Survival Of Pancreatic Cancer Patients Research Articles

Study on the Potential Molecular Mechanism of Xihuang Pill in the Treatment of Pancreatic Cancer Based on Network Pharmacology and Bioinformatics.

Objective We aimed to analyze the possible molecular mechanism of Xihuang pill (XHP) in the treatment of pancreatic cancer based on methods of network pharmacology, molecular docking, and bioinformatics. Methods The main active components and targets were obtained through the TCMSP database, the BATMAN-TCM database, and the Chemistry database. The active ingredients were screened according to the “Absorption, Distribution, Metabolism, Excretion” (ADME) principle and supplemented with literature. We searched GeneCards, OMIM, TTD, and DrugBank databases for pancreatic cancer targets. The targets of disease and ingredients were intersected to obtain candidate key targets. Then, we constructed a protein-protein interaction (PPI) network for protein interaction analysis and a composition-key target map to obtain essential effective ingredients. Metascape was used to perform functional enrichment analysis to screen critical targets and pathways. The expression and prognosis of key targets were examined and analyzed, and molecular docking was carried out. Results A total of 52 active ingredients of XHP, 121 candidate targets, and 52 intersecting targets were obtained. The core active ingredients of XHP for the treatment of pancreatic cancer were quercetin, 17-β-estradiol, ursolic acid, and daidzein. The core targets were EGFR, ESR1, MAPK1, MAPK8, MAPK14, TP53, and JUN, which were highly expressed genes of pancreatic cancer. Among them, EGFR and MAPK1 were significantly correlated with the survival of pancreatic cancer patients. The key pathway was the EGFR/MAPK pathway. The molecular docking results indicated that four active compositions had good binding ability to key targets. Conclusion The molecular mechanism of XHP for the treatment of pancreatic cancer involved multiple components, multiple targets, and multiple pathways. This research theoretically elucidated the ameliorative effect of XHP against pancreatic cancer and might provide new ideas for further research on the treatment of pancreatic cancer.

The Association Between Neoadjuvant Therapy and Pathological Outcomes in Pancreatic Cancer Patients After Resection: Prognostic Significance of Microscopic Venous Invasion.

The impact of neoadjuvant therapy (NAT) on pathological outcomes, including microscopic venous invasion (MVI), remains unclear in pancreatic cancer. A total of 456 patients who underwent pancreatectomy for resectable and borderline resectable pancreatic cancer between July 2012 and February 2020 were retrospectively reviewed. Patients were divided into two groups: patients with NAT (n=120, 26%) and those without NAT (n=336, 74%). Clinicopathological factors, survival outcomes and recurrence patterns were analyzed. Regarding pathological findings, the proportion of MVI was significantly lower in patients with NAT than in those without NAT (43% vs 62%, P=0.001). The 5-year survival rate in patients with NAT was significantly better than that in those without NAT (54% vs 45%, P=0.030). A multivariate analysis showed that MVI was an independent prognostic factor for the overall survival (OS) (hazard ratio 2.86, P=0.003) in patients who underwent NAT. MVI was an independent risk factor for liver recurrence (odds ratio [OR] 2.38, P=0.016) and multiple-site recurrence (OR 1.92, P=0.027) according to a multivariate analysis. The OS in patients with liver recurrence was significantly worse than that in patients with other recurrence patterns (vs lymph node, P=0.047; vs local, P < 0.001; vs lung, P < 0.001). The absence of NAT was a significant risk factor for MVI (OR 1.93, P=0.007). MVI was a crucial prognostic factor associated with liver and multiple-site recurrence in pancreatic cancer patients with NAT. MVI may be reduced by NAT, which may contribute to the improvement of survival in pancreatic cancer patients.

GABRP is a potential prognostic biomarker and correlated with immune infiltration and tumor microenvironment in pancreatic cancer.

