulated miR-877-3p expression to repress the transcription of Bcl-2 and to induce pancreatic cancer cell apoptosis. Accordingly, rutin and miR-877-3p mimics could promote apoptotic protein expression. (4) Conclusions: our findings indicate that rutin plays an important role in anti-pancreatic cancer effects through a rutin-miR-877-3p-Bcl-2 axis and suggests a potential therapeutic strategy for pancreatic cancer.

Homologous recombination repair pathway alterations and their relationship to homologous recombination deficiency in advanced pancreatic cancer patients.

609 Background: Homologous recombination repair (HRR) is critical for limiting DNA damage arising from double strand breaks. Disrupting HRR has emerged as a therapeutic strategy in pancreatic cancer given the development of PARP inhibitors that can specifically target tumors with homologous recombination deficiency (HRD). While HRD is strongly associated with loss-of-function mutations in BRCA1/2, a broad range of pathogenic alterations have been identified in other HRR genes. Identification of pathogenic alterations that predict response to PARP inhibition remains a critical knowledge gap in the field. Methods: We retrospectively analyzed de-identified records from 895 patients with advanced pancreatic cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, matched normal, full transcriptome RNA-seq). HRD-positivity and genome-wide loss of heterozygosity (LOH) were compared across groups, which were defined based on alterations to BRCA1/2 or other HRR pathway genes. Results: We identified 293/895 (33%) pancreatic cancer patients to be HRD-positive. Among HRD positive patients, 23/895 (2.6%) tumors harbored two alterations in BRCA1/2 (BRCA++), 179/895 (20%) harbored a single alteration in BRCA1/2 (BRCA+), 25/895 (2.8%) harbored two alterations in at least one other non-BRCA HRR gene (other HRR++), 367/895 (41%) harbored a single alteration in one other HRR gene (other HRR+), and 143/895 (16%) had pathogenic alterations in neither BRCA1/2 nor other HRR genes. In terms of HRD status, 23/23 (100%) of BRCA++ cases, 179/337 (53%) of BRCA+ cases, 4/25 (16%) of other HRR++ cases, and 87/367 (24%) of other HRR+ cases were HRD-positive. We observed no cases that were HRD-positive without an alteration in either BRCA1/2 or other HRR gene. Within the other HRR+ group, we found that single alterations in CHEK1/2, FANCA/L, MRE11, PALB2, and RAD51B were all significantly associated with HRD-positivity whereas CDK12, for instance, was not (Table). Conclusions: Comprehensive genomic profiling demonstrates that approximately 1 in 4 patients without BRCA alterations may potentially benefit from PARP inhibition due to alterations in other HRR genes. Future studies may examine the role of PARP inhibition in this population of HRR+ pancreatic cancer patients.[Table: see text]

A Novel Therapeutic Strategy for Pancreatic Cancer with Positive Peritoneal Cytology after Neoadjuvant Therapy

Background: Despite a new era of neoadjuvant therapy (NAT) coming for patients with resectable pancreatic cancer (PC), the persistence of positive peritoneal cytology (CY+) after NAT is an emerging issue affecting an adverse prognosis.

Clustering of Chromatin Remodeling Enzymes Predicts Prognosis and Clinical Benefit of Therapeutic Strategy in Pancreatic Cancer.

In recent years, translational research and pharmacological targeting of epigenetic modifications have become the focus of personalized therapy for patients with pancreatic cancer. Preclinical and clinical trials targeting post-translational modifications have been evaluated as monotherapy or in combination with standard chemotherapy. In this study, we selected 43 genes from seven families of chromatin-modifying enzymes and investigated the influences of epigenetic modifications and their interactions on pancreatic ductal adenocarcinoma (PDAC) using hierarchical clustering analysis. Our analysis also evaluated their effects on treatment modalities and regimens of chemotherapy for PDAC. RNA-seq data for a total of 177 patients with pancreatic cancer, obtained from The Cancer Genome Atlas database, were analyzed. Our results suggested that high-risk patients of survival significant chromatin remodeling-associated gene cluster (gene cluster 2), composed of histone methyltransferases, histone acetyltransferases, histone deacetylases, histone demethylases, and 10-11 translocation family, demonstrated inferior progression-free survival and overall survival in patients with PDAC, especially in men. Our novel biomarker, survival significant chromatin remodeling-associated gene cluster, showed superior prediction performance compared with the conventional TNM system. Overall, these findings suggest that epigenetic modifications and interactions play an important role in the prognosis and therapeutic response of patients with PDAC.

Current and emerging therapeutic strategies in pancreatic cancer: Challenges and opportunities.

