Pancreatic adenocarcinoma remains one of the most aggressive and difficult-to-treat solid tumor malignancies, with a high mortality-to-incidence ratio. Globally, pancreatic cancer ranks 12th in terms of incidence but sixth for mortality signifying its aggressive behavior and limited treatment options. While the mortality rates for many other solid tumors have substantially improved over the past few decades, temporal trends in pancreatic cancer mortality rates are quite sobering. In the United States, from 2000 to 2020, the mortality rates from pancreatic cancer have increased, whereas at the same time, mortality rates from other cancers, such as lung, colorectal, or kidney, have fallen appreciably. Is this for lack of treatment innovation? How do we improve survival for patients with pancreatic cancer? In this chapter, we discuss the recent advances and future directions with targeted therapies and immunotherapies in the treatment of pancreatic cancer, and provide the reasons for both optimism and caution for the future of systemic treatment of pancreatic cancer.

More than two decades ago, MD Anderson Cancer group discovered, characterised, and identified the WW domain-containing oxidoreductase (WWOX) as a genes of interest mapping to the chromosomal region 16q23.3-24.2. This was pioneering research since WWOX is a critical tumour suppressor gene implicated in various cancers, involving interactions with numerous signalling pathways and molecular mechanisms. Notably, it inhibits the Wnt/β-catenin pathway, which is often activated in tumours. This inhibition helps prevent tumour formation by regulating cell proliferation and promoting apoptosis. Restoration of WWOX expression in cancer cell lines has been shown to reduce tumour growth and increased sensitivity to treatments. In addition to its role in tumour suppression, WWOX has been found to interact with proteins involved in critical signalling pathways such as TGF-β. Recent advancements allowed to reveal its interactions with key proteins and microRNAs that regulate cellular adhesion, invasion, and motility. Proteomic studies have shown that WWOX directly interacts with signalling molecules like Dishevelled and SMAD3, further underscoring its role in antagonizing metastasis. Challenges remain in translating this knowledge into clinical applications. For instance, the mechanisms underlying WWOX loss in tumours and its role across diverse cancer types require further investigation. Overall, WWOX serves as a vital player in maintaining cellular stability and preventing cancer progression through its multifaceted functions. Here, we include an updated molecular function of WWOX in cancers to possibly contribute to the potential use of WWOX expression as a biomarker regarding prognosis and response to the treatment. CLINICAL TRIAL NUMBER: Not applicable.

O-GlcNAcylation of ribonucleotide reductase large subunit M1 (RRM1) at position 734 influences high glucose-induced genomic instability and cell transformation in normal pancreatic cells. By disrupting the ribonucleotide reductase complex, it reduces dNTPs. Although the impact of RRM1 O-GlcNAcylation on pancreatic cancer progression remains unexplored, our CRISPR knock-in technology created the RRM1-T734A mutation to minimize RRM1 O-GlcNAcylation. In pancreatic cancer PANC-1 cells with this mutation, we observed heightened replication stress-induced DNA damage, S-phase delays, and diminished in vitro tumor cell growth. Mechanistically, RRM1-T734A enhanced its interaction with RRM2 while impairing binding to RRM2B, leading to decreased NTPs and disrupted dNTP equilibrium. Notably, it doubled dTTP levels via TK1 stabilization mediated by thymidine, resulting in S-phase delay. TK1 silencing restored RRM1-T734A-induced effects on S-phase retardation and decreased colony formation. Our findings highlight the pivotal role of O-GlcNAcylation of RRM1 at T734 in maintaining genomic stability and promoting pancreatic cancer malignancy. Furthermore, reducing RRM1 O-GlcNAcylation increased pancreatic cancer cell sensitivity to gemcitabine, proposing a potential therapeutic strategy.

Irinotecan is a critical anticancer drug used to treat metastatic colorectal cancer and advanced pancreatic ductal adenocarcinoma by obstructing topoisomerase 1; however, it can cause minor-to-severe and life-threatening adverse effects. UDP glucuronosyltransferase family 1 member A1 (UGT1A1) polymorphisms increase the risk of irinotecan-induced neutropenia and diarrhea. Hence, screening for UGT1A1 polymorphisms before irinotecan-based chemotherapy is recommended to minimize toxicity, whereas liposomes offer the potential to deliver irinotecan with fewer side effects in patients with pancreatic ductal adenocarcinoma. This review presents a comprehensive overview of the effects of genotype-guided dosing of irinotecan on UGT1A1*28 and UGT1A1*6 variants, incorporating pharmacogenomic research, optimal regimens for metastatic colorectal and pancreatic cancer treatment using irinotecan, guidelines for toxicity reduction, and an evaluation of the cost-effectiveness of UGT1A1 genotype testing.

Lymphocyte activation gene 3 (LAG3) has emerged as a promising cancer immunotherapy target, but the mechanism underlying LAG3 activation upon ligand engagement remains elusive. Here, LAG3 was found to undergo robust non-K48-linked polyubiquitination upon ligand engagement, which promotes LAG3's inhibitory function instead of causing degradation. This ubiquitination could be triggered by the engagement of major histocompatibility complex class II (MHC class II) and membrane-bound (but not soluble) fibrinogen-like protein 1 (FGL1). LAG3 ubiquitination, mediated redundantly by the E3 ligases c-Cbl and Cbl-b, disrupted the membrane binding of the juxtamembrane basic residue-rich sequence, thereby stabilizing the LAG3 cytoplasmic tail in a membrane-dissociated conformation enabling signaling. Furthermore, LAG3 ubiquitination is crucial for the LAG3-mediated suppression of antitumor immunity in vivo. Consistently, LAG3 therapeutic antibodies repress LAG3 ubiquitination, correlating with their checkpoint blockade effects. Moreover, patient cohort analyses suggest that LAG3/CBL coexpression could serve as a biomarker for response to LAG3 blockade. Collectively, our study reveals an immune-checkpoint-triggering mechanism with translational potential in cancer immunotherapy.