BackgroundPancreatic cancer is one of the most commonly diagnosed and lethal malignancies worldwide and has few good biomarkers and therapeutic targets. GABRP is the π subunit of the gamma-aminobutyric acid (GABA) A receptor, which is expressed in a number of non-neuronal tissues. GABRP is significantly upregulated in pancreatic cancer, but its biological and immunological role as well as its clinical diagnostic and prognostic value in pancreatic cancer is still incompletely known.MethodsIn this study, pancreatic adenocarcinoma (PAAD) cohorts from TCGA and GEO datasets were used to compare GABRP mRNA levels in cancerous and normal tissues and protein expression was evaluated using immunohistochemistry. The Kaplan-Meier plotter and GEPIA2 database were used to analyze the correlation between GABRP expression, overall survival, and disease-free survival in pancreatic cancer patients. Gene set enrichment analysis (GSEA) was performed with the Linked Omics database to explore the molecular mechanisms of GABRP in pancreatic cancer. And the correlation between GABRP expression and immune infiltration was explored using the TIMER database, CIBERSORT database and ESTIMATE algorithm.ResultsGABRP mRNA was significantly overexpressed in TCGA-PAAD cohorts (P<0.0001) and enhanced GABRP expression predicted poorer overall survival according to Kaplan-Meier plotter database (P=0.0024) and GEPIA2 (P=0.038). Hypomethylation of promoter (P<0.01) and the regulation of hsa-miR-3655 may contribute to the overexpression of GABRP in pancreatic cancer. GSEA analysis revealed that GABRP played an important role in the immune response. GABRP expression was also correlated with immune infiltration and immune cell markers. Higher GABRP expression was significantly associated with greater infiltration of immune cells and stromal cells into pancreatic cancer microenvironments as well as higher expression of six important immune check point genes including PDCD1 (P<0.05), CD274 (P<0.05), CTLA4 (P<0.01), PDCD1LG2 (P<0.01), TIGHT (P<0.01) and TIM3 (P<0.01).ConclusionsGABRP is a potential prognostic biomarker and is correlated with immune infiltration and tumor microenvironment in pancreatic cancer. This suggests that GABRP may serve as a potential prognostic biomarker and therapeutic target in pancreatic cancer as well as a possible regulator of tumor microenvironment affecting the efficacy of immunotherapy. Further studies are needed to elucidate the molecular mechanism of the immunoregulatory role of GABRP.

Curcumol inhibits the growth of xenograft-tumors in mice and the biological activities of pancreatic cancer cells by regulating the miR-21-5p/SMAD7 axis

ABSTRACT Anti-cancer effects of curcumol on various cancers have been reported previously. This study focused on investigating the role of curcumol in pancreatic cancer from the molecular perspective. The survival of pancreatic cancer patients with high or low expression of miR-21-5pand the target gene of miR-21-5pwere analyzed by bioinformatics. MiR-21-5p expression in cancer tissues was analyzed by RT-qPCR. Anxenograft-tumor BALB/c nude mice model was established and pancreatic cancer cells were cultured. Later, the mice and cells were further treated with curcumol. The tumor size and weightas well as mice body weight were recorded. The viability, proliferation, migration, and invasion of the cells were evaluated by MTT, colony formation, and transwell assays, respectively. The expressions of molecules in the xenograft-tumor tissues or cells were detected by immunohistochemical assay, Western blot, or RT-qPCR. MiR-21-5p was high-expressed in pancreatic cancer tissues and patients with high expression of miR-21-5p had poor survival. Curcumol inhibited the xenograft-tumor size, tumor weight, and PCNA and miR-21-5p expressions while promoting Cleaved caspase-3 expression in xenograft-tumor tissues. Curcumol inhibited the viability, proliferation, migration, invasion, and miR-21-5p expression, but increased SMAD7 expression in cancer cells. MiR-21-5p overexpression reversed the effect of curcumol on cancer cells, and decreased the E-cadherin expression while elevating the expressions of PCNA, N-cadherin, Vimentin, p-SMAD2, and p-SMAD3 in curcumol-treated cells. The overexpression of SMAD7, a target gene of miR-21-5p, reversed the effect of miR-21-5p on curcumol-treated cells. Curcumol inhibited growth of xenograft-tumors and the biological activities of pancreatic cancer cells by regulating the miR-21-5p/SMAD7 axis.

