Treatment Of Pancreatic Ductal Adenocarcinoma Research Articles

Abstract B053: Targeting SMURF1 with low-dose proteasome inhibitors in pancreatic cancer organoids

Abstract Global initiatives focused on whole genome and transcriptome analysis (WGTA) of metastatic pancreatic ductal adenocarcinoma (PDAC) tumor cohorts are driving progress in understanding the clinical impact of PDAC heterogeneity. This knowledge is key to continue the discovery of subsets of patients who could benefit from biomarker-informed targeted therapy and expand the currently limited PDAC treatment options. To identify clinically actionable subtypes in metastatic PDAC (mPDAC), our team analyzes prospectively collected WGTA data from patients enrolled in the PanGen trial (NCT02869802), in parallel with analysis of a set of patient-derived organoids (PDOs). In a cohort of 69 sequenced tumors, four cases (5.8%) had an amplification of chromosome 7q22, which included copy gains of transcriptional co-factor TRRAP, drug metabolizing cytochrome P450 genes CYP3A4 and CYP3A5, and SMURF1. SMURF1 is a ubiquitin-protein ligase that regulates TGFβ receptor signaling, in part via its interaction with SMAD7, and has been implicated in the epithelial-to-mesenchymal program and tumor invasiveness in PDAC. The proteasome inhibitor (PI) bortezomib has been shown to attenuate SMURF1 levels. We investigated whether SMURF1 signaling axis is associated with sensitivity to PIs in mPDAC, by analyzing the cytotoxic effects of the PIs bortezomib, carfilzomib and ixazomib in PDOs. Eight PDOs were treated with PIs at concentrations between 0.1pM-1mM. The presence of live and dead cells was quantified using the IN Cell Analyzer, and cell toxicity was analyzed using GRtoxic metrics (grcalculator.org). The PIs bind catalytic subunits of the 26S proteasome, primarily proteasome subunit beta-5, encoded by PSMB5. The cytotoxic activity of all three PIs negatively correlated with tumor biopsy PSMB5 expression (p<0.05), suggesting that PDOs established from tumors with low expression of PSMB5 are more sensitive to PI-induced cell death. There was a positive correlation between ixazomib cytotoxicity and SMURF1 expression (p<0.05). PanGen patients with high (>75th percentile) tumor SMURF1 expression showed shorter overall survival (OS) compared to the rest of the cohort (median OS 9 vs. 14 months, respectively; p=0.004). Immunohistochemistry analysis of a tumor tissue microarray comprising 175 resected PDAC cases detected an association of concomitant low SMURF1 and high SMAD7 protein levels with adjuvant therapy response (median OS: 40 vs. 12 months with no adjuvant treatment, p=0.002), suggesting that attenuation of SMURF1 in the presence of SMAD7 may improve chemotherapy response in early disease stages. In summary, we present data indicating increased sensitivity to PIs in a subset of tumors with low PSMB5 and high SMURF1 expression, and highlight the translational utility of the investigation of genomic and clinically annotated pre-clinical models in PDAC predictive biomarker discovery. Citation Format: Andrew Metcalfe, Joanna M. Karasinska, James T. Topham, Steve E. Kalloger, Hassan Ali, Dawn Ashforth, Marco A. Marra, Janessa Laskin, Patricia A. Tang, Rachel Goodwin, Oliver F. Bathe, Daniel J. Renouf, David F. Schaeffer. Targeting SMURF1 with low-dose proteasome inhibitors in pancreatic cancer organoids [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 B053.

