Approach For Pancreatic Cancer Research Articles

Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer.

The present review demonstrates the major tumor suppressor genes, including TP53, CDKN2A and SMAD4, associated with pancreatic cancer. Each gene's role, prevalence and impact on tumor development and progression are analyzed, focusing on the intricate molecular landscape of pancreatic cancer. In addition, this review underscores the prognostic significance of specific mutations, such as loss of TP53, and explores some potential targeted therapies tailored to these molecular signatures. The findings highlight the importance of genomic analyses for risk assessment, early detection and the design of personalized treatment approaches in pancreatic cancer. Overall, this review provides a comprehensive analysis of the molecular intricacies of pancreatic tumors, paving the way for more effective and tailored therapeutic interventions.

Abstract B056: Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs

Abstract An innovative approach in pancreatic cancer (PC) research is to utilize large animal models which (i) would be useful for development of technologies that require a human-sized platform and (ii) would produce data that could have greater clinical relevance and accuracy compared to data produced by murine models. To this end, our group has been developing porcine PC models and has reliably induced PC in the KRAS G12D/p53 R167H Oncopig model. The objective of the present study was to generate a slower-growing, early-stage PC model with intraductal injection of adenoviral vector with a Keratin 8 promoter driving the expression of the Cre-Recombinase protein (Ad5mK8-nlsCre) in oncopigs which, we hypothesized, would produce pancreatic neoplasia restricted to the epithelium. Results We first confirmed with scRNA-seq and immunohistochemistry that Keratin-8 expression in the porcine pancreas was restricted to ductal and acinar cells. Using an ex vivo infection assay with the Ad5mK8-nlsCre vector in wild-type porcine pancreas, we then demonstrated that expression of Cre-recombinase was confined to epithelial cells. We then performed a dose-response study of ductal injection (laparotomy) of Ad5mK8-nlsCre (10(7)-10(10) pfu) in Oncopigs. At the planned 2-month endpoint, all Ad5mK8-nlsCre concentrations produced microscopic evidence of ductal hyperplasia, metaplasia, and nuclear atypia, with KRAS-G12D expression by immunohistochemistry. At the higher Ad5mK8-nlsCre concentration, there was increased ductal mucin production. Using an epithelial-specific AdCre vector, we produced microscopic epithelial neoplasia within the pancreas of the Oncopig. Conclusion While further follow-up and characterization is needed, this induction technique may yield a porcine model of early-stage PC, which could be useful to (i) study early tumor biology and progression and (ii) develop diagnostic and interventional technologies for early tumor management. Citation Format: Carlos P. Jara, Al-Murtadha Al-Gahmi, Binh Le, Mark A. Carlson. Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B056.

Online adaptive radiotherapy: Assessment of planning technique and its impact on longitudinal plan quality robustness in pancreatic cancer