Prognostic significance of systemic immune-inflammation index and platelet-albumin-bilirubin grade in patients with pancreatic cancer undergoing radical surgery

Systemic inflammatory markers are associated with patient survival in pancreatic cancer (PC). The aim of this study was to investigate the prognostic significance of the systemic immune-inflammation index (SII) in PC patients who underwent radical surgery. Platelet-albumin-bilirubin (PALBI) grade is a composite evaluation index based on liver function. Patients with pancreatic head cancer are prone to obstructive jaundice, which leads to abnormal liver function. Based on this, we also explored the prognostic value of PALBI grade in PC patients. Patients with pathologically confirmed PC who had undergone radical surgery (with negative surgical margin) for the first time at the Affiliated Hospital of Qingdao University from January 2013 to December 2019 and followed up by December 2020 were retrospectively analyzed. Peripheral blood cell count is easily affected by infection or hematological diseases, which affects the results, so it is excluded. Clinical data and laboratory examination indexes were collected. The SII and PALBI grade were calculated. The cutoff values were determined using the Youden index. The Cox proportional hazards regression model was used to analyze the prognostic value of the SII and PALBI grade through univariate and multivariate survival analysis. A total of 214 patients [median age, 60.29 years; 128 (59.8%) men] met the inclusion criteria. There were 140 patients (65.4%) with pancreatic head cancer according to the tumor location. They were divided into high and low SII or PALBI groups by cutoff values of 705 and -5.6, respectively. According to the multivariate analysis, SII (P<0.001) was an independent factor negatively associated with overall survival (OS) and disease-free survival (DFS). In patients with pancreatic head cancer, PALBI grade was associated with shorter OS (P=0.031). The combination of high SII and high PALBI grade had stronger predictive value for poor prognosis (log-rank test, P<0.001), which the OS was 11.3 months less than the combination of low two groups. SII was a promising prognostic biomarker in PC. And PALBI grade also showed predictive value for patients with pancreatic head cancer. Therefore, it can help predict the treatment outcomes in these patients.

TGF-β1-induced RAP2 regulates invasion in pancreatic cancer.

Pancreatic cancer is highly lethal due to its aggressive invasive properties and capacity for metastatic dissemination. Additional therapeutic targets and effective treatment options for patients with tumours of high invasive capacity are required. Ras-related protein-2a (RAP2) is a member of the GTP-binding proteins. RAP2 has been reported to be widely upregulated in many types of cancers via regulating cytoskeleton reorganization, cell proliferation, migration, and adhesion, as well as inflammation. As a member of the RAS oncogene family, which has been demonstrated to drive pancreatic cancer oncogenesis and many other malignancies, the physiological roles of RAP2 in pancreatic cancer have seldom been discussed. In the present study, we explored the correlation between RAP2 expression and the prediction of overall survival of pancreatic cancer patients. Mechanistic studies were carried out to shed light on the role of RAP2 in pancreatic cancer invasion and how RAP2 is regulated in the invasive process. Our results demonstrated that patients with higher RAP2 expression showed unfavourable prognoses. studies demonstrated that silencing of inhibited the invasion of pancreatic cancer cells. Moreover, our results demonstrated that transforming growth factor-β1 (TGF-β1), an inducer of the metastatic potential of pancreatic cancer cells, regulates the expression of RAP2 via the transcription factor c-Myc. In conclusion, the present study uncovered RAP2 as a novel predictive marker and therapeutic target for pancreatic cancer.

Ferroptosis-Related IncRNAs Are Prognostic Biomarker of Overall Survival in Pancreatic Cancer Patients.

Pancreatic cancer (PC) is one of the most lethal malignancies, the mortality and morbidity of which have been increasing over the past decade. Ferroptosis, a newly identified iron-dependent cell death pattern, can be induced by iron chelators and small lipophilic antioxidants. Nonetheless, the prognostic significance of ferroptosis-related lncRNAs in PC remains to be clarified. We obtained the lncRNA expression matrix and clinicopathological information of PC patients from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets in the current study. Firstly, we conducted Pearson correlation analysis to delve into the ferroptosis-related lncRNAs, and univariate Cox analysis was implemented to examine the prognostic values in PC patients. Twenty-three prognostic ferroptosis-related lncRNAs were confirmed and loaded into the least absolute shrinkage and selection operator Cox (LASSO-Cox) analysis, then a ferroptosis-related lncRNA prognostic marker (Fe-LPM) was established in the TCGA dataset. Risk scores of patients were calculated and segregated PC patients into low-risk and high-risk subgroups in each dataset. The prognostic capability of Fe-LPM was also confirmed in the ICGC dataset. Gene set enrichment analysis (GSEA) revealed that several ferroptosis-related pathways were enriched in low-risk subgroups. Furthermore, we adopted a multivariate Cox regression to establish a nomogram based on risk score, age, pathological T stage and primary therapy outcome. A competing endogenous RNA (ceRNA) network was also created relied on four of the twenty-three ferroptosis-related lncRNAs. In conclusion, the eight Fe-LPM can be utilized to anticipate the overall survival (OS) of PC patients, which are meaningful to guiding clinical strategies in PC.