Systemic Chemotherapy With or Without Hepatic Arterial Infusion Chemotherapy for Liver Metastases From Pancreatic Cancer: A Propensity Score Matching Analysis

BackgroundThe significance of systemic chemotherapy (SCT) combined with hepatic arterial infusion (HAI) chemotherapy in the treatment of pancreatic ductal adenocarcinoma with liver metastases (PACLM) remains unclear. Based on previous studies, this single-center propensity score matching (PSM) study aimed to explore the efficacy of SCT with or without HAI for PACLM. Patient and MethodsThe PSM method was used to screen 661 cases of PACLM who received SCT at Tianjin Medical University Cancer Institute and Hospital from 2001 to 2020. According to the 1:6 ratio with PSM, 385 patients were divided into the SCT+HAI group (n = 55) and the SCT group (n = 330). After a median follow-up of 49 (range 7-153) months, overall survival (OS) and survival-related prognostic factors were analyzed. ResultsThe main baseline characteristics of the SCT+HAI group and the SCT alone group were matched appropriately (P > .05). After PSM, the median OS for patients in the 2 groups was 10.6 and 7.6 months, respectively (P = .02). Multivariate analysis revealed that peritoneal metastases (P = .03), CA199 ≥ 500U/mL (P = .03), and lactate dehydrogenase (LDH) ≥ 250U/L (P = .03) were prognostic factors of poor survival, modern SCT plus HAI (P = .04) was a protective factor. ConclusionOur findings indicated that adequate cycles of SCT+HAI result in better survival than SCT alone in patients with PACLM. Patients with peritoneal metastases, markedly elevated CA19-9 and LDH have a poorer prognosis. The conclusion has yet to be validated in randomized controlled clinical trials.

Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by poor treatment response and low survival time. The current clinical treatment for advanced PDAC is still not effective. In recent years, the research and application of immunotherapy have developed rapidly and achieved substantial results in many malignant tumors. However, the translational application in PDAC is still far from satisfactory and needs to be developed urgently. To carry out the study of immunotherapy, it is necessary to fully decipher the immune characteristics of PDAC. This review summarizes the recent progress of the tumor microenvironment (TME) of PDAC and highlights its link with immunotherapy. We describe the molecular cues and corresponding intervention methods, collate several promising targets and progress worthy of further study, and put forward the importance of integrated immunotherapy to provide ideas for future research of TME and immunotherapy of PDAC.

Liposomal co-delivery system encapsulating celastrol and paclitaxel displays highly enhanced efficiency and low toxicity against pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreas cancer and difficult to treat. Various combination strategies have been utilized to improve the poor therapeutic effect and serious systemic toxicity of clinical PDAC treatments. Here, we report a new combination therapy strategy against PDAC using a liposomal carrier co-loading with anti-inflammatory agent celastrol (CLT) and chemotherapeutic drug paclitaxel (PTX). First, the synergistic effect of CLT and PTX was verified and it is discovered that this effect peaks at 1:2 (CLT/PTX, mol/mol). Then, the co-delivery system CP-Lip with high loading capabilities (97.48% ± 1.14 for CLT, 86.29% ± 3.03 for PTX), sustained release profile and favorable long-circulating feature was fabricated. Tumor-specific accumulation of CP-Lip was significantly improved compared with that of free drug. Moreover, CP-Lip showed comparable cytotoxicity with free CLT and PTX (CLT/PTX) on Pan02 cells in vitro and significantly improved anti-tumor efficacy in vivo with a ∼4-fold increase of tumor inhibition rate compared to single drug treatment in mice model. Furthermore, safety evaluation found no significant damages induced by CP-Lip. Therefore, CLT-PTX combined treatment has good clinic potential, and the simple and effective CP-Lip system fabricated here offers a promising candidate for future development.

Evaluating the Quality of Online Information Regarding Neoadjuvant Therapy for Pancreatic Cancer.

Neoadjuvant therapy (NT) is increasingly utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). Patients with cancer have high information needs and the Internet has materialized as a leading source of information for many patients. Nevertheless, little is known about the availability, accessibility, quality, and readability of online information regarding NT for PDAC. A search of online patient informational materials (PIMs) pertaining to NT for PDAC was conducted using a combination of common search engines and browsers. Two independent researchers evaluated the readability, quality, and availability of unique PIMs from the top 25 websites from each search using validated measures. Among the 130 websites retrieved, 46 (35.4%) unique PIMs focused on treatment of PDAC. Only 30 (23%) mentioned NT as a possible treatment option. Downstaging was the rationale for NT mentioned in the majority (90%) of websites. The mean quality and reliability of the 30 PIMs, assessed using the DISCERN instrument, was 3.3 ± 0.7, suggesting moderate quality/reliability. The mean readability score, assessed using the SMOG Grade tool, was 10.96 ± 1.49, which is equivalent to an 11th grade reading level. The low availability, poor readability, and moderate quality of online informational materials regarding NT for PDAC highlight the need for new patient-centered resources to educate patients and caregivers on an increasingly utilized treatment strategy for localized PDAC.

