Metabolites derived from gut microbiota mitigate chemoresistance in pancreatic cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of tumor-related deaths. The gut microbiota has gained attention in cancer treatment, due to its influence on the immune system and drug activity. AREAS COVERED: Tintelnot and collaborators highlight distinct gut microbiota composition in metastatic PDAC (mPDAC) patients responding versus non-responding to chemotherapy. In the context of chemotherapy treatment, the gut microbiota of responders can metabolize tryptophan from food into indole-3-acetic acid (3-IAA). The presence of neutrophil-derived myeloperoxidase facilitates the role of 3-IAA in promoting the accumulation of reactive oxygen species in tumor cells. This accumulation, in turn, inducing tumor cell cytotoxicity. Additionally, 3-IAA can inhibit tumor cell autophagy activity, diminishing tumor cells' ability to adapt to cell stress. This manuscript provides a comprehensive analysis of the latest research on microbiota, metabolites, and PDAC, sourced from PubMed, ScienceDirect, and Google Scholar. EXPERT OPINION: The evaluated study noted an elevation of the bacterial metabolite 3-IAA in responsive PDAC patients' serum, suggesting its potential to enhance chemotherapy sensitivity. Gaining a thorough comprehension of the impact of gut microbiota metabolites on drug activity is beneficial for broadening our strategies to mitigate chemotherapy resistance in tumors and identifying markers that predict chemotherapy outcomes.

Targeting a key FAK-tor: the therapeutic potential of combining focal adhesion kinase (FAK) inhibitors and chemotherapy for chemoresistant non-small cell lung cancer.

INTRODUCTION: NSCLC is the leading cause of cancer-related deaths globally, with a low survival rate primarily due to NSCLC frequently becoming chemoresistant. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in pathways regulating multiple processes in the cell, including survival, migration, and the TME, that contribute to both tumor progression and drug resistance. Recently, FAK inhibitors (FAKi) have shown promising potential for the treatment of NSCLC. AREAS COVERED: This narrative review aims to summarize key signaling pathways involving FAK that contribute to tumor progression and drug resistance. It will further provide an overview of FAKi currently in pre- and early-phase clinical trials for solid tumors, as well as the therapeutic potential of combining FAKi with chemotherapy, as this has emerged as a promising strategy to overcome chemoresistance in NSCLC. EXPERT OPINION: It is becoming increasingly clear that FAK is not an oncogenic driver but rather contributes to tumor progression and drug resistance. Hence, while FAKi have only demonstrated modest results in clinical trials when given by themselves, treatment regimens combining other therapies with FAKi have shown promising potential to overcome drug resistance. Lastly, of particular novelty are FAK-PROTACs (proteolysis-targeting chimaeras), which uniquely target both cytosolic and nuclear FAK.

The role of l-leucovorin uptake and metabolism in the modulation of 5-fluorouracil efficacy and antifolate toxicity.

Background: L-Leucovorin (l-LV; 5-formyltetrahydrofolate, folinic acid) is a precursor for 5,10-methylenetetrahydrofolate (5,10-CH2-THF), which is important for the potentiation of the antitumor activity of 5-fluorouracil (5FU). LV is also used to rescue antifolate toxicity. LV is commonly administered as a racemic mixture of its l-LV and d-LV stereoisomers. We compared dl-LV with l-LV and investigated whether d-LV would interfere with the activity of l-LV. Methods: Using radioactive substrates, we characterized the transport properties of l-LV and d-LV, and compared the efficacy of l-LV with d-LV to potentiate 5FU-mediated thymidylate synthase (TS) inhibition. Using proliferation assays, we investigated their potential to protect cancer cells from cytotoxicity of the antifolates methotrexate, pemetrexed (Alimta), raltitrexed (Tomudex) and pralatrexate (Folotyn). Results: l-LV displayed an 8-fold and 3.5-fold higher substrate affinity than d-LV for the reduced folate carrier (RFC/SLC19A1) and proton coupled folate transporter (PCFT/SLC46A1), respectively. In selected colon cancer cell lines, the greatest enhanced efficacy of 5FU was observed for l-LV (2-fold) followed by the racemic mixture, whereas d-LV was ineffective. The cytotoxicity of antifolates in lymphoma and various solid tumor cell lines could be protected very efficiently by l-LV but not by d-LV. This protective effect of l-LV was dependent on cellular RFC expression as corroborated in RFC/PCFT-knockout and RFC/PCFT-transfected cells. Assessment of TS activity in situ showed that TS inhibition by 5FU could be enhanced by l-LV and dl-LV and only partially by d-LV. However, protection from inhibition by various antifolates was solely achieved by l-LV and dl-LV. Conclusion: In general l-LV acts similar to the dl-LV formulations, however disparate effects were observed when d-LV and l-LV were used in combination, conceivably by d-LV affecting (anti)folate transport and intracellular metabolism.

Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC. METHODS: Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin's effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin's effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients' cohort. RESULTS: In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI50 of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine. CONCLUSION: This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.

Unravelling the complexities of resistance mechanism in pancreatic cancer: insights from in vitro and ex-vivo model systems.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis and rising global deaths. Late diagnosis, due to absent early symptoms and biomarkers, limits treatment mainly to chemotherapy, which soon encounters resistance. PDAC treatment innovation is hampered by its complex and heterogeneous resistant nature, including mutations in key genes and a stromal-rich, immunosuppressive tumour microenvironment. Recent studies on PDAC resistance stress the need for suitable in vitro and ex vivo models to replicate its complex molecular and microenvironmental landscape. This review summarises advances in these models, which can aid in combating chemoresistance and serve as platforms for discovering new therapeutics. Immortalised cell lines offer homogeneity, unlimited proliferation, and reproducibility, but while many gemcitabine-resistant PDAC cell lines exist, fewer models are available for resistance to other drugs. Organoids from PDAC patients show promise in mimicking tumour heterogeneity and chemosensitivity. Bioreactors, co-culture systems and organotypic slices, incorporating stromal and immune cells, are being developed to understand tumour-stroma interactions and the tumour microenvironment's role in drug resistance. Lastly, another innovative approach is three-dimensional bioprinting, which creates tissue-like structures resembling PDAC architecture, allowing for drug screening. These advanced models can guide researchers in selecting optimal in vitro tests, potentially improving therapeutic strategies and patient outcomes.

Lactic acid: a narrative review of a promoter of the liver cancer microenvironment.

Background and Objective: Lactic acid is a metabolite of glycolysis produced in the body, and its production is thought to be a mechanism by which cancer cells evade immune surveillance. Immune evasion and metabolic changes are well established as basic hallmarks of cancer. Although lactate has long been considered a waste product, it is now generally recognized to be a versatile small-molecule chemical that plays an important part in the tumor microenvironment (TME), with increased lactate production linked to the development of human malignancies. Metabolism in liver cancer is redirected toward glycolysis, which enhances the production of metabolic compounds used by tumor cells to produce proteins, lipids, and nucleotides, enabling them to maintain high proliferation rates and to establish the TME. Dysregulation of metabolic activity in liver cancer may impair antitumor responses owing to the immunosuppressive activity of the lactate produced by anaerobic glycolytic rates in tumor cells. This review primarily explores the link connection between lactic acid and the TME; evaluates the role of lactic acid in the occurrence, metastasis, prognosis, and treatment of liver cancer. Additionally, it investigates the associated pathways as potential targets for liver cancer treatment. Methods: Literature searches were conducted in PubMed, Web of Science, and Google Scholar, with the publication date of the most recent article included being January 2024. After eliminating duplicate articles and less relevant articles through titles and abstracts, we selected 113 articles for this review. We categorized references into two categories. One is to classify the content into lactate-related, liver cancer-related and tumor metabolism-related. The other is to classify the article types, which are divided into reviews, research articles and clinical trials. Additionally, we consulted the reference lists of the relevant articles to ensure coverage was comprehensive and unbiased. Key Content and Findings: The connection between lactic acid and the TME has recently become an area of intense research interest, and many related articles have been published in this field. The main finding of this review is to summarize the proven link between lactate and the TME and its possible impact on the TME of liver cancer. And analyzed the potential of lactate in liver cancer treatment and prognosis prediction. Conclusions: Lactate may be key to developing novel approaches in the future treatment of liver cancer. Related research on the combination of classic therapies and molecular targeted drugs may provide innovative medicines that more selectively regulate immune cell activity.

The Current Role of Single-Site Robotic Approach in Liver Resection: A Systematic Review.