Impact of venous thromboembolism in hospitalized patients with pancreatic cancer: A nationwide inpatient sample (NIS) study.

535 Background: Pancreatic cancer (PC) has a strong association with venous thromboembolism (VTE) but the impact of it on mortality and morbidity is unknown. Inpatient costs contribute significantly to the overall cancer care costs even though there is a modest improvement in survival of pancreatic cancer patients. This study aims to determine the mortality trends and associated health care utilization in PC patients with and without VTE and to analyze its impact on hospitalized patients. Methods: We used National Inpatient Sample (NIS) to extract data for all patients above 18years of age hospitalized with a primary diagnosis of Pancreatic cancer from 2002-2018 using ICD-9 and ICD-10 codes. Unadjusted odds ratio for dichotomous outcomes were calculated, and independent t test analysis was done for continuous outcomes. Results: The odds of all-cause mortality (OR 1.35, 95% CI 1.33-1.37, p&lt;0.001) and stroke (OR 1.82, 95% CI, 1.76-1.87, p&lt;0.001) were significantly higher in pancreatic cancer patients with VTE compared to without VTE. PC patients with VTE were found to have significantly higher average cost of hospitalization (US $56101 vs US $46325, p&lt;0.001) and longer length of stay(LOS) (8.20 vs 6.83, p&lt;0.001) when compared to patients without VTE. Conclusions: Hospitalized PC patients with VTE have higher odds of mortality and stroke when compared to PC patients without VTE. Similarly, VTE in PC patients is shown to increase the hospitalization costs and overall length of stay.[Table: see text]

Latest Advances in the Use of Therapeutic Focused Ultrasound in the Treatment of Pancreatic Cancer.

Simple SummaryPancreatic cancer is a devastating disease with the worst survival rates of all cancers. Advances in immunotherapy have revolutionized the treatment of cancer, providing cures to patients with a previously lethal disease. Sadly, clinical trials of currently established immunotherapies have not provided significant therapeutic benefits to pancreatic cancer patients. For this reason, alternative treatment approaches that could sensitise the pancreatic tumours to immunotherapy are needed. Therapeutic focused ultrasound is a non-invasive physical modality that can kill cells by raising the temperature, and by disrupting and destroying tissue mechanically. It can also sensitise tumours to the effects of radiotherapy. This review article describes the use of therapeutic focused ultrasound in the treatment of pancreatic cancer. Attention is given to the immunological effects induced by therapeutic focused ultrasound, and how these can be used to sensitise the pancreatic tumours to immunotherapy.Traditional oncological interventions have failed to improve survival for pancreatic cancer patients significantly. Novel treatment modalities able to release cancer-specific antigens, render immunologically “cold” pancreatic tumours “hot” and disrupt or reprogram the pancreatic tumour microenvironment are thus urgently needed. Therapeutic focused ultrasound exerts thermal and mechanical effects on tissue, killing cancer cells and inducing an anti-cancer immune response. The most important advances in therapeutic focused ultrasound use for initiation and augmentation of the cancer immunity cycle against pancreatic cancer are described. We provide a comprehensive review of the use of therapeutic focused ultrasound for the treatment of pancreatic cancer patients and describe recent studies that have shown an ultrasound-induced anti-cancer immune response in several tumour models. Published studies that have investigated the immunological effects of therapeutic focused ultrasound in pancreatic cancer are described. This article shows that therapeutic focused ultrasound has been deemed to be a safe technique for treating pancreatic cancer patients, providing pain relief and improving survival rates in pancreatic cancer patients. Promotion of an immune response in the clinic and sensitisation of tumours to the effects of immunotherapy in preclinical models of pancreatic cancer is shown, making it a promising candidate for use in the clinic.