Nanotechnology-augmented sonodynamic therapy and associated immune-mediated effects for the treatment of pancreatic ductal adenocarcinoma

PurposeSonodynamic therapy (SDT) is emerging as a cancer treatment alternative with significant advantages over conventional therapies, including its minimally invasive and site-specific nature, its radical antitumour efficacy with minimal side effects, and its capacity to raise an antitumour immune response. The study explores the efficacy of SDT in combination with nanotechnology against pancreatic ductal adenocarcinoma.MethodsA nanoparticulate formulation (HPNP) based on a cathepsin B-degradable glutamate-tyrosine co-polymer that carries hematoporphyrin was used in this study for the SDT-based treatment of PDAC. Cathepsin B levels in BxPC-3 and PANC-1 cells were correlated to cellular uptake of HPNP. The HPNP efficiency to induce a sonodynamic effect at varying ultrasound parameters, and at different oxygenation and pH conditions, was investigated. The biodistribution, tumour accumulation profile, and antitumour efficacy of HPNP in SDT were examined in immunocompetent mice carrying bilateral ectopic murine pancreatic tumours. The immune response profile of excised tumour tissues was also examined.ResultsThe HPNP formulation significantly improved cellular uptake of hematoporphyrin for both BxPC-3 and PANC-1 cells, while increase of cellular uptake was positively correlated in PANC-1 cells. There was a clear SDT-induced cytotoxicity at the ultrasound conditions tested, and the treatment impaired the capacity of both BxPC-3 and PANC-1 cells to form colonies. The overall acoustic energy and pulse length, rather than the power density, were key in eliciting the effects observed in vitro. The SDT treatment in combination with HPNP resulted in 21% and 27% reduction of the target and off-target tumour volumes, respectively, within 24 h. A single SDT treatment elicited an antitumour effect that was characterized by an SDT-induced decrease in immunosuppressive T cell phenotypes.ConclusionSDT has significant potential to serve as a monotherapy or adjunctive treatment for inoperable or borderline resectable PDAC.

1,2,3,4,6-Penta-O-galloyl-β-D-glucose Inhibits CD44v3, a cancer stem cell marker, by regulating its transcription factor, in human pancreatic cancer cell line

ABSTRACT Inhibition of cluster of differentiation 44 (CD44), a pancreatic cancer stem cell (CSC) marker, is a potential treatment for pancreatic ductal adenocarcinoma (PDAC). In this study, we evaluated the effect of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG), a gallotannin contained in various medicinal plants, on CD44 standard (CD44s) and CD44 variant 3 (CD44v3) in Mia-PaCa-2, human pancreatic cancer cells and explored the underlying mechanisms. PGG showed cytotoxic effects and inhibited the proliferation of Mia-PaCa-2 cells. It also inhibited clonogenic activity, adhesion to fibronectin, and cell migration, which are characteristics of CSCs. PGG inhibited the expression of CD44s and CD44v3 by inducing the phosphorylation of p53 and suppressing NF-κB and Foxo3. Inhibition of Foxo3 induces CD44v3 ubiquitination. Indeed, PGG increased proteasome activity and promoted CD44v3 ubiquitination. PGG downregulated the CSC regulatory factors Nanog, Oct-4, and Sox-2, which act downstream of CD44v3 signaling. These data indicate that PGG may have therapeutic effects in pancreatic cancer mediated by inhibition of CSC markers.