Background and PurposePlanning on a static dataset that reflects the simulation day anatomy is routine for SBRT. We hypothesize the quality of on-table adaptive plans is similar to the baseline plan when delivering stereotactic MR-guided adaptive radiotherapy (SMART) for pancreatic cancer (PCa). Materials and MethodsSixty-seven inoperable PCa patients were prescribed 50 Gy/5-fraction SMART. Baseline planning included: 3–5 mm gastrointestinal (GI) PRV, 50 Gy optimization target (PTVopt) based on GI PRV, conformality rings, and contracted GTV to guide the hotspot. For each adaptation, GI anatomy was re-contoured, followed by re-optimization. Plan quality was evaluated for target coverage (TC = PTVopt V100%/volume), PTV D90% and D80%, homogeneity index (HI = PTVopt D2%/D98%), prescription isodose/target volume (PITV), low-dose conformity (D2cm = maximum dose at 2 cm from PTVopt/Rx dose), and gradient index (R50%=50% Rx isodose volume/PTVopt volume).A novel global planning metric, termed the Pancreas Adaptive Radiotherapy Score (PARTS), was developed and implemented based on GI OAR sparing, PTV/GTV coverage, and conformality. Adaptive robustness (baseline to fraction 1) and stability (difference between two fractions with highest GI PRV variation) were quantified. ResultsOAR constraints were met on all baseline (n = 67) and adaptive (n = 318) plans. Coverage for baseline/adaptive plans was mean ± SD at 44.9 ± 5.8 Gy/44.3 ± 5.5 Gy (PTV D80%), 50.1 ± 4.2 Gy/49.1 ± 4.7 Gy (PTVopt D80%), and 80%±18%/74%±18% (TC), respectively. Mean homogeneity and conformality for baseline/adaptive plans were 0.87 ± 0.25/0.81 ± 0.30 (PITV), 3.81 ± 1.87/3.87 ± 2.0 (R50%), 1.53 ± 0.23/1.55 ± 0.23 (HI), and 58%±7%/59%±7% (D2cm), respectively. PARTS was found to be a sensitive metric due to its additive influence of geometry changes on PARTS’ sub-metrics. There were no statistical differences (p > 0.05) for stability, except for PARTS (p = 0.04, median difference −0.6%). Statistical differences for robustness when significant were small for most metrics (<2.0% median). Median adaptive re-optimizations were 2. ConclusionWe describe a 5-fraction ablative SMART planning approach for PCa that is robust and stable during on-table adaption, due to gradients controlled by a GI PRV technique and the use of rings. These findings are noteworthy given that daily interfraction anatomic GI OAR differences are routine, thus necessitating on-table adaptation. This work supports feasibility towards utilizing a patient-independent, template on-table adaptive approach.

Therapeutic Approaches in Pancreatic Cancer: Recent Updates.

Cancer is a significant challenge for effective treatment due to its complex mechanism, different progressing stages, and lack of adequate procedures for screening and identification. Pancreatic cancer is typically identified in its advanced progression phase with a low survival of ~5 years. Among cancers, pancreatic cancer is also considered a high mortality-causing casualty over other accidental or disease-based mortality, and it is ranked seventh among all mortality-associated cancers globally. Henceforth, developing diagnostic procedures for its early detection, understanding pancreatic cancer-linked mechanisms, and various therapeutic strategies are crucial. This review describes the recent development in pancreatic cancer progression, mechanisms, and therapeutic approaches, including molecular techniques and biomedicines for effectively treating cancer.

Tandem duplicator phenotype: A novel targetable subgroup in pancreatic cancer?

4161 Background: Validated biomarkers are urgently needed to provide a more precise approach in pancreatic cancer (PDAC). Homologous recombination deficiency (HRD) is a heterogenous cohort in PDAC and predicts platinum and PARP inhibitor sensitivity. The BRCA-1 genotype associates with distinct tandem duplications (TDs), however non-BRCA 1 TD phenotypes (TDP) have been observed across tumour types and may be associated with perturbations in CDK12, FBXW17, and CCNE1. Here, we characterize the prevalence and outcomes of TDP in a large series of prospectively sequenced PDAC. Methods: Whole-genome sequencing was performed in 191 early stage resected and 275 advanced PDAC cases in the PanCuRx initiative and the COMPASS trial at the Ontario Institute for Cancer Research and Princess Margaret Cancer Centre. Tumors underwent laser capture enrichment prior to sequencing. TD scores were calculated as previously described by Menghi et al, and HRDetect scores assigned. Samples were classified as classical or basal-like by Moffitt. Outcomes of patients with TDP tumors were evaluated. Tumors that are nonHRD and nonTDP are referred to as typicals. Results: Of 466 cases, 46 were identified as TDP (9.9%; 17 resected, 29 advanced). Subgroups of TDP by etiology included BRCA1 (n=8; 6 germline, 2 somatic), somatic CCNE1 (n=1), and unknown (n=37; no identified alterations in TDP-related genes). Pathogenic germline variants were not found in unique genes other than BRCA1. HRD TDP was associated with a significantly smaller TD size compared to nonHRD TDP (median 12 kb vs. 125 kb, p&lt;0.0001) and median TD load of 114. NonHRD TDP genomes exhibited elevated TD load (median 70 vs. 13, p&lt;0.0001) and HRDetect scores (p&lt;0.0001) compared with typicals. NonHRD TDP was not prognostic in resected PDAC disease (p=0.6361) compared with typicals. We observed a trend towards improved response to 1st-line platinum therapy in nonHRD TDP vs. typicals (p=0.066) for patients with advanced disease. When stratified for only ‘classical’ RNA subtype cases as per Moffitt classification (HRD TDP:2 basal-like, 8 classical, 1 unknown; nonHRD TDP: 9 basal-like, 25 classical, 1 unknown), platinum therapy was correlated with better response in non-HRD TDP vs. typicals (n= 10, 70% ORR, p=0.0108) highlighting the chemoresistance of the basal-like subgroup. Superior survival was not observed in this small cohort. Conclusions: In PDAC, the etiology of nonHRD TDP is unclear but may represent a potential marker for platinum and DNA damage response agents. Further investigation is warranted with a larger sample size.