Multi-Modal Fusion of Radiomics and Pathomics to Predict the Survival of Pancreatic Cancer Patients Based on Asymmetric Twinning Information Interaction Network

Multi-Modal Fusion of Radiomics and Pathomics to Predict the Survival of Pancreatic Cancer Patients Based on Asymmetric Twinning Information Interaction Network

Risk factors and prognostic index model for pancreatic cancer.

Pancreatic cancer is a highly malignant tumor with poor prognosis. Chronic inflammation contributes to the progression of pancreatic cancer. However, few studies have examined the prognostic role of inflammatory markers in this cancer. Our study sought to analyze the prognostic risk factors of and construct a prognostic index (PI) model using inflammatory markers for pancreatic cancer. Forty-eight patients diagnosed with pancreatic cancer at our hospital were selected for this retrospective analysis. Data on the general clinical characteristics, tumor-related features, blood index factors, and treatment methods were collected. The Cox proportional-hazards model was used to analyze the factors affecting the prognosis, and the Kaplan-Meier analysis was used to draw the survival curve. The median overall survival time was 14.5 months, and the 1-, 2-, and 3-year survival rates were 20.83% (10/48), 6.25% (3/48), and 4.17% (2/48), respectively. The univariate analysis showed that tumor grade, vascular invasion, adjacent tissue invasion, lymph node metastasis, tumor-node-metastasis (TNM) stage, the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the lymphocyte-monocyte ratio (LMR) were significantly correlated with the median survival of pancreatic cancer patients (P<0.05). The Cox regression equation showed that tumor grade III-IV (X1), vascular invasion (X2), TNM stage III-IV (X3), a NLR >3.8 (X4), and a PLR >182.1 (X5) were independent risk factors affecting the prognosis of patients with pancreatic cancer (all P<0.05). The prognostic model for pancreatic cancer can be expressed as: PI =3.521X1+4.157X2+1.282X3+2.441X4+6.015X5. Patients with tumor grade I-II, non-vascular invasion, TNM stage I-II, a NLR ≤3.8, and a PLR ≤182.1 exhibited a higher 1-year survival rate. The areas under the receiver operating characteristic (ROC) curves for the NLR >3.8 and the PLR >182.1 were 0.778 and 0.713, respectively. Tumor grade, vascular invasion, TNM staging, the NLR, and the PLR are independent risk factors affecting the prognosis of pancreatic cancer patients. The NLR and PLR have good clinical value in predicting the survival outcomes of pancreatic cancer patients.

Inhibition of the Renin-Angiotensin System and Survival in Patients with Pancreatic Cancer

Introduction: The renin-angiotensin system may mediate tumor growth in pancreatic cancer. Drugs inhibiting this system may therefore be associated with survival in patients with pancreatic cancer. We examined the association between prediagnostic use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) and survival in pancreatic cancer patients.

Expression of CD98hc in Pancreatic Cancer and Its Role in Cancer Cell Behavior.

Background: Cluster of differentiation 98 heavy chain (CD98hc) is a transmembrane protein, which functions both as a coreceptor of ß-integrins, enhancing intracellular integrin-dependent downstream signaling, and as a transporter of branched-chain and aromatic amino acids. As such, it is pivotal in cell cycle regulation and protection of oxidative, nutritional and DNA replication stress. Overexpression of CD98hc occurs widely in cancer cells and is associated with poor clinical prognosis. The role of CD98hc in pancreatic cancer remains to be elucidated. The aim of this study was to determine the expression of CD98hc in pancreatic ductal adenocarcinoma and to define its potential functional role in cancer cell biology.Methods: Immunohistochemical staining for CD98hc was performed on 222 tissue samples of patients with pancreatic ductal adenocarcinoma. The pancreatic cancer cell lines PANC-1 and BxPC-3 were used to determine the effect of CD98hc expression on cancer cell behavior using cell adhesion, cell trans-migration and cell spreading assays. Flow cytometry was performed to study the rate of apoptosis after detachment or serum starvation. shRNA-lentiviral constructs were used to knock down or reconstitute full length or mutated CD98hc.Results: Up to 20% of pancreatic ductal adenocarcinomas express CD98hc in the acinar cells (13%) and islet cells (20%) embedded in tumor tissue. Although expression of CD98hc in tumor tissue was not associated with a particular tumor stage or grade, our data show a trend towards longer overall survival of pancreatic cancer patients without CD98hc expression as compared to those with immunohistochemical positivity. In vitro downregulation of CD98hc in the pancreatic cancer cell lines PANC-1 and BxPC-3 significantly inhibits cell proliferation (p<0.05), self-renewal (p<0.05) and anchorage-independent growth (p<0.05).Conclusion: CD98hc is expressed in a remarkable percentage of pancreatic ductal adenocarcinomas. Due to its important role in cell behavior and malignant cell transformation, it may be a promising molecular target for potential new therapeutic approaches in pancreatic cancer in the future.