440P Targeting KRASG12C: Repurposing of potential therapeutics for the treatment of pancreatic ductal adenocarcinoma (PDAC)

Pancreatic ductal adenocarcinoma (PDAC), accounting for more than 90% of all pancreatic malignancies, and the fourth most frequent cause of cancer-related mortalities worldwide with a 5-year overall survival of less than 8%. The main molecular trait of this deadly disease is the MAPK pathway activation due to KRAS mutation. The KRASG12C, an oncogenic driver mutation in PDAC, was studied to identify potential therapeutic candidates.

TRAIL Receptor Targeting Agents Potentiate PARP Inhibitor Efficacy in Pancreatic Cancer Independently of BRCA2 Mutation Status.

Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.

CXCR4-CXCL12-CXCR7 and PD-1/PD-L1 in Pancreatic Cancer: CXCL12 Predicts Survival of Radically Resected Patients.

Pancreatic ductal adenocarcinoma (PDAC) is currently the most deadly cancer. Although characterized by 5-20% of neoplastic cells in the highly fibrotic stroma, immunotherapy is not a valid option in PDAC treatment. As CXCR4-CXCL12 regulates tumor invasion and T-cell access and PD-1/PD-L1 controls immune tolerance, 76 PDACs were evaluated for CXCR4-CXCL12-CXCR7 and PD-1/PD-L1 in the epithelial and stromal component. Neoplastic CXCR4 and CXCL12 discriminated PDACs for recurrence-free survival (RFS), while CXCL12 and CXCR7 discriminated patients for cancer-specific survival (CSS). Interestingly, among patients with radical resection (R0), high tumor CXCR4 clustered patients with worse RFS, high CXCL12 identified poor prognostic patients for both RFS and CSS, while stromal lymphocytic-monocytic PD-L1 associated with improved RFS and CSS. PD-1 was only sporadically expressed (<1%) in focal lymphocyte infiltrate and does not impact prognosis. In multivariate analysis, tumoral CXCL12, perineural invasion, and AJCC lymph node status were independent prognostic factors for RFS; tumoral CXCL12, AJCC Stage, and vascular invasion were independent prognostic factors for CSS. CXCL12's poor prognostic meaning was confirmed in an additional perspective-independent 13 fine-needle aspiration cytology advanced stage-PDACs. Thus, CXCR4-CXCL12 evaluation in PDAC identifies prognostic categories and could orient therapeutic approaches.

Current Practice Patterns among Radiation Oncologists at High-Volume Pancreatic Cancer Centers Participating in the Canopy Cancer Collective Learning Health Network

<h3>Purpose/Objective(s)</h3> Radiation therapy (RT) for localized pancreatic ductal adenocarcinoma (PDAC) remains controversial, with conflicting data likely resulting in variable practice patterns. The Canopy Cancer Collective (CCC) is a learning health network of 14 institutions with high-volume multidisciplinary PDAC teams. To characterize the current state of RT for PDAC at high-volume, academic centers, radiation oncology faculty at CCC member institutions were surveyed. <h3>Materials/Methods</h3> A survey focusing on RT practice patterns for localized PDAC was distributed to 18 faculty with expertise in gastrointestinal RT at CCC sites. Survey results are descriptively reported. <h3>Results</h3> The survey was completed by 17/18 (94%) faculty. Among respondents, the number of localized PDAC patients treated per year with RT included >50 (n=5, 29%), 26-50 (n=8, 47%), 10-25 (n=3, 18%), and <10 (n=1, 6%). Two (12%) respondents reported that they routinely offer pre-operative RT for resectable PDAC. Majority of respondents (n=15, 88%) indicated that pre-operative RT is offered to certain patients with borderline resectable pancreatic cancer (BPRC), but the specific proportion of BRPC patients receiving pre-operative RT was variable across respondents (median 70%, range: 10-100%). Similarly, majority of respondents (n=16, 94%) indicated that RT is offered as definitive treatment for certain patients with locally advanced pancreatic cancer (LAPC), but the specific proportion of LAPC patients receiving RT was also variable (median 80%, range: 20-100%), as was the estimated proportion of LAPC patients who eventually undergo resection (median 25%, range 2-50%). Table 1 summarizes the distribution of preferred planning techniques and target volumes used by respondents in both the pre-operative and definitive settings. Variation was also seen in use of fiducials (n=12, 71%), preferred motion management strategy (breath-hold: n=12, 71%; gating: n=5, 29%), systematic use of adjunctive imaging beyond CT for target delineation (MRI: n=6, 35%; PET: n=3, 18%), and use of prophylactic anti-emetics (n=5, 29%) and proton pump inhibitors (n=11, 65%). <h3>Conclusion</h3> RT practice patterns for the treatment of localized PDAC remain disparate, with significant variation in institutional standards across stage of disease as well as in basic treatment parameters such as prescription dose and target volume design. A better understanding of the basis for such variation may help guide future avenues of study.