Pancreatic carcinoma (PC) is one of the leading causes of cancer-related deaths worldwide. Despite early detection and advances in therapeutics, the prognosis remains dismal. The outcome and therapeutic approach are dependent on the stage of PC at the time of diagnosis. The standard of care is surgery, followed by adjuvant chemotherapy. The advent of newer drugs has changed the landscape of adjuvant therapy. Moreover, recent trials have highlighted the role of neoadjuvant therapy and chemoradiotherapy for resectable and borderline resectable PC. As we progress towards a better understanding of tumor biology, genetics, and microenvironment, novel therapeutic strategies and targeted agents are now on the horizon. We have described the current and emerging therapeutic strategies in PC.

A new pancreatic adenocarcinoma-derived organoid model of acquired chemoresistance to FOLFIRINOX: First insight of the underlying mechanisms.

Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO. We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness. We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse. To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.

Long Intergenic Nonprotein Coding RNA 173 Inhibits Tumor Growth and Promotes Apoptosis by Repressing Sphingosine Kinase 1 Protein Expression in Pancreatic Cancer.

Pancreatic cancer is a common malignant tumor worldwide. Extensive studies have been conducted on the functional role of long noncoding RNAs in pancreatic cancer. In this study, long intergenic nonprotein coding RNA 173 (LINC00173) was highly expressed in pancreatic cancer tissues. In vitro functional experiments showed that LINC00173 overexpression inhibited the proliferation and invasion of pancreatic cancer cells and promoted cell apoptosis in MIA PaCa-2 and PANC-1 cells. RNA sequencing analysis and Western blot assays demonstrated that LINC00173 reduced the expression of sphingosine kinase 1 (SPHK1) and then inhibited the protein expression of activated phospho-protein kinase B (AKT) and NF-κB. In vivo functional assays also revealed that LINC00173 inhibited the growth of pancreatic cancer xenografts, repressed cell proliferation, promoted cell apoptosis, and inhibited SPHK1 expression. The combined results of this study indicate that LINC00173 inhibits pancreatic cancer progression by repressing SPHK1 expression. Improving LINC00173 may represent a therapeutic strategy for pancreatic cancer in the future.

Fully‐humanized bioengineered miR‐1291 modulates key nutrient transport and metabolism to exert synergistic anticancer effects with chemotherapeutics

Metabolism of cancer cells is different from normal cells and heterogeneous. To meet energetic and material needs for high-rate proliferation and tumorigenesis, cancer cells generally rely more heavily on vital exogenous nutrients (e.g. glucose, amino acids, and vitamins) than normal cells. Therefore, control of nutrient transport and metabolism in cancer cells is a novel anticancer strategy. Our previous studies have suggested that microRNA-1291-5p (miR-1291-5p) is downregulated in pancreatic cancer (PC) cells and acts a tumor suppressor. The current study aimed to develop a new approach to produce and employ fully-humanized recombinant miR-1291 agent to investigate its mechanistic actions in the regulation of PC cell metabolism and combination therapy with other metabolic modulators. We first cloned and achieved high-level heterogenous expression of humanized recombinant pre-miR-1291 in bacteria using human serine-tRNA (htRNASer) as a carrier. We then produced htRNASer/pre-miR-1291 (htRNASer/miR-1291) on large scale and purified it to high purity (> 4 mg RNA per liter of culture, > 97% homogeneity). Deep sequencing analyses revealed that htRNASer/miR-1291 was selectively processed to target miR-1291-5p to modulate PC cell transcriptome. Proteomics study showed that a number of proteins were reduced remarkably in AsPC-1 cells by biologic miR-1291-5p, among which PNPO, an enzyme that mediates the synthesis of essential nutrient vitamin B6 (VB6), was revealed as a leading target of miR-1291-5p. In addition to PNPO and previously reported SLC2A1/GLUT1, transporter SLC7A5/LAT1 was verified as a direct target for miR-1291-5p. Downregulation of PNPO, LAT1, GLUT1 protein expression by biological miR-1291 led to sharp alteration of homeostasis of glucose, amino acids, and VB6 in human PC cells, and subsequently an increase of oxidative stress. Subsequently, the glycolysis capacity and mitochondrial function of PC cells were significantly suppressed as demonstrated by Seahorse live cell analyses. In addition, combination treatment with htRNASer/miR-1291 and 5-FU exerted synergism in the inhibition of PC cell growth. Overall, our studies revealed a critical role of miR-1291 in the regulation of PC cell metabolism which may provide novel insight in developing new therapeutic strategies for PC.