Pancreatic adenocarcinoma (PDAC) unfortunately remains a highly fatal disease with a 5-year survival rate of only 11%. If surgical resection is not possible, systemic chemotherapy represents the standard-of-care approach to management. Combination chemotherapy regimens using fluorouracil (fluorouracil, oxaliplatin, leucovorin, and irinotecan; and fluorouracil, leucovorin, and oxaliplatin) or gemcitabine with albumin-bound paclitaxel have the potential to improve overall survival for patients with advanced disease. With the increasing understanding of the molecular drivers of pancreatic cancer, novel therapeutic approaches have made incremental progress for these patients. The molecular landscape of PDAC has been studied extensively. Approximately 90% of PDACs harbor mutations in the KRAS gene, a driver mutation that has long been considered undruggable. However, novel KRAS inhibitors have shown therapeutic promise in early-phase clinical trials, with larger studies ongoing. Less frequently encountered genomic aberrations that have therapeutic potential include NRG, BRAF, NTRK, HER2, BRCA, PALB2, and claudin. Immune checkpoint inhibitors have unfortunately yielded disappointing efficacy for the majority of patients with pancreatic cancer, except for those with tumors exhibiting deficiency in mismatch repair proteins. Alternative approaches to incorporate immunotherapy have shown more promise such as use of immune checkpoint inhibitors for selected patients in the maintenance setting and potential vaccine therapies in the postsurgery adjuvant setting. It is vital to perform molecular profiling in all patients with PDAC to identify potential treatment targets, and to enroll patients in clinical trials whenever possible.

This study aims to review the existing literature on the efficacy and safety of unconventional treatments among pancreatic cancer patients, including the use of natural products, dietary supplements, probiotics, whole medical systems, and body-based therapies.

An electronic, systematic, and comprehensive literature review was conducted searching for studies up to November 2024 following the PRISMA 2020 guidelines. Randomized controlled trials and prospective and retrospective studies assessing the efficacy and safety of unconventional treatments for pancreatic cancer were considered eligible. Data on overall survival, quality of life, and treatment tolerability were extracted.

A total of 21 studies, providing data from 3095 patients, met the inclusion criteria. Various types of unconventional treatments are used in pancreatic cancer patients, including Chinese herbal medicine (CHM), mistletoe extract (ME), curcumin, and electroacupuncture. Among these, the use of CHM and curcumin concomitant with standard therapy was associated with survival and quality-of-life benefits. Electroacupuncture reduced pancreatic cancer pain intensity in a cost-effective manner. The data on ME are mixed and of insufficient quality for drawing definitive conclusions.

Some unconventional treatments showed potential benefits in improving overall survival and quality of life in pancreatic cancer patients within an integrative oncology setting. Further high-quality studies are needed to provide robust, rigorous, and ethical evidence to support their integration into future guidelines, ensuring a holistic approach to cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) is among the cancer types with poorest prognosis and survival rates primarily due to resistance to standard-of-care therapies, including gemcitabine (GEM) and olaparib. Particularly, wild-type (wt)BRCA tumours, the most prevalent in PDAC, are more resistant to DNA-targeting agents like olaparib, restraining their clinical application. Recently, we disclosed a monoterpene indole alkaloid derivative (BBIT20) as a new inhibitor of homologous recombination (HR) DNA repair with anticancer activity in breast and ovarian cancer. Since inhibition of DNA repair enhances the sensitivity of cancer cells to chemotherapy, we aimed to investigate the anticancer potential of BBIT20 against PDAC, particularly carrying wtBRCA.

In vitro and in vivo PDAC models, particularly human cell lines (including GEM-resistant PDAC cells), patient-derived organoids and xenograft mice of PDAC were used to evaluate the anticancer potential of BBIT20, alone and in combination with GEM or olaparib. Disruption of the BRCA1-BARD1 interaction by BBIT20 was assessed by co-immunoprecipitation, immunofluorescence and yeast two-hybrid assay.

The potent antiproliferative activity of BBIT20, superior to olaparib, was demonstrated in PDAC cells regardless of BRCA status, by inducing cell cycle arrest, apoptosis, and DNA damage, while downregulating HR. The disruption of DNA double-strand breaks repair by BBIT20 was further reinforced by non-homologous end joining (NHEJ) suppression. The inhibition of BRCA1-BARD1 heterodimer by BBIT20 was demonstrated in PDAC cells and confirmed in a yeast two-hybrid assay. In GEM-resistant PDAC cells, BBIT20 showed potent antiproliferative, anti-migratory and anti-invasive activity, overcoming GEM resistance by inhibiting the multidrug resistance P-glycoprotein, upregulating the intracellular GEM-transporter ENT1, and downregulating GEM resistance-related microRNA-20a and GEM metabolism enzymes as RRM1/2. Furthermore, BBIT20 did not induce resistance in PDAC cells. It inhibited the growth of patient-derived PDAC organoids, by inducing apoptosis, repressing HR, and potentiating olaparib and GEM cytotoxicity. The enhancement of olaparib antitumor activity by BBIT20 was confirmed in xenograft mice of PDAC. Notably, it hindered tumour growth and liver metastasis formation, improving survival of orthotopic xenograft mice of PDAC. Furthermore, its potential as a stroma-targeting agent, reducing fibrotic extracellular matrix and overcoming desmoplasia, associated with an enhancement of immune cell response by depleting PD-L1 expression in tumour tissues, renders BBIT20 even more appealing for combination therapy, particularly with immunotherapy.