Adjuvant and neoadjuvant approaches in pancreatic cancer.

Pancreatic cancer treatment remains a challenging problem for surgeons and oncologists. This review aims to summarize the current advances on adjuvant and neoadjuvant treatment approaches for resectable pancreatic cancer. Recent phase III randomized trials of adjuvant therapy showed improvement of overall survival in both experimental and control groups. Effectiveness of adjuvant therapy in specific subgroups as elderly patients, intraductal papillary mucinous neoplasms, stage I, and DNA damage repair gene germline variants has been reported. Completion of all cycles of planned adjuvant chemotherapy is confirmed as an independent prognostic factor. Adjuvant chemotherapy remains underutilized, mainly because of early recurrence, prolonged recovery, or older age older than 75 years. So, neoadjuvant treatment is a logical approach to administer systemic treatment to more patients. Meta-analysis did not demonstrate an overall survival benefit of neoadjuvant treatments in resectable pancreatic cancer, and definitive conclusions cannot be drawn from available randomized controlled trials. Upfront surgery and adjuvant chemotherapy should still be considered a standard approach in resectable pancreatic cancer. Adjuvant chemotherapy with mFOLFIRINOX remains the standard of care in fit patients with resected pancreatic cancer, and limited high-level evidence support the use of neoadjuvant therapy in upfront resectable pancreatic cancer.

KRAS Pathway-based Therapeutic Approaches in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly aggressive malignancies and the leading cause of cancer-related deaths. Despite recent advancements, the overall therapeutic responses in PDAC patients remained relatively low or short-lived. While KRAS is the most frequently mutated proto-oncogene and represents a critical driver, it remains challenging to target all mutant variants. Thus, strategies to target the downstream signaling cascades (RAS-RAF-MEK-ERK) in PDAC were associated with improved response rates. Nevertheless, the activation of other oncogenic cascades, such as PI3K/AKT/mTOR, has also been documented within the same context and implicated in the development of acquired tumor resistance mechanisms and/or reduced efficacy of therapeutic agents. Therefore, an in-depth understanding of overlapping and intersecting pathways is required to overcome the tumor resistance mechanisms to devise novel approaches to enhance the effectiveness of ongoing treatment options. The current review highlights the mechanistic insights from cellular and preclinical studies with particular emphasis on KRAS (i.e., MEK and ERK)-based approaches for PDAC treatment.

AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer

Targeting KRAS downstream signaling remains an important therapeutic approach in pancreatic cancer. We used primary pancreatic ductal epithelial cells and mouse models allowing the conditional expression of oncogenic KrasG12D, to investigate KRAS signaling integrators. We observed that the AP1 family member FRA1 is tightly linked to the KRAS signal and expressed in pre-malignant lesions and the basal-like subtype of pancreatic cancer. However, genetic-loss-of-function experiments revealed that FRA1 is dispensable for KrasG12D-induced pancreatic cancer development in mice. Using FRA1 gain- and loss-of-function models in an unbiased drug screen, we observed that FRA1 is a modulator of the responsiveness of pancreatic cancer to inhibitors of the RAF–MEK–ERK cascade. Mechanistically, context-dependent FRA1-associated adaptive rewiring of oncogenic ERK signaling was observed and correlated with sensitivity to inhibitors of canonical KRAS signaling. Furthermore, pharmacological-induced degradation of FRA1 synergizes with MEK inhibitors. Our studies establish FRA1 as a part of the molecular machinery controlling sensitivity to MAPK cascade inhibition allowing the development of mechanism-based therapies.

Abstract IA011: Precision oncology approaches in pancreatic cancer

Abstract Advances in next generation sequencing and therapies have led to an explosion of possibilities for precision oncology in pancreatic cancer. The talk will focus on current and up and coming precision approaches for patients with pancreatic cancer. Citation Format: Jen Jen Yeh. Precision oncology approaches in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA011.

Abstract 3197: Blockade of regulatory signaling pathways reduces immunosuppression in the PDAC tumor microenvironment

Abstract Pancreatic cancer (PDAC) has the highest mortality rate of all major cancers, with few treatment options that provide long-term benefit to patients. Cancer associated fibroblasts (CAFs), the primary cellular component of the pancreatic tumor stroma, play a key role in the formation of an immunosuppressive tumor microenvironment (TME). A better understanding of the disease biology and cellular pathways that could be targeted for treatment of PDAC are needed. To investigate mechanisms driving immune suppression and pathways that might be targetable for treatment in PDAC, we used models where cross-talk between stromal and tumor cells could be evaluated. Three PDAC tumor cell lines were co-cultured (CC) with primary CAFs from multiple donors for 3 days, and secretion of numerous immunosuppressive cytokines, including IL6, IL8, IL10, CXCL12, was found to be upregulated in CC vs single culture (SC). IL6 and IL8 were shown to increase 2-38-fold in CC vs SC CAFs, and 1.5-20,000-fold vs SC PANCs, dependent upon cell line. By whole genome array, an upregulation of genes involved in NFkB, IL6, IL8, and AKT signaling was also observed (-log(p-value)&amp;gt;4) in CAF cells following CC. Multiple pathways have been implicated in regulating the immunosuppressive PDAC TME, including: CD73, a critical mediator of adenosine formation which is known to alter immune activity; and IL1, which is secreted by PDAC tumor cells, known to increase inflammation in the TME, and promote PDAC progression. The effects of CD73 inhibition and IL1R inhibition were evaluated to better characterize the downstream effects of these pathways on regulating tumor immunosuppression. Inhibition of CD73 in the CC reduced production of the immunosuppressive cytokines IL6, IL8, MCP1 CXCL12, IL1a, IL1b, IL10 (16-59%). Preliminary genomic studies indicated that inhibition of CD73 decreased genes involved in invasion, migration, metastasis, EMT and angiogenesis, as well as increasing genes involved in type 1 IFN activation, including OAS1, DDX60, IFIT1 and IRF7 (FC 1.5-2). Similarly, blockade of IL1R (which is highly expressed on PDAC CAFs and is the receptor for both IL1a and IL1b) reduced immune suppressive cytokine production from PDAC tumor conditioned media-stimulated CAFs, e.g. lowering secretion of IL6 and IL8 (4-20-fold) in a dose-dependent manner. Blocking IL1R in a PDAC dissociated tumor cell (DTC) model resulted in decreased secretion of CXCL1 and IL6 (60-75% over 3-6 days in culture), and an upregulation of IFNg (2-10-fold) in this culture by d3. These results suggest that a blockade of regulatory signaling pathways may be useful to reduce immune suppression and return the PDAC TME to a phenotype more amenable to immune checkpoint inhibition. Further characterization of these pathways may lead to new therapeutic combination approaches for pancreatic cancer. Citation Format: Lydia Greenlees, Li Cheng, Bilal Omar, Yelena Lazdun, Jixin Wang, Fernanda Pilataxi, Michael Kuziora, Zachary Cooper, Luis Vence, Katie Streicher. Blockade of regulatory signaling pathways reduces immunosuppression in the PDAC tumor microenvironment [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 3197.