Preclinical evaluation of a novel anti-mesothelin immunotoxin based on a single domain antibody as the targeting ligand

Pancreatic cancer, as one of the most aggressive and lethal malignancies in the world, is lack of effective treatment. Constructing immunotoxin molecules to target the mesothelin (MSLN) receptor is a potential therapeutic strategy for pancreatic cancer and other related malignant tumors, with some molecules being tested in clinical trials. However, currently, there are still some limitations in its applications, such as the difficulty of the preparation of drug molecules, the limited effectiveness of drugs, and the inadequacy of drug safety and immunogenicity. In this study, we constructed a novel type of anti-MSLN immunotoxin, A1-PE24X7, in which a single domain antibody (sdAb) molecule was used as the target ligand and an improved PE24X7 toxin with reduced off-target toxicity and immunogenicity was used as the effector. Unlike conventional immunotoxins, the designed A1-PE24X7 could be easily expressed in the E. coli system in the form of a soluble protein with a good yield (15-–20 mg/L), avoiding the complex process of denaturation and refolding of inclusion bodies, and it can be conveniently stored in PBS solution for more than 7 days at 4 °C, showing high storage stability. Cell-based experiments showed that A1-PE24X7 entered MSLN-expressing tumor cells in a receptor-mediated manner and killed these cells with an EC50 in the low nanomolar range (0.13 nM against NCI-N87 cells and 0.79 nM against AsPC-1 cells) and it showed ideal selectivity for the MSLN receptor (>100 nM against receptor negative PC3 cells). In animal-based experiments, A1-PE24X7 had tumor enrichment ability in relation to MSLN-positive tumors and showed strong tumor killing and inhibition in mouse models of pancreatic cancer and gastric cancer. Five injections of 3.0 mg/kg A1-PE24X7 significantly reduced the tumor volume of gastric NCI-N87 cancer and also significantly inhibited the growth of pancreatic AsPC-1 cancer. In addition, the maximum tolerable dosage (MSD) of A1-PE24X7 to mice was higher than 15 mg/kg, showing that A1-PE24X7 has a relatively broad therapeutic window. These preclinical results indicate that this strategy has good potential for application to the treatment of pancreatic cancer and other tumors with high MSLN expression.

High-Fat Diet Drives an Aggressive Pancreatic Cancer Phenotype

Emerging evidence indicates associations between high-fat diet (HFD), metabolic syndrome (MetS), and increased risk of pancreatic cancer. However, individual components of an HFD that increase cancer risk have not been isolated. In addition, a specific pattern of cytokine elevation by which MetS drives pancreatic tumor progression is not well described. We hypothesized that oleic acid (OA), a major component of HFD, would augment pancreatic neoplastic processes. An orthotopic pancreatic cancer model with Panc02cells was used to compare the effect of low-fat diet to OA-based HFD on cancer progression. Tumors were quantitated, analyzed by immunohistochemistry. In addition, serum cytokine levels were quantitated. Proliferation, migration assays, and expression of epithelial-to-mesenchymal transition factors were evaluated on Panc02 and MiaPaCa-2 pancreatic cancer cells cultured in high concentrations of OA. HFD tumor-bearing mice (n=8) had an 18% weight increase (P<0.001) and increased tumor burden (P<0.05) compared with the low-fat diet tumor-bearing group (n=6). HFD tumors had significantly increased angiogenesis (P<0.001) and decreased apoptosis (P<0.05). Serum of HFD mice demonstrated increased levels of glucagon and glucagon-like peptide-1. Two pancreatic cancer cell lines cultured in OA demonstrated significant increases in proliferation (P<0.001) and a >2.5-fold increase in cell migration (P<0.001) when treated with OA. Panc02 treated with OA had increased expression of epithelial-to-mesenchymal transition factors SNAI-1 (Snail) and Zeb-1(P<0.01). High-fat conditions invitro and invivo resulted in an aggressive pancreatic cancer phenotype. Our data support further investigations elucidating molecular pathways augmented by MetS conditions to identify novel therapeutic strategies for pancreatic cancer.

Solasodine, Isolated from Solanum sisymbriifolium Fruits, Has a Potent Anti-Tumor Activity Against Pancreatic Cancer.