These findings underscore the great potential of BBIT20 as a novel multifaceted anticancer drug candidate for PDAC treatment.

Pancreatic cancer comes with one of the poorest prognoses of all cancers and as such it is crucial that new therapies are developed to improve on the current statistics. Currently, chemotherapy is the cornerstone of pancreatic cancer treatment with several drugs, and combinations of drugs being utilised for their anti-cancer effect. However, pancreatic cancer has a dense stroma around the tumour and intratumoral bacteria which result in drugs having difficulty penetrating the tumour or being metabolised by bacteria rendering them inactive. The utilisation of nanotechnology in chemotherapy for pancreatic cancer has been a huge area of focus for researchers worldwide with most of the focus being on lipid-based, inorganic and polymer-based nanoparticles. Solid lipid nanoparticles which have been studied since being first published in the 1990s, have been poorly researched for pancreatic cancer applications. Being composed of physiological lipids, solid lipid nanoparticles offer a greatly reduced risk of acute or chronic toxicities arising compared to inorganic or polymeric nanoparticles. They also possess the ability to improve on circulation time, permeability, and bioavailability of many first-line chemotherapeutics.

Pancreatic ductal adenocarcinoma (PC) is an aggressive form of cancer treated with chemotherapy regimens such as leucovorin, 5-fluorouracil (5-FU), irinotecan, oxaliplatin (FOLFIRINOX), and gemcitabine plus albumin-bound paclitaxel (nab-Paclitaxel). Maintenance chemotherapy is increasingly being studied as an option for patients with a prior response to chemotherapy, prolonged stable disease, and those unable to tolerate the toxicities of traditional chemotherapy.

Our retrospective analysis aims to evaluate the effectiveness and tolerability of capecitabine as maintenance therapy in patients with PC.

Thirty-three patients treated for PC with capecitabine (an oral formulation of 5-FU) maintenance therapy at our single institution between 8/01/2013 and 9/02/2021 were identified on chart review via the electronic medical record (EMR).

Kaplan-Meier curves were fit to evaluate patient progression-free survival (PFS) and overall survival (OS).

Thirty-three individuals were identified: 21 males and 12 females, with a median age of 69 years. Fifteen of 33 had stage IV PC. Nineteen had progression of disease; 8 completed therapy and transitioned to observation or other treatments; 2 did not tolerate treatment; and 4 were still undergoing treatment. The median PFS was 13.01 months (396.0 days), and the median OS was 28.42 months (865.0 days).

Maintenance with capecitabine seems safe and may represent a valuable option in patients with advanced PC controlled using FOLFIRINOX or gemcitabine/nab-Paclitaxel induction treatment.

Pancreatic ductal adenocarcinoma (PDAC) cell lines are classified into two types: epithelial and mesenchymal protein-expressing. Using scanning electron microscopy, we reported that these two groups differ in terms of morphology when they formed tumor spheres under three-dimensional (3D) culturing. In this study, we used transmission electron microscopy (TEM) to examine the intracellular microstructures of five epithelial and three mesenchymal PDAC cell lines in 3D culture, and compared them to the morphologies of the same cell types in two-dimensional (2D) cultures. Microvilli were present in all PDAC cells cultured in 2D and 3D, and were well developed in epithelial PDAC cells. Desmosome-like structures were only observed in epithelial PDAC cells, and were more common in 3D cultures. Secretory granules were observed in epithelial PDAC and mesenchymal PANC-1 cells, and were more common in 3D cultures. Intracytoplasmic lumina were only observed in epithelial PK-59 and T3M-4 cells cultured in 3D. Abundant filamentous aggregates were observed in 2D-cultured T3M-4 and MIA PaCa-2 cells. By contrast, entosis was observed in 3D-cultured PK-59, PK-1, and KP4 cells. Microstructural differences enhanced by 3D culturing revealed significant phenotypic diversity among PDAC cells, and may provide key insights into curing intractable pancreatic cancer.

This is a single arm, open label trial to assess the safety and efficacy of NALIRIFOX in Japanese participants who have not previously received therapy for metastatic adenocarcinoma of the pancreas. Forty-one participants will receive the treatment NALIRIFOX (liposomal irinotecan, 5-fluorouracil, levoleucovorin and oxaliplatin) until progression or unacceptable toxicity. Anti-tumor activity will be evaluated in terms of objective response rate according to RECIST v1.1 by independent central review. Safety will be carefully monitored, with a dedicated Safety Monitoring Committee reviewing the data from the initial six participants to safeguard the well-being of all individuals involved in the study. Other evaluations will include pharmacokinetics and the relationship between mutations in the UGT1A1 genes and safety. This study aims to show that the results of the NAPOLI 3 study in the global population can be reproduced in the Japanese population.Clinical trials registration: NCT06225999 (clinicaltrials.gov); jRCT2031230733 (Japanese clinical trials registry).