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.

Promising 3D in vitro models for studying tumour heterogeneity and testing novel therapeutic approaches in pancreatic cancer

In this study we produced 3D organotypic cultures and spheroids to mimic the complex microenvironment of pancreatic cancer and to test alternative therapeutic strategies.

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer.

Simple SummaryPancreatic ductal adenocarcinoma (PDAC), comprising 90–95% of all pancreatic cancers, is one of the deadliest human cancers, with a gloomy prognosis and ~6-month median survival in metastatic tumors. Even patients with resectable tumors show a poor survival rate after surgery. Thus, PDAC represents an unmet therapeutic challenge. The aim of this review was to put into context the conundrum of pancreatic cancer treatment and the advent of a novel therapeutic approach, examining: (a) anatomical factors, demographics, statistics, and therapeutic approaches, affecting tumor detection, treatment, and prognosis; (b) the importance of the endoplasmic reticulum as a major target for pancreatic cancer due to its high abundance and activity in pancreatic cells; (c) the identification of the alkylphospholipid analog edelfosine as a novel drug against pancreatic cancer, showing two outstanding features—selective uptake by tumor tissue, and direct accumulation in the endoplasmic reticulum, leading to persistent endoplasmic reticulum stress and subsequent apoptosis.Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

Abstract 1658: Gemcitabine impacts expression of antigen presentation proteins by pancreatic cancer cells

Abstract Background: Pancreatic adenocarcinoma is one of the deadliest type of cancers with a 5-year overall survival rate of 10%. A standard chemotherapy approach for pancreatic cancer is treatment with gemcitabine. Gemcitabine is also considered a potential immunomodulatory agent, capable of increasing human leukocyte antigen (HLA) class I. HLA class I is a heterodimer of a highly polymorphic alpha heavy chain (HLA-A, -B, or -C) and the light chain beta-2-microglobulin (β2m) that is loaded with an endogenous antigen in the endoplasmic reticulum. The pool of antigens available for HLA class I loading is selected by the transporter associated with antigen processing protein (TAP). However, HLA class I peptide loading can occur independently of TAP, causing the HLA class I molecules to present a different antigen pool to cytotoxic T cells. Because many cancers downregulate HLA class I and prevent intracellular tumor antigens from being presented to cytotoxic T cells, understanding more about gemcitabine's capability to increase HLA class I expression is of great importance. Methods: Alterations in HLA class I and TAP protein levels were monitored via western blot analysis in a pancreatic cancer cell line (S2-013) in both a time and dose-dependent manner. The time points and dosages which solicited the largest increase in HLA class I expression were also examined by flow cytometry. Results: Administration of gemcitabine to S2-013 pancreatic cancer cells increased total HLA class I α heavy chain protein, with maximal increases of 141% (HLA-A) and 323% HLA-B/C. Flow cytometry revealed a 3-fold increase in HLA-A2 surface expression post-gemcitabine treatment and a maximal 2-fold increase in HLA-B/C expression at the corresponding gemcitabine concentration, but differing time point. Both western blot and flow cytometry analyses indicate HLA-B/C generally has its largest increase in expression at an earlier time point than HLA-A. In addition, high concentrations of gemcitabine that promoted HLA-A,B,C surface expression were associated with a large decrease in TAP total protein. Conclusion: In summary, gemcitabine demonstrates an ability to stimulate expression of HLA class I in pancreatic cancer cells, with the rate dependent on the HLA class I allele. Because gemcitabine treatment increases HLA class I surface expression with a simultaneous decrease in TAP expression, our findings indicate that gemcitabine may induce TAP-independent peptide loading of HLA class I. These results suggest the potential for gemcitabine treatment as a priming mechanism to enhance immunotherapy efficacy and potentially alter vaccination strategies in pancreatic cancer. Citation Format: Alaina C. Larson, Shelby M. Knoche, Joyce C. Solheim. Gemcitabine impacts expression of antigen presentation proteins by pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1658.

