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Past, Present and Further Looking for Therapeutic Management of Pancreatic...
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Past, Present and Further Looking for Therapeutic Management of Pancreatic Ductal Adenocarcinoma

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 September 2024) | Viewed by 8811

Special Issue Editors

Dr. Gennaro Nappo

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Guest Editor
Pancreatic Surgery Unit, Humanitas Clinical and Research Center, Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
Interests: pancreatic cancer; periampullary tumors; ampullary carcinoma; distal cholangiocarcinoma; therapeutic targets; diagnostic molecular markers; predictive molecular markers; prognostic molecular markers; preclinical models; conventional and unconventional chemoterapeutic approaches; teragnostics
Special Issues, Collections and Topics in MDPI journals
Dr. Niccola Funel

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Guest Editor
Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza ONLUS, 56017 Pisa, Italy
Interests: pancreatic cancers; pancreatic ductal adenocarcinoma; IPMN; histopathology; primary cell cultures; molecular biology; molecular pathology; laser microdissection; miRNAs; oncomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pancreatic ductal adenocarcinoma (PDAC) still represents one of the cancers with the poorest prognosis. Currently, surgery remains the only curative treatment for PDAC, but the 5-year survival rate of resected patients is only about 20–25%. During the last decades, some improvements have been done in terms of chemotherapic treatment, with the development of specific multi-chemotherapic regimens (FOLFIRINOX, gemcitabine + nab-paclitaxel, PAX-G) that have improved oncological results if compared with historical adopted single chemotherapic agents (gemcitabine). Moreover, if historically, for resectable PDAC, the gold standard strategy was surgery followed by adjuvant therapy, currently the scenario is radically changing. More often, the growing idea is to perform neoadjuvant therapy followed by surgery and, eventually, adjuvant treatment. The rationale for this approach is the early management of micro-metastatic disease and to allow a better selection of patient candidates to surgery. Thus, the analyses of old, recent and upcoming molecular markers could change the landscape of clinical management of the PDAC. However, preclinical models of PDAC, including all different levels of models approaching PDAC, will be appreciated in order to show experimental attempts to validate the role of biomolecular markers and their affinity for chemotherapy. Indeed, other new frontiers of PDAC treatment, including phytotherapy and theragnostic molecules, are welcome.

This Special Issue aims to evaluate all the novel therapeutic approaches for the management of PDAC (resectable, borderline-resectable, locally advanced and metastatic disease): pre-clinical and clinical studies focusing on this topic will be included in this Special Issue.

Dr. Gennaro Nappo
Dr. Niccola Funel
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pancreatic cancer
  • pancreatic ductal adenocarcinoma
  • treatment pancreatic cancer
  • chemotherapy pancreatic cancer
  • radiotherapy pancreatic cancer
  • pancreatic cancer biology
  • PDAC preclinical model
  • biomolecular markers
  • theragnostic molecules
  • target therapy

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Related Special Issue

Published Papers (5 papers)