C/EBPδ Suppresses Motility-Associated Gene Signatures and Reduces PDAC Cell Migration.

Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive human cancers and occurs globally at an increasing incidence. Metastases are the primary cause of cancer-related death and, in the majority of cases, PDAC is accompanied by metastatic disease at the time of diagnosis, making it a particularly lethal cancer. Regrettably, to date, no curative treatment has been developed for patients with metastatic disease, resulting in a 5-year survival rate of only 11%. We previously found that the protein expression of the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) negatively correlates with lymph node involvement in PDAC patients. To better comprehend the etiology of metastatic PDAC, we explored the role of C/EBPδ at different steps of the metastatic cascade, using established in vitro models. We found that C/EBPδ has a major impact on cell motility, an important prerequisite for tumor cells to leave the primary tumor and to reach distant sites. Our data suggest that C/EBPδ induces downstream pathways that modulate actin cytoskeleton dynamics to reduce cell migration and to induce a more epithelial-like cellular phenotype. Understanding the mechanisms dictating epithelial and mesenchymal features holds great promise for improving the treatment of PDAC.

Intratumoral neutrophil extracellular traps are associated with unfavorable clinical outcomes and immunogenic context in pancreatic ductal adenocarcinoma.

Extracellular traps (ETs) and tumor-infiltrating immune cells play crucial roles in tumor progression. However, little is known about the clinical significance of tumor-infiltrating neutrophils and macrophages and the related ETs in pancreatic ductal adenocarcinoma (PDAC). This study investigates the associations between neutrophil or macrophage infiltration or ET formation and the clinicopathological features, molecular characteristics, immune checkpoint molecules, clinical outcomes, and response to adjuvant chemotherapy (ACT) in PDAC. We performed multiplex immunofluorescence staining to detect ET formation by neutrophils or macrophages using tissue microarrays obtained from 205 patients, and analyzed the immunohistochemistry data for PD-L1, PD-L2, B7-H3, and B7-H4. The ET expression rates in macrophages and neutrophils were 23.9% and 45.4%, respectively. Patients with a high density of neutrophils or positive expression of neutrophil ETs exhibited poorer progression-free survival (PFS) and disease-specific survival (DSS), whereas macrophage ETs were not related to PFS and DSS. Neutrophil infiltration and ET formation were identified as independent prognostic predictors of DSS using univariate and multivariate Cox analyses. Patients with PDAC with lower neutrophil infiltration or negative staining for neutrophil ETs are more likely to benefit from ACT. Patients with PDAC were more accurately stratified based on the infiltration of neutrophils and presence of neutrophil ETs, and patients with low neutrophil infiltration and negative staining for neutrophil ETs showed the best survival. Patients with positive neutrophil ETs demonstrated inferior DSS compared to those with negative neutrophil ETs in the PD-L1 tumor proportion score (TPS) < 1% and PD-L1 IC < 1% subgroups. However, the positive expression of neutrophil ETs was not related to DSS in the PD-L1 TPS ≥ 1% or PD-L1 IC ≥ 1% subgroup. Our findings emphasize the potential of neutrophil infiltration and ETs as prognostic markers that could guide the formulation of more effective personalized treatments for PDAC.