Pancreatic cancer is highly lethal, and survival chances improve only with early detection at a precancerous stage. However, there remains a significant gap in developing tools for large-scale, rapid screening. To this end, a high-throughput On-Target Array Extraction Platform (OTAEP) by direct sintering of a series of metal-organic frameworks (MOFs) for dual in situ extraction, encompassing both exosomes and their metabolic profiles, is developed. Based on the principle of geometry-dependent photothermal conversion efficiency and standard testing, the appropriate MOF functional unit is identified. This unit enables exosome enrichment within 10 min and metabolic fingerprint extraction in under 1 s of laser irradiation, with over five reuse. To further accelerate and enhance the quality of metabolic profile analysis, the application of Surrogate Variable Analysis to eliminate hidden confounding factors within the profiles is proposed, and five biomarkers demonstrated by MS/MS experiments are identified. These biomarkers enable early diagnosis, risk stratification, and staging of pancreatic cancer simultaneously, with sensitivity of 94.1%, specificity of 98.8%, and precision of 94.9%. This work represents a breakthrough for overcoming throughput challenges in large-scale testing and for addressing confounding factors in big data analysis.

Background: Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS, as well as downstream MAPK pathway effectors, have shown limited clinical success. While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Methods: Our therapeutic study targeted the PI3K pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with two different MAPK pathway inhibitors: Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099; SHP2 inhibitor). Western blot analysis demonstrated that the application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT). Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MAPK and PI3K-AKT, and effectively suppress PDAC growth. Results: In vitro studies demonstrated that, in several cell lines, both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. In vivo oral administration of combined Omipalisib/Trametinib treatment was significantly more effective than Omipalisib/SHP099 in reducing implanted tumor growth, and the Omipalisib/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone. Conclusions: Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers.

Glycolysis is a critical metabolic pathway in cancer cells, fulfilling their energy requirements, supporting biosynthesis, maintaining redox balance, and enabling survival in hostile environments. Alpha-enolase (ENO1) has been identified as a key promoter of tumor progression through its involvement in glycolysis. This study aims to elucidate the relationship between ENO1, glycolysis, and gemcitabine sensitivity in pancreatic cancer (PC). The expression levels of ENO1 in PC were analyzed using the GEPIA2 database, Kaplan-Meier survival plots, and immunohistochemistry (IHC). To assess the impact of ENO1 on gemcitabine sensitivity, we manipulated ENO1 expression in PC cell lines through overexpression and silencing techniques. Subsequent analyses included flow cytometry assays, glucose uptake and lactate production measurements, and cytotoxicity assays. The underlying mechanisms by which ENO1 modulates gemcitabine sensitivity were explored using Western blotting (WB). ENO1 was found to be significantly overexpressed in PC tissues, and elevated ENO1 levels were associated with poorer prognosis in PC patients. Overexpression of ENO1 reduced the sensitivity of PC cells to gemcitabine, enhancing cell proliferation, migration, and invasion by altering the cell cycle and inhibiting apoptosis. Conversely, silencing ENO1 decreased glycolysis in PC cells and heightened their sensitivity to gemcitabine. Furthermore, glycolysis inhibition-achieved through ENO1 knockdown, glucose deprivation, or treatment with 2-Deoxy-D-glucose (2-DG)-further enhanced the susceptibility of PC cells to gemcitabine. Mechanistically, ENO1 was found to regulate the expression of gemcitabine resistance-related genes, particularly ribonucleotide reductase catalytic subunit M1 (RRM1), via MYC through the glycolytic pathway, thereby contributing to gemcitabine resistance. This study demonstrates that ENO1 plays a crucial role in PC progression and is closely linked to gemcitabine resistance through its regulation of the glycolytic pathway.

Pancreatic cancer (PC) is a highly aggressive malignancy with limited treatment options. Although gemcitabine monotherapy (G treatment) has long been a standard treatment, combination therapies, such as gemcitabine with albumin-bound paclitaxel (AG treatment), have shown improved outcomes and were approved by the FDA for the PC. However, the AG treatment is also associated with increased adverse events (AEs), which remain inadequately evaluated in real-world settings.

We utilized the FDA Adverse Event Reporting System (FAERS) to conduct a large-scale pharmacovigilance analysis comparing the safety profiles of G and AG treatments for PC. By analyzing adverse event data from the third quarter of 2013 to the second quarter of 2024 and quantifying AE signals with reporting odds ratio (ROR) and proportional reporting ratio (PRR) methods, we compared the risk of AEs between the groups. Time to onset (TTO), subgroup and logistic regression analyses were also performed.

The study revealed a higher proportion of male (n = 2307, 54.1%) and elderly patients (age ≥ 65years, n = 2172, 50.9%) in the AG treatment group compared to the G treatment group. We found 17 preferred terms with positive signals at the top 50 common AEs, especially in gastrointestinal and blood systems. Cardiac and neurological AEs also needed to be vigilant. Biliary sepsis and infectious enterocolitis were newly identified AEs and deserve attention. Median TTO was 34 (IQR: 8-103) days (G) and 41 (IQR: 10-104) days (AG), with most AEs occurring within the first month (48.3% and 44%). Subgroup analysis revealed that male patients using the AG treatment had the highest risk of immune-mediated hepatitis (ROR = 23.51, 95% CI = 3.21-172.1), while elderly patients had elevated risks for presyncope (ROR = 24.84, 95% CI = 3.40-181.28) and falls (ROR = 18.60, 95% CI = 2.53-136.97). Logistic regression showed higher-risk fatal outcomes in males (adjusted OR = 1.42, 95% CI = 1.15-1.76, P < 0.01) and elderly patients (adjusted OR = 1.36, 95% CI = 1.10-1.69, P < 0.01).

This research offers critical safety insights in real-world settings, emphasizing patients at heightened AEs risk and informing clinical decision-making in PC treatment.