Pancreatic Cancer Exposome Profile to Aid Early Detection and Inform Prevention Strategies.

Pancreatic cancer (PCa) is associated with a poor prognosis and high mortality rate. The causes of PCa are not fully elucidated yet, although certain exposome factors have been identified. The exposome is defined as the sum of all environmental factors influencing the occurrence of a disease during a life span. The development of an exposome approach for PCa has the potential to discover new disease-associated factors to better understand the carcinogenesis of PCa and help with early detection strategies. Our systematic review of the literature identified several exposome factors that have been associated with PCa alone and in combination with other exposures. A potential inflammatory signature has been observed among the interaction of several exposures (i.e., smoking, alcohol consumption, diabetes mellitus, obesity, and inflammatory markers) that further increases the incidence and progression of PCa. A large number of exposures have been identified such as genetic, hormonal, microorganism infections and immune responses that warrant further investigation. Future early detection strategies should utilize this information to assess individuals’ risk for PCa.

A radiomics model that predicts lymph node status in pancreatic cancer to guide clinical decision making: A retrospective study.

Purpose: To construct a radiomics-based model for predicting lymph node (LN) metastasis status in pancreatic ductal adenocarcinoma (PDAC) before therapy and to evaluate its prognostic clinical value.Materials and Methods: We retrospectively collected preoperative CT scans of 130 PDAC patients who underwent original tumor resection and LN dissection in the entire cohort between January 2014 and December 2017. Radiomics features were systematically extracted and analyzed from CT scans of 89 patients in the primary cohort. To construct a radiomics signature, the least absolute shrinkage and selection operator methods were employed with LN metastasis status as classification labels. Pathological analysis of LN status which were assessed by experienced pathologists was used as the evaluation label. We subjected the clinical nomogram to multivariable logistic regression analysis and conducted performance evaluation based on its discrimination, calibration, and clinical value. The model was tested and validated in 41 patients with PDAC in a separate validation cohort.Results: Four radiomics features closely associated with LN metastasis were selected in the primary and validation cohorts (P < 0.01). Following the integration of CT-reported results and radiomics signatures into the radiomics nomogram, we reported better performance in the primary (area under the curve, 0.80) and validation (area under the curve, 0.78) cohorts.Conclusion: The noninvasive tool constructed from the portal venous phase CT based on radiomics showed better performance for LN metastasis prediction than traditional approaches in pancreatic cancer. It may assist surgeons in crafting detailed procedures before treatment, this subsequently improves tumor staging and resection of patients.

Identification of potential common molecular factors of pancreatic cancer and diabetes mellitus using microarray data analysis combined with bioinformatics techniques and experimental validation