Importance of triple tumor markers as biomarkers in patients with pancreatic ductal adenocarcinoma.

There is an urgent need to establish biomarkers for the treatment of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the usefulness of the combined assessment of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and duke pancreatic monoclonal antigen type 2 (DUPAN-2) in PDAC. We retrospectively investigated the impact of three tumor markers on overall survival (OS) and recurrence-free survival (RFS). Patients were classified into two groups: upfront surgery (US) and neoadjuvant chemoradiation (NACRT) groups. In total, 310 patients were evaluated. In the US group, patients who had all three elevated markers showed a significantly worse prognosis than the others (median: 16.4months, P=.005). In the NACRT group, patients who had elevated CA 19-9 and CEA levels after NACRT had significantly worse prognosis than the others (median: 26.2months, P < .001). The elevated DUPAN-2 levels before NACRT were associated with significantly worse prognosis than normal levels (median: 44.0 vs 59.2 months, P=.030). Patients who had elevated DUPAN-2 levels before NACRT with elevated CA 19-9 and CEA levels after NACRT showed extremely poor RFS (median: 5.9months). Multivariate analysis revealed that a modified triple-positive tumor marker indicating elevated DUPAN-2 levels before NACRT and elevated CA19-9 and CEA levels after NACRT was an independent prognostic factor of OS (hazard ratio: 2.49, P=.007) and RFS (hazard ration: 2.47, P=.007). The combined evaluation of three tumor markers may provide useful information for the treatment of patients with PDAC.

Preclinical Evaluation of 68Ga- and 177Lu-Labeled Integrin αvβ6-Targeting Radiotheranostic Peptides.

The integrin αvβ6, an epithelium-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas. Here, we developed and tested a novel αvβ6-targeting peptide, DOTA-5G (1) radiolabeled with 68Ga, for PET/CT imaging and 177Lu for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-albumin-binding moiety-5G (2). Methods: Peptides 1 and 2 were synthesized on solid phase, and their affinity for αvβ6 was assessed by enzyme-linked immunosorbent assay. The peptides were radiolabeled with 68Ga and 177Lu. In vitro cell binding, internalization, and efflux of 68Ga-1 and 177Lu-2 were evaluated in αvβ6-positive BxPC-3 human pancreatic cancer cells. PET/CT imaging of 68Ga-1 and 68Ga-2 was performed on female nu/nu mice bearing subcutaneous BxPC-3 tumors. Biodistribution was performed for 68Ga-1 (1 and 2 h after injection), 68Ga-2 (2 and 4 h after injection), and 177Lu-1 and 177Lu-2 (1, 24, 48, and 72 h after injection). The 177Lu-2 biodistribution data were extrapolated for human dosimetry data estimates using OLINDA/EXM 1.1. Therapeutic efficacy of 177Lu-2 was evaluated in mice bearing BxPC-3 tumors. Results: Peptides 1 and 2 demonstrated high affinity (<55 nM) for αvβ6 by enzyme-linked immunosorbent assay. 68Ga-1, 68Ga-2, 177Lu-1, and 177Lu-2 were synthesized in high radiochemical purity. Rapid invitro binding and internalization of 68Ga-1 and 177Lu-2 were observed in BxPC-3 cells. PET/CT imaging and biodistribution studies demonstrated uptake in BxPC-3 tumors. Introduction of the albumin-binding moiety in 177Lu-2 resulted in a 5-fold increase in tumor uptake and retention over time. Based on the extended dosimetry data, the dose-limiting organ for 177Lu-2 is the kidney. Treatment with 177Lu-2 prolonged median survival by 1.5- to 2-fold versus controls. Conclusion: 68Ga-1 and 177Lu-2 demonstrated high affinity for the integrin αvβ6 both invitro and invivo, were rapidly internalized into BxPC-3 cells, and were stable in mouse and human serum. Both radiotracers showed favorable pharmacokinetics in preclinical studies, with predominantly renal excretion and good tumor-to-normal-tissue ratios. Favorable human dosimetry data suggest the potential of 177Lu-2 as a treatment for pancreatic ductal adenocarcinoma.