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Research

31 pages, 5937 KiB  
Article
Oncolytic Tanapoxvirus Variants Expressing mIL-2 and mCCL-2 Regress Human Pancreatic Cancer Xenografts in Nude Mice
by Scott D. Haller and Karim Essani
Biomedicines 2024, 12(8), 1834; https://doi.org/10.3390/biomedicines12081834 - 12 Aug 2024
Viewed by 812
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death and presents the lowest 5-year survival rate of any form of cancer in the US. Only 20% of PDAC patients are suitable for surgical resection and adjuvant chemotherapy, which remains the [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death and presents the lowest 5-year survival rate of any form of cancer in the US. Only 20% of PDAC patients are suitable for surgical resection and adjuvant chemotherapy, which remains the only curative treatment. Chemotherapeutic and gene therapy treatments are associated with adverse effects and lack specificity/efficacy. In this study, we assess the oncolytic potential of immuno-oncolytic tanapoxvirus (TPV) recombinants expressing mouse monocyte chemoattractant protein (mMCP-1 or mCCL2) and mouse interleukin (mIL)-2 in human pancreatic BxPc-3 cells using immunocompromised and CD-3+ T-cell-reconstituted mice. Intratumoral treatment with TPV/∆66R/mCCL2 and TPV/∆66R/mIL-2 resulted in a regression in BxPc-3 xenograft volume compared to control in immunocompromised mice; mCCL-2 expressing TPV OV resulted in a significant difference from control at p < 0.05. Histological analysis of immunocompromised mice treated with TPV/∆66R/mCCL2 or TPV/∆66R/mIL-2 demonstrated multiple biomarkers indicative of increased severity of chronic, active inflammation compared to controls. In conclusion, TPV recombinants expressing mCCL2 and mIL-2 demonstrated a therapeutic effect via regression in BxPc-3 tumor xenografts. Considering the enhanced oncolytic potency of TPV recombinants demonstrated against PDAC in this study, further investigation as an alternative or combination treatment option for human PDAC may be warranted. Full article
(This article belongs to the Special Issue Past, Present and Further Looking for Therapeutic Management of Pancreatic Ductal Adenocarcinoma)
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12 pages, 1072 KiB  
Article
The Role of Pretreatment Serum Interleukin 6 in Predicting Short-Term Mortality in Patients with Advanced Pancreatic Cancer
by Se Jun Park, Ju Yeon Park, Kabsoo Shin, Tae Ho Hong, Younghoon Kim, In-Ho Kim and MyungAh Lee
Biomedicines 2024, 12(4), 903; https://doi.org/10.3390/biomedicines12040903 - 18 Apr 2024
Viewed by 1195
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its aggressive progression and dismal survival rates, with this study highlighting elevated interleukin 6 (IL-6) levels in patients as a key marker of increased disease severity and a potential prognostic indicator. Analyzing pre-treatment serum from 77 [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its aggressive progression and dismal survival rates, with this study highlighting elevated interleukin 6 (IL-6) levels in patients as a key marker of increased disease severity and a potential prognostic indicator. Analyzing pre-treatment serum from 77 advanced PDAC patients via ELISA, the research determined optimal cutoff values for IL-6 and the IL-6:sIL-6Rα ratio using receiver operating characteristic curve analysis, which then facilitated the division of patients into low and high IL-6 groups, showing significantly different survival outcomes. Notably, high IL-6 levels correlated with adverse features such as poorly differentiated histology, higher tumor burden, and low albumin levels, indicating a stronger likelihood of poorer prognosis. With a median follow-up of 9.28 months, patients with lower IL-6 levels experienced markedly better median overall survival and progression-free survival than those with higher levels, underscoring IL-6’s role in predicting disease prognosis. Multivariate analysis further confirmed IL-6 levels, alongside older age, and elevated neutrophil-to-lymphocyte ratio, as predictors of worse outcomes, suggesting that IL-6 could be a critical biomarker for tailoring treatment strategies in advanced PDAC, warranting further investigation into its role in systemic inflammation and the tumor microenvironment. Full article
(This article belongs to the Special Issue Past, Present and Further Looking for Therapeutic Management of Pancreatic Ductal Adenocarcinoma)
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18 pages, 3014 KiB  
Article
L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy
by Bruna Victorasso Jardim-Perassi, Pietro Irrera, Oluwaseyi E. Oluwatola, Dominique Abrahams, Veronica C. Estrella, Bryce Ordway, Samantha R. Byrne, Andrew A. Ojeda, Christopher J. Whelan, Jongphil Kim, Matthew S. Beatty, Sultan Damgaci-Erturk, Dario Livio Longo, Kim J. Gaspar, Gabrielle M. Siegers, Barbara A. Centeno, Justin Y. C. Lau, Shari A. Pilon-Thomas, Arig Ibrahim-Hashim and Robert J. Gillies
Biomedicines 2024, 12(2), 461; https://doi.org/10.3390/biomedicines12020461 - 19 Feb 2024
Cited by 2 | Viewed by 2149
Abstract
Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 [...] Read more.
Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer–magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks. Full article
(This article belongs to the Special Issue Past, Present and Further Looking for Therapeutic Management of Pancreatic Ductal Adenocarcinoma)