A TP53-associated immune prognostic signature for the prediction of the overall survival and therapeutic responses in pancreatic cancer.

Pancreatic cancer (PC) is a highly fatal disease correlated with an inferior prognosis. The tumor protein p53 (TP53) is one of the frequent mutant genes in PC and has been implicated in prognosis. We collected somatic mutation data, RNA sequencing data, and clinical information of PC samples in the Cancer Genome Atlas (TCGA) database. TP53 mutation was an independent prognostic predictor of PC patients. According to TP53 status, Gene set enrichment analysis (GSEA) suggested that TP53 mutations were related to the immunophenotype of pancreatic cancer. We identified 102 differentially expressed immune genes (DEIGs) based on TP53 mutation status and developed a TP53-associated immune prognostic model (TIPM), including Epiregulin (EREG) and Prolactin receptor (PRLR). TIPM identified the high-risk group with poor outcomes and more significant response potential to cisplatin, gemcitabine, and paclitaxel therapies. And we verified the TIPM in the International Cancer Genome Consortium (ICGC) cohort (PACA-AU) and Gene Expression Omnibus (GEO) cohort (GSE78229 and GSE28735). Finally, we developed a nomogram that reliably predicts overall survival in PC patients on the bias of TIPM and other clinicopathological factors. Our study indicates that the TIPM derived from TP53 mutation patterns might be an underlying prognostic therapeutic target. But more comprehensive researches with a large sample size is necessary to confirm the potential.

Differential Expression of Polyamine Pathways in Human Pancreatic Tumor Progression and Effects of Polyamine Blockade on Tumor Microenvironment.

Simple SummaryPancreatic cancer has a five-year survival rate of less than 8% and is the fourth leading cause of cancer death in the United States. Existing therapeutics have failed to improve pancreatic ductal adenocarcinoma (PDAC) patient outcomes. There has been success with other tumor types in targeting aberrant polyamine upregulation as a therapeutic strategy. The present study identified dysregulation of polyamine pathways to be evident in human PDAC progression. Additionally, reduced survival of pancreatic cancer patients was associated with increased expression of specific polyamine-related genes. Polyamine blockade therapy significantly increased overall survival of pancreatic tumor-bearing mice, along with macrophage presence (F4/80) and significantly increased T-cell co-stimulatory marker (CD86) in the tumor microenvironment. Based on these findings, we hypothesized that a polyamine blockade therapy could potentially prime the tumor microenvironment to be more susceptible to existing therapeutics. Future studies which test polyamine blockade therapy with existing therapeutics could increase the molecular tools available to treat PDAC.Pancreatic cancer is the fourth leading cause of cancer death. Existing therapies only moderately improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The present study investigates the importance of the polyamine metabolism in the pancreatic tumor microenvironment. Relative mRNA expression analysis identified differential expression of polyamine biosynthesis, homeostasis, and transport mediators in both pancreatic epithelial and stromal cells from low-grade pancreatic intraepithelial neoplasia (PanIN-1) or primary PDAC patient samples. We found dysregulated mRNA levels that encode for proteins associated with the polyamine pathway of PDAC tumors compared to early lesions. Next, bioinformatic databases were used to assess expression of select genes involved in polyamine metabolism and their impact on patient survival. Higher expression of pro-polyamine genes was associated with poor patient prognosis, supporting the use of a polyamine blockade therapy (PBT) strategy for inhibiting pancreatic tumor progression. Moreover, PBT treatment of syngeneic mice injected intra-pancreatic with PAN 02 tumor cells resulted in increased survival and decreased tumor weights of PDAC-bearing mice. Histological assessment of PBT-treated tumors revealed macrophage presence and significantly increased expression of CD86, a T cell co-stimulatory marker. Collectively, therapies which target polyamine metabolism can be used to disrupt tumor progression, modulate tumor microenvironment, and extend overall survival.