Pancreatic cancer is a challenging disease with limited treatment options and a high mortality rate. Just few therapy advances have been made in recent years. Tumor microenvironment, immunosuppressive features and mutational status represent important obstacles in the improvement of survival outcomes. Up to now, first-line therapy did achieve a median overall survival of less than 12 months and this discouraging data lead clinicians all over the world to focus their efforts on various fields of investigation: 1) sequential cycling of different systemic therapy in order to overcome mechanisms of resistance; 2) discovery of new predictive bio-markers, in order to target specific patient population; 3) combination treatment, in order to modulate the tumor microenvironment of pancreatic cancer; 4) new modalities of the delivery of drugs in order to pass the physical barrier of desmoplasia and tumor stroma. This review shows future directions of treatment strategies in advanced pancreatic cancer through a deep analysis of these recent macro areas of research.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape for several malignancies, but their efficacy in unresectable pancreatic adenocarcinoma remains uncertain. This systematic review aimed to evaluate the effectiveness and safety of ICIs in this context, focusing on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity. A comprehensive search of MEDLINE, EMBASE, CENTRAL, and Scopus identified 34 eligible studies, including randomized controlled trials and observational cohorts. Quantitative synthesis involved 21 studies comprising 937 patients, with additional qualitative analyses on biomarker-driven subgroups and early-phase trials. The median OS across studies was 8.65 months, while the median PFS was 2.55 months. The ORR and DCR were 16.2% and 50.3%, respectively, with grade ≥3 treatment-related adverse events occurring in 22% of patients. Promising outcomes were observed in MSI-H/dMMR populations, although these represented only 1-2% of cases. Combination strategies with chemotherapy demonstrated synergistic potential but lacked definitive evidence due to heterogeneity and the absence of phase III trials. ICIs showed a manageable toxicity profile, highlighting their feasibility in selected patients. Future research should focus on overcoming tumor microenvironment barriers and identifying biomarkers to optimize responsiveness and expand the applicability of ICIs in pancreatic cancer.

Pancreatic cancer is known as one of the poor prognostic cancers, and the most of patients are unable to undergo radical resection due to local progression or distant metastasis at initial diagnosis. In spite of the advancements in surgery and chemotherapy, there are many cases of recurrence after surgery or chemoradiotherapy mainly due to the presence of cancer stem cells (CSCs). CSCs are potential therapeutic target, but current issue is that an identification of CSCs is difficult since they are only present in a small number of tumor cells. Here we demonstrate that hydrogel PCDME can rapidly induce pancreatic cancer cell spheroids with elevated levels of stem cell markers including Sox2, Oct3/4, and Nanog, and the growth rate was reduced. CSCs showed activation of YAP/TAZ signaling, and microarray analysis showed markedly elevated expression of thioredoxin-interacting protein (TXNIP). Primary pancreatic cancer cells also increased TXNIP in addition to stemness markers on gel. In metabolic analysis, CSCs showed a shift of energy production from glycolysis to oxidative phosphorylation (OXPHOS). Furthermore, knockdown of TXNIP on PCDME gel using shRNAs decreased growth speed and in vivo tumorigenicity, suggesting that TXNIP may be involved in CSCs induction.

The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such rationale is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

Gemcitabine is widely used in the treatment of various cancers. This study aims to evaluate gemcitabine-associated adverse events (AEs) using the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

We analyzed data spanning from January 2004 to June 2023. Employing reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) algorithms, we identified AEs with positive signals in patients administered gemcitabine.

Out of 16,623,939 reports, 23,645 involved gemcitabine as the 'primary suspected (PS)' resulting in 74,306 AEs. Consistent with the reports in the specification and clinical trials, thrombocytopenia, pyrexia, neutropenia, and anemia were the most common AEs. Notably, our study identified some unexpected AEs such as abdominal pain, pleural effusion, ascites, and gastrointestinal hemorrhage, among others. The most significant SOC was 'Blood and lymphatic system disorders'. The median onset time for gemcitabine-related AEs was 24 days (interquartile range [IQR] 6-82 days), with most cases occurring within the initial 30 days following gemcitabine administration.

Gemcitabine is associated with a broad spectrum of AEs affecting multiple organ systems, with a notable incidence of hospitalization. The study highlights both expected and unexpected AEs, which could enhance future clinical applications and safety of gemcitabine.

This study investigated the effectiveness and safety of liposomal irinotecan plus 5-fluorouracil (5-FU) and leucovorin (LV) as a second-line treatment for patients with pancreatic ductal adenocarcinoma (PDAC) and borderline performance status. These patients are often excluded from clinical trials, but may still receive this therapy due to limited alternatives.

A retrospective analysis was conducted on 31 patients with metastatic PDAC and a Karnofsky Performance Status (KPS) of 40-60, who received liposomal irinotecan plus 5-FU/LV at two institutions between 2018 and 2019 in Taiwan. The NAPOLI nomogram was utilized to stratify patients into prognostic groups for survival comparison, with the good prognostic group defined as having total NAPOLI nomogram points ≥ the median value, and the poor prognostic group defined as having total NAPOLI nomogram points < the median value.

The median overall survival (OS) for the entire cohort was 4.2 months [95% confidence interval (CI)=3.0-5.3 months]. Patients in the NAPOLI nomogram's good prognostic group had a median OS of 4.9 months (95%CI=3.7-6.1 months), compared to 2.0 months (95%CI=1.5-2.4 months) in the poor prognostic group (p=0.014). Tumor response rates to liposomal irinotecan + 5-FU/LV were partial response in 3%, stable disease in 23%, and progressive disease in 74%, with significant differences in disease progression rates between good (56%) and poor (93%) prognostic groups (p=0.011). The most common grade 3 or 4 chemotherapy-related adverse events included anemia (26%), neutropenia (23%), non-neutropenic infection (19%), mucositis (13%), diarrhea (10%), and fatigue (3%).