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19 pages, 4060 KiB  
Article
DLL3 Is a Prognostic and Potentially Predictive Biomarker for Immunotherapy Linked to PD/PD-L Axis and NOTCH1 in Pancreatic Cancer
by Carlos Lacalle-Gonzalez, Maria Florez-Cespedes, Lara Sanz-Criado, Michael Ochieng’ Otieno, Edurne Ramos-Muñoz, Maria Jesus Fernandez-Aceñero, Luis Ortega-Medina, Jesus Garcia-Foncillas and Javier Martinez-Useros
Biomedicines 2023, 11(10), 2812; https://doi.org/10.3390/biomedicines11102812 - 17 Oct 2023
Cited by 3 | Viewed by 1951
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm with very poor patient survival outcomes despite available treatments. There is an urgent need for new potential treatment options and novel biomarkers for these patients. Delta-like canonical Notch ligand 3 (DLL3) interacts with the Notch [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm with very poor patient survival outcomes despite available treatments. There is an urgent need for new potential treatment options and novel biomarkers for these patients. Delta-like canonical Notch ligand 3 (DLL3) interacts with the Notch receptor and causes inhibition of Notch signaling, which confers a survival advantage to PDAC cells. Thus, DLL3 expression could affect cell survival, and its inhibition could increase a patient’s survival. To test this hypothesis, a survival analysis was conducted using the progression-free and overall survival from two independent datasets of PDAC patients, with one using mRNA z-score levels and the other using the Hscore protein expression level; both were carried out using a log-rank test and plotted using Kaplan–Meier curves. DLL3 at the mRNA expression level showed an association between high mRNA expression and both a longer progression-free survival (PFS) and overall survival (OS) of patients. Then, we designed a retrospective study with resected PDAC samples. Our primary objective with this dataset was to assess the relationship between PFS and OS and DLL3 protein expression. The secondary assessment was to provide a rationale for the use of anti-DLL3-based treatments in combination with immunotherapy that is supported by the link between DLL3 and other factors that are involved in immune checkpoints. The survival analyses revealed a protective effect of high DLL3 protein expression levels in both PFS and OS. Interestingly, high DLL3 protein expression levels were significantly correlated with PD-L1/2 and negatively correlated with NOTCH1. Therefore, DLL3 could be considered a biomarker for better prognosis in resectable PDAC patients as well as a therapeutic biomarker for immunotherapy response. These facts set a rationale for testing anti-DLL3-based treatments either alone or combined with immunotherapy or other NOTCH1 inhibitors. Full article
(This article belongs to the Special Issue Past, Present and Further Looking for Therapeutic Management of Pancreatic Ductal Adenocarcinoma)
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12 pages, 2262 KiB  
Article
Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations
by Anthony Tarabay, Alice Boileve, Cristina Smolenschi, Leony Antoun, Marine Valery, Alina Fuerea, Audrey Perret, Pascal Burtin, Simona Cosconea, Hichem Belkhodja, David Malka, Valérie Boige, Antoine Hollebecque and Michel Ducreux
Biomedicines 2023, 11(9), 2569; https://doi.org/10.3390/biomedicines11092569 - 19 Sep 2023
Cited by 1 | Viewed by 1412
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of which are considered for molecular targeted [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of which are considered for molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. However, the applicability of molecular profiling (MP) for precision medicine in PDAC remains to be demonstrated. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years with histologically confirmed PDAC, who underwent tumor MP between 2010 and 2020 in our institution as part of personalized medicine trials. The primary study endpoint was overall survival (OS), and (minimal follow-up was 6 months after MP). Results: Of 115 eligible patients, MP was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Based on ESCAT classification, actionable GAs were found in 29 patients (28%), involving mainly BRCA1 or BRCA2 (5 (18%)), HER2 (5 (18%)), MTAP (5 (18%)), and FGFR (3 (11%)). Only 12 of these 29 patients (41%, or 10% of the whole population) received MTTs, with a median progression-free survival of 1.6 months. Median OS was 19 months in patients with actionable GAs treated with MTTs (n = 12 (11.8%)), 14 months in patients with actionable GAs treated with standard therapies (n = 17 (16.7%)), and 17 months in patients without actionable GAs treated with standard therapies (n = 73 (71.5%); p = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, p = 0.01). The highest OS following MTT was observed in patients with BRCA mutations treated with olaparib. Interpretation: Actionable GAs were found in more than a quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study with limited patient numbers. However, selected GA/MTT combinations (e.g., BRCA mutations/olaparib) were associated with a better outcome. Full article
(This article belongs to the Special Issue Past, Present and Further Looking for Therapeutic Management of Pancreatic Ductal Adenocarcinoma)
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