Long-term outcomes of standard versus extended lymphadenectomy in pancreatoduodenectomy for pancreatic ductal adenocarcinoma: A Chinese multi-center prospective randomized controlled trial

IntroductionThe value of extended lymphadenectomy in pancreatoduodenectomy (PD) has been discussed by five randomized controlled studies. However, the limitations in the studies made their conclusions not sufficiently reliable. ObjectivesThis multi-center randomized controlled study was designed to clarify the efficacy of extended lymphadenectomy in PD for pancreatic ductal adenocarcinoma (PDAC). MethodsFrom December 2016 to October 2018, 170 consecutive patients undergoing PD were enrolled and randomized to standard or extended lymphadenectomy for the treatment of PDAC from three high-volume institutions in China. Demographic, pathological characteristics and survival data of these patients were collected and analyzed. No neoadjuvant treatment was performed. The primary endpoint was the 3-year overall survival. ResultsFor all patients, the 3-year survival rate was 25.88 %. There was no between-group difference in 3-year survival rate (27.16 % vs 24.72 % p = 0.717). The median survival time for the standard group was 18 months, while for the extended group it was 15 months. The demographic and pathological characteristics were similar between groups. More positive lymph nodes could be found in the extended group (2.34 ± 3.46 vs 1.41 ± 2.12, p = 0.035), which led to nodule stage migration. All patients received chemotherapy. But patients in extended group were more likely to fail in completion of all-cycles chemotherapy before recurrence (31.46 % vs 17.28 %, p = 0.032). Incomplete chemotherapy before recurrence, higher N status and abnormal CA125 were independent risk factors for 1-year survival (p < 0.001, 95 % CI 0.076–0.368; p = 0.017, 95 % CI 1.113–3.021; p = 0.021, 95 % CI 1.136–4.960, respectively), which was higher in the standard group (75.31 % vs 58.43 %, p = 0.020). ConclusionThe extended lymphadenectomy in PD did not improve the long-term survival in patients with PDAC. Patients with extended lymphadenectomy had a worse 1-year overall survival. However, the nodule stage migration facilitated by the extended lymphadenectomy contributed to the precise tumor staging.

S3422 Hepatic Parenchyma and Cholecystectomy Clip in Duodenum? An Interesting Case of Pancreatic Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death in many industrialized countries. Patients with PDAC typically report non-specific symptoms such as abdominal pain, weight loss, and jaundice. Given the lack of effective screening, many patients are diagnosed at the time of metastasis. Here we present a case of a patient who was diagnosed with metastatic PDAC with contained perforation in the duodenum. Case Description/Methods: A 74-year-old man with a history of prostate cancer requiring prostatectomy presented with a 2-month history of abdominal pain, nausea, vomiting, unintentional weight loss, and melena. He had normocytic and normochromic anemia with normal liver enzymes and lipase. Tumor markers ordered around the same time as EGD, including CEA/PSA, were unremarkable, but CA 19-9 was 6959 U/mL. EGD revealed a large necrotic, ulcerated duodenal mass in the first portion with suspicion of contained perforation. A metallic object was also identified which was likely a cholecystectomy clip as confirmed on subsequent CT. Pathology showed necrotic tissue and hepatic parenchymal cells, but there were no diagnostic neoplastic elements. CT abdomen showed a proximal duodenal mass with ulcer-like outpouching extending into the gallbladder fossa, abnormal perfusion of liver segments 4 and 5 with soft tissue mass adjacent to the pancreatic head suspicious of locally invasive primary duodenal malignancy. Whipple's procedure was performed, given the lesion's appearance and extent, and for diagnosis. Pathology revealed a poorly differentiated ductal adenocarcinoma of the head of the pancreas, with a signet ring pattern invading the duodenum wall, anterior surface of the pancreas. There was lymph node metastasis. The patient elected for hospice, given his poor prognosis (Figure). Discussion: Patients with PDAC often report epigastric pain, jaundice, and weight loss. Our patient presented with abdominal pain and weight loss. However, the melena and anemia raised concern for GI bleed; hence an EGD was performed, which led to the diagnosis of pancreatic adenocarcinoma with contained perforation in the duodenum. There are no practical screening tools for pancreatic cancer. Liver enzymes, CA 19-9, in addition to ultrasound abdomen or abdominal CT, depending upon the patient's symptoms and age, can be considered as part of work up. Curative treatment for PDAC is surgical resection with negative surgical margins and adjuvant therapies; however, the five-year survival rate remains low.Figure 1.: Necrotic duodenal lesion with cholecystectomy clip.