Liposomal irinotecan plus 5-FU/LV regimen is a feasible second-line treatment option for PDAC patients with borderline performance status, with a safety profile consistent with clinical trial findings.

There has been a rapid expansion of novel therapeutics for hematologic malignancies, including monoclonal antibodies, small molecules, and cellular therapies, which confer different treatment-related toxicities and symptomatic adverse events (AEs) than traditional cytotoxic chemotherapies. Given that patients with blood cancers are living longer with these newer treatments, with some therapies requiring indefinite or time-intensive administration, consideration of patient-reported tolerability and effects on health-related quality of life (HRQoL) are increasingly relevant. Historically, clinical trials have focused on the efficacy and safety of therapies. While related to safety and not intended to replace it, "treatment tolerability" is a distinct construct defined as the extent to which symptomatic and nonsymptomatic AEs impact a patient's ability and desire to continue with current treatment dosing, which also encompasses how patients feel and function while undergoing anticancer therapies. Assessment of tolerability requires the systematic and rigorous measurement of patient-reported outcomes (PROs). In this review, we discuss the introduction of patient-reported outcomes measures (PROMs) into hematology clinical trials and how PROs inform the measurement of treatment tolerability, including symptomatic adverse events, physical and role functioning, and overall side effect burden. Selected PROMs for measurement of these core tolerability domains are outlined, with a focus on novel analytic tools that have been developed for the longitudinal analysis of tolerability data. Further, we outline ongoing studies to accelerate integration of PROs throughout the cancer care spectrum, from early-stage drug development to routine clinical care, with the goal of improving both HRQoL and survival.

For metastatic pancreatic ductal adenocarcinoma (mPDAC), there are no established third-line chemotherapy options. We examined the efficacy and safety of third-line chemotherapy in patients with mPDAC in real-world practice.

We retrospectively analyzed 257 patients with mPDAC and progressive disease after first-line treatment with gemcitabine-based regimens and second-line treatment with liposomal irinotecan plus 5-fluorouracil and leucovorin at five Taiwanese medical centers from 2018 to 2022. Treatment efficacy and toxicity were analyzed in 77 of 257 patients receiving third-line treatment subsequently. We performed univariate and multivariate analyses to identify prognostic factors for overall survival (OS) in patients receiving third-line treatment.

Patients receiving third-line treatment had a median OS of 4.5 months (95 % confidence interval [CI], 3.6-5.4), compared to 1.6 months (95 % CI, 1.3-1.9) for those who did not. Independent poor prognostic factors for OS included the absence of previous pancreatectomy (adjusted hazard ratio [aHR] 3.03, 95 % CI, 1.30-7.14, P = 0.001), an ECOG score of ≥2 ((aHR 9.81, 95 % CI 4.34-22.1, P < 0.001), and progressive disease response during second-line treatment (aHR 1.90, 95 % CI 1.21-8.91, P = 0.020, P = 0.020). Median OS for patients with none, one, two, and three poor prognostic factors were 15.9 (95 % CI, 12.3-19.6), 7.0 (2.6-13.3), 4.4 (3.5-5.2), and 2.0 (1.7-2.2) months, respectively. 43 of 77 patients (56 %) experienced at least one grade 3 or 4 toxicity.

In real-world settings, patients with mPDAC receiving third-line chemotherapy may have a moderate survival advantage, although clinicians should carefully select patients owing to high incidence of grade 3/4 toxicities.

Surface-altered, targeted nanocarriers play crucial roles in chemotherapy. Incorporating ligands into polymers may alter their chemical composition, potentially compromising their drug storage and encapsulation capacity. Polydopamine (PDA) is a novel, biocompatible, and versatile agent for producing targeted nanoparticles that serve as a base for conjugating specific ligands to non-reactive polymeric nanocarriers. This investigation aimed to evaluate whether gemcitabine (GEM)-loaded liposomes conjugated with PDA could enhance cancer treatment.

A series of liposomes, named plain GEM, GEM@FA, and GEM@FA/PDA, was designed. Transmission Electron Microscopy (TEM), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray Photoelectron Spectroscopy (XPS) were used to confirm the presence of PDA coating and folic acid (FA) and PDA conjugations. Cellular uptake, cytotoxicity, and cell death were evaluated using biochemical and flow cytometric assays.

Compared to typical liposomes, GEM@FA/PDA liposomes were smaller, more stable, and exhibited a spherical shape with excellent cellular uptake. GEM@FA and GEM@FA/PDA liposomes showed significantly higher cytotoxicity against lung cancer (H1299) cells compared to GEM liposomes and pure GEM solution at all concentrations, while causing much less cytotoxicity to normal cells (NIH3T3).

GEM@FA/PDA liposomes demonstrated enhanced cancer-fighting effectiveness while minimizing harm to healthy tissues, making them a promising approach for chemotherapy.

Advanced pancreatic cancer results in high morbidity and mortality. The standard of care treatment in the advanced setting changed in 2011 with the introduction of FOLFIRINOX (FFX) chemotherapy. However, it was highly toxic with significant risk of complications. We assessed the practice patterns of medical oncologists across Canada.