Abstract PO-120: Differential expression of polyamine pathways in human pancreatic tumor progression and effects of polyamine blockade therapy on the in vivo pancreatic tumor microenvironment

Abstract Pancreatic cancer is the fourth leading cause of cancer death in the United States, with a five-year survival rate of less than 8%. Existing therapies have failed to improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The dense desmoplastic reaction which occurs in PDAC makes it challenging for drugs and immune cells to infiltrate the fibrotic barrier. There is a need to exploit lesser explored targets in PDAC that can influence both the tumor and its microenvironment. One such avenue could be via targeting polyamine metabolism which is upregulated in pancreatic tumors. Though aberrant polyamine upregulation in pancreatic tumors has been known for decades, there has been little progress in translating this information into a PDAC therapeutic strategy. Additionally, there is a dearth of information regarding the dysregulation of polyamine metabolism in human PDAC and its association with clinical outcomes. Thus far, preclinical studies targeting polyamines using polyamine blockade therapy (PBT) has improved survival of pancreatic tumor bearing mice. Literature shows effectiveness of PBT in eliciting an anti-tumor immune response in other tumor types. Whether these results translate to the immune-privileged PDAC microenvironment need to be determined. The present study explores polyamine gene expression in human PDAC samples by mRNA expression analysis of frozen PDAC and Pancreatic intraepithelial neoplasia (PanIN). The Cancer Genome Atlas in the public domain was used to identify clinical outcomes of PDAC patients associated with select polyamine gene expression. Further, the anti-tumor effects of PBT and associated tumor microenvironment changes were identified using in vivo PDAC models and histological assessment. Polyamine dysregulation was found to be evident in human PDAC progression. Also, increased expression of certain polyamine-related genes was associated with poorer survival of pancreatic cancer patients. When targeting polyamines using PBT in immunocompetent C57Bl/6 mice with Pan02 tumor cells injected in the pancreas, PBT significantly increased overall survival. PBT also resulted in an increase in the infiltration of macrophages (F4/80) and expression of T-cell co-stimulatory marker (CD86) as assessed by immunohistochemistry and further quantification of imaging. Based on these changes, we hypothesized that PBT could prime the tumor microenvironment to be more susceptible to existing therapeutics. In conclusion, targeting polyamines using PBT results in increased survival and immune modulation in PDAC. Citation Format: Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jignesh G. Parikh, Dirk Geerts, Kenneth P. Olive, Otto Phanstiel, Deborah A. Altomare, Carlo Maurer. Differential expression of polyamine pathways in human pancreatic tumor progression and effects of polyamine blockade therapy on the in vivo pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-120.

LncRNAs: Novel Biomarkers for Pancreatic Cancer.

Pancreatic cancer is one of the most deadly neoplasms and the seventh major cause of cancer-related deaths among both males and females. This cancer has a poor prognosis due to the lack of appropriate methods for early detection of cancer. Long non-coding RNAs (lncRNAs) have been recently found to influence the progression and initiation of pancreatic cancer. MACC1-AS1, LINC00976, LINC00462, LINC01559, HOXA-AS2, LINC00152, TP73-AS1, XIST, SNHG12, LUCAT1, and UCA1 are among the oncogenic lncRNAs in pancreatic cancer. On the other hand, LINC01111, LINC01963, DGCR5, MEG3, GAS5, and LINC00261 are among tumor suppressor lncRNAs in this tissue. In the current review, we summarize the roles of these two classes of lncRNAs in pancreatic cancer and discuss their potential as attractive diagnostic and prognostic biomarkers for pancreatic cancer. We also identified that the low expression of MEG3, LINC01963, and LINC00261 and the high expression of MACC1-AS1, LINC00462, LINC01559, and UCA1 were significantly correlated with worse survival in pancreatic cancer patients. Further research on these lncRNAs will provide new clues that could potentially improve the early diagnosis, prognostic prediction, and personalized treatments of patients with pancreatic cancer.