Berberine Overcomes Gemcitabine-Associated Chemoresistance through Regulation of Rap1/PI3K-Akt Signaling in Pancreatic Ductal Adenocarcinoma.

Gemcitabine (Gem)-based chemotherapy is one of the first-line treatments for pancreatic ductal adenocarcinoma (PDAC). However, its clinical effect is limited due to development of chemoresistance. Various naturally occurring compounds, including Berberine (BBR), provide an anti-cancer efficacy with time-tested safety, individually and in combination with chemotherapeutic drugs. Accordingly, we hypothesized that BBR might enhance the chemosensitivity to Gem in PDAC. In this study, cell culture studies using MIA PaCa-2 and BxPC-3 cells, followed by analysis in patient-derived organoids were performed to evaluate the anti-cancer effects of BBR in PDAC. Considering that cancer is a significant manifestation of increased chronic inflammatory stress, systems biology approaches are prudent for the identification of molecular pathways and networks responsible for phytochemical-induced anti-cancer activity, we used these approaches for BBR-mediated chemosensitization to Gem. Firstly, Gem-resistant (Gem-R) PDAC cells were established, and the combination of BBR and Gem revealed superior anti-cancer efficacy in Gem-R cells. Furthermore, the combination treatment induced cell cycle arrest and apoptosis in Gem-R PDAC cells. Transcriptomic profiling investigated the Rap1 and PI3K-Akt signaling pathway as a key regulator of Gem-resistance and was a key mediator for BBR-mediated chemosensitization in PDAC cells. All cell culture-based findings were successfully validated in patient-derived organoids. In conclusion, we demonstrate that BBR-mediated reversal of chemoresistance to Gem manifests through Rap1/PI3K-Akt signaling in PDAC.

Identification and verification of CCNB1 as a potential prognostic biomarker by comprehensive analysis

As one of the most common types of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) is highly invasive and lethal. This study aims to develop biomarkers and targets for the diagnosis and treatment of PDAC. Differentially expressed genes (DEGs) were screened via GEO2R, protein network was constructed through STRING and Cytoscape. Functional enrichment analysis was performed, followed by survival analysis and expression validation. A total of 115 DEGs were identified, including 108 upregulated and 7 downregulated genes. After enrichment, survival analysis, one potential gene, Cyclin B1 (CCNB1), was selected for further expression verification at the mRNA and protein level. Taker together, CCNB1 may act as a potential biomarker which provided new idea for elucidation of the pathogenesis of PDAC.

Molecular Markers of Pancreatic Cancer: A 10-Year Retrospective Review of Molecular Advances.

Pancreatic cancer remains the third leading cause of death amongst men and women in the United States. Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer maintains its reputation of being the most aggressive with a poor prognosis. One of the contributing factors to the high mortality of PDAC is the absence of biomarkers for early detection of disease and the complexity of tumor biology and genomics. In this review, we explored the current understanding of epigenetics and diagnostic biomarkers in PDAC and summarized recent advances in molecular biology. We discussed current guidelines on diagnosis, prognosis, and treatment, especially in high-risk individuals. We also reviewed studies that have touched on identifying biomarkers and the role they play in making early diagnosis although there are currently no screening tools for PDAC. We explored the recent understanding of epigenetic alterations of PDAC and the future implications for early detection and prognosis. In conclusion, the new and emerging advances in the detection and treatment of PDAC can lead to an improvement in the current outcome of PDAC.