BackgroundIncreasing evidences have revealed that solasodine, isolated from Solanum sisymbriifolium fruits, has multiple functions such as anti-oxidant, anti-tumor and anti-infection. However, its role in pancreatic cancer has not been well studied.MethodsTo explore the role of solasodine in pancreatic cancer, human pancreatic cell lines including SW1990 and PANC1 were treated with different concentrations of solasodine for 48 h, and cell viability was evaluated by MTT assay, cell invasion and migration were evaluated by Transwell assay. The effect of solasodine on the apoptosis of SW1990 and PANC1 cells was detected by flow cytometry. To further explore the antitumor effect of solasodine in vivo, an SW1990 tumor-bearing mouse model was constructed. The effects of solasodine on cytokines in the serum of SW1990 tumor-bearing mice were also evaluated by ELISA assay.ResultsSpecifically, in vitro, solasodine could significantly inhibit the proliferation of pancreatic cancer cell lines SW1990 and PANC1 cells. Flow cytometric analysis indicated that solasodine could induce apoptosis of SW1990 and PANC1 cells. Western blot assay indicated that solasodine could significantly inhibit the activation of Cox-2/Akt/GSK3β signal pathway. Meanwhile, the release of Cytochrome c from mitochondria to cytoplasm which can raise the caspases cascade (C-caspase 3 and C-caspase 9) was significantly enhanced by solasodine. In vivo, the results showed that solasodine had potent anti-tumor activities with a lower cytotoxicity. In addition, the serum TNF-α, IL-2 and IFN-γ levels in SW1990 tumor-bearing mice after the treatment of solasodine was significantly increased.ConclusionTaken together, our results suggested that the solasodine could prevent the progression of pancreatic cancer by inhibiting proliferation and promoting apoptosis, as well as stimulating immunity, suggesting that solasodine might be a potential therapeutic strategy for pancreatic cancer.

Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.

Systematic Analysis of the Expression and Prognostic Significance of P4HA1 in Pancreatic Cancer and Construction of a lncRNA-miRNA-P4HA1 Regulatory Axis.

Objectives Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) plays a crucial role in modulating extracellular matrix component and promoting tumor progression by changing tumor adhesion, migration, and other biological behaviors in some cancers. However, its expression pattern, biological function, and underlying mechanism in pancreatic cancer remain largely unclear. Materials and Methods In this study, a set of bioinformatics tools were used to analyze the expression of P4HA1 and its prognostic value in pancreatic cancer. In addition, the mechanism through which P4HA1 promotes the progression of pancreatic cancer was explored by constructing a competing endogenous RNA (ceRNA) regulatory axis. Results It was found that the mRNA and protein expression of P4HA1 was significantly higher in pancreatic cancer tissues than in normal tissues. Its high P4HA1 expression correlated with poor clinicopathological features (T stage: P = 0.0078; N stage: P = 0.0124; TNM stage: P = 0.0013; pathological grade: P = 0.0108) and poor prognosis [OS: HR = 1, 95% CI (1-1.01), P = 0.00028; DSS: HR = 1, 95% CI (1-1.01), P = 0.00049; PFI: HR = 1.01, 95% CI (1.01-1.02), P = 0.0057; and DFI: HR = 1, 95% CI (1-1.01), P = 0.0034]. The LINC01503/miR-335-5p/P4HA1 axis might mediate the effects of P4HA1 in promoting the progression on pancreatic cancer. Conclusions Collectively, our findings suggest that high expression of P4HA1 may be used as a promising prognostic biomarker and could be considered for the development of a novel therapeutic strategy for pancreatic cancer in the future.

Purinergic Signaling in Pancreas-From Physiology to Therapeutic Strategies in Pancreatic Cancer.

The purinergic signaling has an important role in regulating pancreatic exocrine secretion. The exocrine pancreas is also a site of one of the most serious cancer forms, the pancreatic ductal adenocarcinoma (PDAC). Here, we explore how the network of purinergic and adenosine receptors, as well as ecto-nucleotidases regulate normal pancreatic cells and various cells within the pancreatic tumor microenvironment. In particular, we focus on the P2X7 receptor, P2Y2 and P2Y12 receptors, as well as A2 receptors and ecto-nucleotidases CD39 and CD73. Recent studies indicate that targeting one or more of these candidates could present new therapeutic approaches to treat pancreatic cancer. In pancreatic cancer, as much as possible of normal pancreatic function should be preserved, and therefore physiology of purinergic signaling in pancreas needs to be considered.

Nanoformulation of PROteolysis TArgeting Chimera targeting 'undruggable' c-Myc for the treatment of pancreatic cancer.

Aim: To explore the anticancer activity of a novel BRD4 protein degrader ARV-825 (ARV) and its nanoformulation development (ARV-NP) for treatment of pancreatic cancer. Materials & methods: ARV-NP were prepared using nanoprecipitation method and characterized for their physicochemical properties and various anticancer cell culture assays. Results: ARV-NP (89.63±16.39nm) demonstrated good physical stability, negligible hemolysis and improved half-life of ARV. ARV-NP showed significant cytotoxicity, apoptosis and anticlonogenic effect in pancreatic cancer cells. Significant downregulation of target proteins BRD4, c-Myc, Bcl-2 and upregulation of apoptotic marker cleaved caspase-3 was observed. Most importantly, ARV-NP treatment significantly inhibited the cell viability of 3D tumor spheroids of pancreatic cancer. Conclusion: ARV-NP represents a novel therapeutic strategy for pancreatic cancer.