We performed a retrospective study of consecutive patients with advanced pancreatic cancer treated with FFX at eight Canadian cancer centers. Demographic, treatment, and outcome data were collected and analyzed.

The median age of the patients was 61 (range 24-80), 43% were female, 96% had an ECOG PS of 0 or 1, and 50% had three or more metastatic sites. The median follow-up time was 20.8 months (95%CI 18.6-24.9). Physicians started FFX at the standard dose 31% of the time. Physicians prescribed GCSF for primary prophylaxis most when giving standard-dose FFX (30% of the time) in comparison to reduced dose with or without the 5-FU bolus. Dose reductions occurred in 78.1% of patients, while dose delay occurred in 65.2% of patients.

Medical oncologists in Canada historically prescribed FFX to patients with advanced pancreatic cancer in a fashion that was not uniform, prior to the emergence of evidence for upfront dose reductions.

The Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation is one of the most prevailing mutations in various tumors and is difficult to cure. Long-term proliferation in carcinogenesis is primarily initiated by oncogenic KRAS-downstream signaling. Recent research suggests that it also activates the autocrine effect and interplays the tumor microenvironment (TME). Here, we discuss the emerging research, including KRAS mutations to immune evasion in TME, which induce immunological modulation that promotes tumor development. This review gives an overview of the existing knowledge of the underlying connection between KRAS mutations and tumor immune modulation. It also addresses the mechanisms to reduce the effect of oncogenes on the immune system and recent advances in clinical trials for immunotherapy in KRAS-mutated cancers.

Pancreatic cancer (PCa) has insidious onset, high malignancy and poor prognosis. Gemcitabine (GEM) is one of the first-line chemotherapy drugs for PCa. However, GEM resistance has always been a bottleneck problem leading to recurrence and death of PCa patients. RNA-binding proteins (RBPs) are important proteins that regulate transportation, splicing, stability and translation of RNA. Abnormal expression of RBPs often lead to a series of abnormal accumulation or degradation of downstream RNA resulting in various diseases. In our study, we utilized RIP seq, RIP-qPCR, in vitro and in vivo experiments and found that pumilio2 (PUM2) was high expression in PCa, and promoted GEM resistance of PCa by regulating mRNA stability of integrin Alpha 3 (ITGA3) and other genes in focal adhesion pathway, and there was positive feedback regulation between PUM2 and transcription factor early growth response gene 1 (EGR1), that is PUM2 binding to 3'UTR region of EGR1 mRNA, and EGR1 binding to promoter region of PUM2 gene. The discovery of EGR1/PUM2/ITGA3 axis provided a solid experimental basis for the selection of chemotherapy regiments for PCa patients and exploration of combined regimens to reverse GEM resistance in the future.

Pancreatic carcinoma (PC) is the sixth leading cause of cancer death in both sexes in 2022, responsible for almost 5% of all cancer deaths worldwide; it is characterized by a poor prognosis since most patients present with an unresectable and metastatic tumor. To date, the decreasing trend in mortality rates related to the most common cancers has contributed to making pancreatic cancer a serious public health problem. In the last few years, scientific research has led to many advances in diagnostic approaches, perioperative management, radiotherapy techniques, and systemic therapies for advanced disease, but only with modest incremental progress in PC patient outcomes. Most of the causes of this high mortality are, unfortunately, late diagnosis and an important therapeutic resistance; for this reason, the most recent high-throughput proteomics technologies focus on the identification of novel biomarkers and molecular profiling to generate new insights in the study of PC, to improve diagnosis and prognosis and to monitor the therapies progress. In this work, we present and discuss the integration of results from different revised studies on protein biomarkers in a global proteomic meta-analysis to understand which path to pursue scientific research. In particular, cancer signaling, inflammatory response, and cell migration and signaling have emerged as the main pathways described in PC, as well as scavenging of free radicals and metabolic alteration concurrently highlighted new research insights on this disease. Interestingly, from the study of upstream regulators, some were found to be shared by collecting data relating to both biological fluid and tissue biomarkers, side by side: specifically, TNF, LPS, p38-MAPK, AGT, miR-323-5p, and miR-34a-5p. By integrating many biological components with their interactions and environmental relationships, it's possible to achieve an in-depth description of the pathological condition in PC and define correlations between concomitant symptoms and tumor genesis and progression. In conclusion, our work may represent a strategy to combine the results from different studies on various biological samples in a more comprehensive way.