Identification of DNA methylation-driven genes and construction of a nomogram to predict overall survival in pancreatic cancer

BackgroundThe incidence and mortality of pancreatic cancer (PC) has gradually increased. The aim of this study was to identify survival-related DNA methylation (DNAm)-driven genes and establish a nomogram to predict outcomes in patients with PC.MethodsThe gene expression, DNA methylation database, and PC clinical samples were downloaded from TCGA. DNAm-driven genes were identified by integrating analyses of gene expression and DNA methylation data. Survival-related DNAm-driven genes were screened via univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to develop a risk score model for prognosis. Based on analyses of clinical parameters and risk score, a nomogram was built and validated. The independent cohort from GEO database were used for external validation.ResultsA total of 16 differentially expressed methylation-driven genes were identified. Based on LASSO Cox regression and multivariate Cox regression analysis, six genes (FERMT1, LIPH, LAMA3, PPP1R14D, NQO1, VSIG2) were chosen to develop the risk score model. In the Kaplan–Meier analysis, age, T stage, N stage, AJCC stage, radiation therapy history, tumor size, surgery type performed, pathological type, chemotherapy history, and risk score were potential prognostic factors in PC (P < 0.1). In the multivariate analysis, stage, chemotherapy, and risk score were significantly correlated to overall survival (P < 0.05). The nomogram was constructed with the three variables (stage, chemotherapy, and risk score) for predicting the 1-year, 2-year, and 3-year survival rates of PC patients. Nomogram performance was assessed by receiver operating characteristic (ROC) curves and calibration curves. 1-year, 2-year and 3-year AUC of nomogram model was 0.899, 0.765 and 0.776, respectively.ConclusionsIn our study, we successfully identified the six DNAm-driven genes (FERMT1, LIPH, LAMA3, PPP1R14D, NQO1, VSIG2) with a relationship to the outcomes of PC patients. The nomogram including stage, chemotherapy, and risk score could be used to predict survival in PC patients.

The prognostic value of intratumoral and peritumoral tumor-infiltrating FoxP3+Treg cells in of pancreatic adenocarcinoma: a meta-analysis

BackgroundTumor-infiltrating lymphocytes (TILs) are major participants in the tumor microenvironment. The prognostic value of TILs in patients with pancreatic cancer is still controversial.MethodsThe aim of our meta-analysis was to determine the impact of FoxP3+Treg cells on the survival of pancreatic cancer patients. We searched for related studies in PubMed, EMBASE, Ovid, and Cochrane Library from the time the databases were established to Mar 30, 2017. We identified studies reporting the prognostic value of FoxP3+Treg cells in patients with pancreatic cancer. Overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS) were investigated by pooling the data. The pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to evaluate the association between FoxP3+Treg cells and survival outcomes of pancreatic cancer patients. A total of 972 pancreatic cancer patients from 8 studies were included in our meta-analysis.ResultsHigh levels of infiltration with FoxP3+Treg cells were significantly associated with poor OS (HR=2.13; 95% CI 1.64–2.77; P<0.05) and poor DFS/PFS/RFS (HR=1.70; 95% CI 1.04 ~ 2.78; P< 0.05). Similar results were also observed in the peritumoral tissue; high levels of FoxP3+Treg cells were associated with poor OS (HR =2.1795% CI, CI 1.50–3.13).ConclusionThis meta-analysis indicated that high levels of intratumoral or peritumoral FoxP3+Treg cell infiltration could be recognized as a negative factor in the prognosis of pancreatic cancer.

Transcription factors specificity protein and nuclear receptor 4A1 in pancreatic cancer.

Specificity protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4, and the orphan nuclear receptor 4A1 (NR4A1) are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival. Results of knockdown and overexpression of Sp1, Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members. NR4A1 is also a pro-oncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth, survival, migration and invasion. There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin, epidermal growth factor receptor, PAX3-FOXO1, α5- and α6-integrins, β1-, β3- and β4-integrins; this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites. Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells, and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.