Background and Aim: Detection of early-stage pancreatic cancer (PaC) patients can decrease the mortality rate through surgical resection thanks to a screening approach of high-risk and asymptomatic individuals. Up to 80% of PaC patients are either hyperglycemic or diabetic at the time of diagnosis. Diabetes mellitus (DM) identification as an early manifestation of PaC may lead to detection of this malignancy at early and presymptomatic stages. Therefore, the current study aims to identify common molecular factors between DM and PaC to shed light on a potential screening for DM as a diagnostic approach for PaC. Methods: The study was divided into three steps including dataset selection and identification of key genes, quantitative real-time polymerase chain reaction (qRT-PCR) to validate these genes, and enrichment analysis of their target genes. Results: Using GEO2R analysis, conducted on microarray dataset (GSE15932), SPI1 and Yin Yang 1 (YY1) genes were found to be expressed in peripheral blood mononuclear cells of PaC, DM, and PaC + DM patients. Moreover, qRT-PCR results in validation of microarray data showed a significant increment of these two genes among all patient groups. Furthermore, enrichment analyses of SPI1 and YY1 target genes revealed that they are mainly expressed in hematopoietic cells and associated with immune responses as well as immune signaling pathways. Discussion: We speculate that this study on SPI1 and YY1 genes and their targets can result in a successful strategy to investigate diabetes as a screening step for better management of PaC screening using standard serologic tests.

Meta-analysis of the studies dedicated to the predictive significance of circulating tumor DNA in pancreatic cancer

The method of liquid biopsy allows detection of circulating tumor DNA (ctDNA) in patient blood, but the clinical significance of this approach in pancreatic cancer is still unclear. In this regard, we have carried out a meta-analysis of the studies dedicated to the predictive significance of ctDNA in pancreatic cancer.&#x0D; Materials and methods.We carried out the search for the articles and abstracts in PubMed, ASCO and ESMO databases published before February 2020, containing data about the connection between ctDNA and the prognosis of pancreatic cancer. The exclusion criteria were the studies including 10 or less participating patients, absence of the data about the relative risk of mortality and/or progression, and the 95% confidence interval. The meta-analysis was carried out by using the Review Manager software (RevMan), Version 5.3.&#x0D; Results.There were no significant systematic errors associated with the publications. The presence of ctDNA in patient blood showed poor overall survival of patients (odds ratio OR 2.21, 95% confidence interval CI 1.35-3.33,p=0.001) regardless of the prevalence of the disease. In case of the resectable process, the detection of ctDNA in patient blood both before and after surgery was a factor of worse progression-free survival (OR 2.32, 95% CI 1.543.5,p0.001 and OR 3.06, 95% CI 1.635.76,р=0.0005 and overall survival (OR2.01, 95% CI 1.123.63,р=0,02 and OR 3.39, 95% CI 2.125.44,р0.00001, respectively).&#x0D; Conclusions.The detection of ctDNA in the bloodstream in pancreatic cancer patients is a factor of poor prognosis in both localized and advanced cancer. It is very important to make further prospective studies to develop the optimal protocol for detecting ctDNA in patient bloodstream.

Diversity in the Extracellular Vesicle-Derived Microbiome of Tissues According to Tumor Progression in Pancreatic Cancer.

This study was conducted to identify the composition and diversity of the microbiome in tissues of pancreatic cancer and to determine its role. First, extracellular vesicles (EVs) were obtained from the paired tumor and normal tissues, and 16s rRNA gene sequencing was performed. We identified the microbiomes, compared the diversity between groups, and found that Tepidimonas was more abundant in tumors. Second, larger tumors resulted in lower levels of Leuconostoc and Sutterella, and increased lymph node metastasis resulted in higher levels of Comamonas and Turicibacter in tumor tissues. Moreover, in the case of tumor recurrence, the levels of Streptococcus and Akkermansia were decreased in tumor tissues. Finally, with the supernatant of Tepidimonas fonticaldi, proliferation and migration of cells increased, and epithelial-mesenchymal transition and the Tricarboxylic Acid (TCA) cycle-related metabolites were enhanced. The composition and diversity of EV-derived microbiomes are important for providing novel insights into theragnostic approaches in pancreatic cancer.

Retraction: Concomitant Targeting of EGF Receptor, TGF-beta and Src Points to a Novel Therapeutic Approach in Pancreatic Cancer.

Retraction: Concomitant Targeting of EGF Receptor, TGF-beta and Src Points to a Novel Therapeutic Approach in Pancreatic Cancer.