Gemcitabine (Gem) is approved for use in pancreatic cancer chemotherapy. However, Gem undergoes rapid metabolism in the blood, producing an inactive metabolite. Due to this rapid metabolism, the effective dose of Gem is high, thereby predisposing patients to severe adverse effects. This study aimed to improve Gem's metabolic and therapeutic stability by modifying the amine group (4-NH2) with hydroxylamine to form 4-N-hydroxylGem hydrochloride (GemAGY). Micro-elemental analysis and Nuclear Magnetic Resonance (NMR) were used to characterize GemAGY, and its anticancer activity was investigated against MiaPaCa-2, BxPC-3, and PANC-1 pancreatic cancer cell lines. The GemAGY metabolic stability was evaluated in human liver microsomal solution. In the 2D cytotoxicity assay, the IC50 values of GemAGY-treated MiaPaCa-2, PANC-1, and BxPC-3 cells were significantly lower when compared to GemHCl-treated cultures. More so, in 3D spheroid assay results, GemAGY IC50 values were found to be 9.5 ± 1.1 µM and 12.6 ± 1.0 µM when compared to GemHCl IC50 values of 24.1 ± 1.6 µM and 30.2 ± 1.8 µM in MiaPaCa-2 and PANC-1 cells, respectively. GemAGY was stable, with 60% remaining intact after 2 hours of digestion in microsomal enzymes, compared to GemHCl, which had less than 45% remaining intact after 30 minutes. GemAGY-treated MiaPaCa-2 and PANC-1 cells at 3.12 and 6.25 μM concentrations demonstrated a significantly reduced cell migration towards the wound area compared to the GemHCl-treated cultures at the same concentrations. Further, GemAGY-treated MiaPaCa-2 cells significantly increased the expression of p53 and BAX compared to GemHCl-treated cells. GemAGY demonstrated significant anticancer activity and improved metabolic stability compared to GemHCl and is most likely to have potential anticancer activity against pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death worldwide, and its global burden has increased significantly over the past few years. The incidence of pancreatic cancer has also increased in the United States, and most of this increase is attributed to the population's aging process in addition to the rise in the prevalence of risk factors such as obesity, diabetes, smoking, and alcohol intake. Most patients with pancreatic cancer present with advanced unresectable or metastatic disease. Only a few patients present at an early stage with localized disease, and a multidisciplinary approach is required to maximize survival and outcomes. The surgical approach is an option for localized disease, and surgery's safety and efficacy have also been improved in recent years due to the increasing use of minimally invasive surgical techniques. Moreover, systematic chemotherapy has also been used and has had a significant impact on survival. More recently, neoadjuvant therapy has been used for pancreatic cancer along with radiation therapy, optimizing survival among those patients. Targeted therapies have been introduced based on genetic testing in metastatic pancreatic cancer and have shown promising results. Moreover, immune checkpoint inhibitors and targeted agents such as PARP inhibitors and vaccines have emerged with optimal results in terms of survival. To conclude, pancreatic cancer is considered a disease with poor long-term survival; however, recent developments in pharmacotherapy have changed its treatment and have improved outcomes with improved survival. Our review summarizes ongoing therapeutic options for local and metastatic pancreatic cancer. It also summarizes new state-of-the-art therapies that have emerged or are in trials, which can change the pancreatic cancer treatment perspective.

Pancreatic ductal adenocarcinoma (PDA) is one of the most malignant solid cancers. KRAS mutation accounts for over 90% of cases. p21-activated kinases (PAKs) act downstream of KRAS and are involved in tumorigenesis. The inhibition of PAK4 suppresses PDA by stimulating the tumor infiltration of cytotoxic T cells. The major histocompatibility complex class I (MHC I) is a key in presenting antigens to cytotoxic T cells. MHC I degradation via autophagy promotes the immune evasion of pancreatic cancer. We investigated the effect of PAK4 inhibition on MHC I expression and autophagy.

In this study, using proteomic analysis, fluorescence-activated cell sorting (FACS), and immunoblotting, we examined the effect of PAK4 knockout (KO) in human PDA cells on the expression of MHC I and autophagy to identify the mechanism involved in the stimulation of cytotoxic T cells by PAK4 inhibition.

We found that PAK4 KO increased MHC I expression in two human PDA cell lines: MiaPaCa-2 and PANC-1. PAK4 KO also increased cancer cell autophagy. However, the inhibition of autophagy by chloroquine (CQ) did not affect the effect of PAK4 KO on apoptosis and cell death. More importantly, the inhibition of autophagy by CQ did not alter the expression of MHC I stimulated by PAK4 KO, indicating that PAK4 KO stimulated MHC I expression via an autophagy-independent pathway.

We identified a role of PAK4 in MHC I expression by PDA cells, which is independent of autophagy.

Cancer is the world's leading cause of death impacting millions of lives globally. The increasing research over the past several decades has focused on the development of new anticancer drugs, but still cancer continues to be a global health challenge. Thus, several new alternative therapeutic strategies have been tried for the drug design and discovery. Purine and pyrimidine heterocyclic compounds have received attention recently due to their potential in targeting various cancers. It is evident from the recently published data over the last decade that incorporation of the purine and pyrimidine rings in the synthesized derivatives resulted in the development of potent anticancer molecules. This review presents synthetic strategies encompassing several examples of recently developed purine and pyrimidine-containing compounds as anticancer agents. In addition, their structure-activity relationships are represented in the schemes indicating the fragment or groups that are essential for the enhanced anticancer activities. Purine and pyrimidines combined with other heterocyclic compounds have resulted in many novel anticancer molecules that address the challenges of drug resistance. The purine and pyrimidine derivatives showed significantly enhanced anticancer activities against targeted receptor proteins with numerous compounds with an IC50 value in the nanomolar range. The review will support medicinal chemists and contribute in progression and development of synthesis of more potent chemotherapeutic drug candidates to mitigate the burden of this dreadful disease.

Pancreatic ductal adenocarcinoma (PDAC) ranks among the leading causes of cancer-related deaths worldwide. Despite advances in precision oncology in other malignancies, treatment of PDAC still largely relies on conventional chemotherapy. Given the dismal prognosis and heterogeneity in PDAC, there is an urgent need for personalized therapeutic strategies to improve treatment response. Organoids, generated from patients' tumor tissue, have emerged as a powerful tool in cancer research. These three-dimensional models faithfully recapitulate the morphological and genetic features of the parental tumor and retain patient-specific heterogeneity. This review summarizes existing precision oncology approaches in PDAC, explores current applications and limitations of organoid cultures in personalized medicine, details preclinical studies correlating in vitro organoid prediction and patient treatment response, and provides an overview of ongoing organoid-based clinical trials.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.