BACKGROUND: Liver resection is a critical surgical procedure for treating various hepatic pathologies. Minimally invasive approaches have gradually gained importance, and, in recent years, the introduction of robotic surgery has transformed the surgical landscape, providing potential advantages such as enhanced precision and stable ergonomic vision. Among robotic techniques, the single-site approach has garnered increasing attention due to its potential to minimize surgical trauma and improve cosmetic outcomes. However, the full extent of its utility and efficacy in liver resection has yet to be thoroughly explored. METHODS: We conducted a comprehensive systematic review to evaluate the current role of the single-site robotic approach in liver resection. A detailed search of PubMed was performed to identify relevant studies published up to January 2024. Eligible studies were critically appraised, and data concerning surgical outcomes, perioperative parameters, and post-operative complications were extracted and analyzed. RESULTS: Our review synthesizes evidence from six studies, encompassing a total of seven cases undergoing robotic single-site hepatic resection (SSHR) using various versions of the da Vinci© system. Specifically, the procedures included five left lateral segmentectomy, one right hepatectomy, and one caudate lobe resection. We provide a summary of the surgical techniques, indications, selection criteria, and outcomes associated with this approach. CONCLUSION: The single-site robotic approach represents an option among the minimally invasive approaches in liver surgery. However, although the feasibility has been demonstrated, further studies are needed to elucidate its optimal utilization, long-term outcomes, and comparative effectiveness against the other techniques. This systematic review provides valuable insights into the current state of single-site robotic liver resection and underscores the need for continued research in this rapidly evolving field.

Exploring the therapeutic potential of a novel series of imidazothiadiazoles targeting focal adhesion kinase (FAK) for pancreatic cancer treatment: synthesis, mechanistic insights and promising antitumor and safety profile.

Focal Adhesion Kinase (FAK) is a non-receptor protein tyrosine kinase that plays a crucial role in various oncogenic processes related to cell adhesion, migration, proliferation, and survival. The strategic targeting of FAK represents a burgeoning approach to address resistant tumours, such as pancreatic ductal adenocarcinoma (PDAC). Herein, we report a new series of twenty imidazo[2,1-b][1, 3, 4]thiadiazole derivatives assayed for their antiproliferative activity against the National Cancer Institute (NCI-60) panel and a wide panel of PDAC models. Lead compound 10l exhibited effective antiproliferative activity against immortalised (SUIT-2, CAPAN-1, PANC-1, PATU-T, BxPC-3), primary (PDAC-3) and gemcitabine-resistant clone (PANC-1-GR) PDAC cells, eliciting IC50 values in the low micromolar range (1.04-3.44 µM), associated with a significant reduction in cell-migration and spheroid shrinkage in vitro. High-throughput kinase arrays revealed a significant inhibition of the FAK signalling network, associated to induction of cell cycle arrest in G2/M phase, suppression of tumour cell invasion and apoptosis induction. The high selectivity index/toxicity prompted studies using PDAC mouse xenografts, demonstrating significant inhibition of tumour growth and safety. In conclusion, compound 10l displayed antitumor activity and safety in both in vitro and in vivo models, emerging as a highly promising lead for the development of FAK inhibitors in PDAC.

Unlocking the diagnostic power of plasma extracellular vesicle miR-200 family in pancreatic ductal adenocarcinoma.

BACKGROUND: Distinguishing benign from malignant pancreaticobiliary disease is challenging because of the absence of reliable biomarkers. Circulating extracellular vesicles (EVs) have emerged as functional mediators between cells. Their cargos, including microRNAs (miRNAs), are increasingly acknowledged as an important source of potential biomarkers. This multicentric, prospective study aimed to establish a diagnostic plasma EV-derived miRNA signature to discriminate pancreatic ductal adenocarcinoma (PDAC) from benign pancreaticobiliary disease. METHODS: Plasma EVs were isolated using size exclusion chromatography (SEC) and characterised using nanoparticle tracking analysis, electron microscopy and Western blotting. EV-RNAs underwent small RNA sequencing to discover differentially expressed markers for PDAC (n = 10 benign vs. 10 PDAC). Candidate EV-miRNAs were then validated in a cohort of 61 patients (n = 31 benign vs. 30 PDAC) by RT-qPCR. Logistic regression and optimal thresholds (Youden Index) were used to develop an EV-miR-200 family model to detect cancer. This model was tested in an independent cohort of 95 patients (n = 30 benign, 33 PDAC, and 32 cholangiocarcinoma). RESULTS: Small RNA sequencing and RT-qPCR showed that EV-miR-200 family members were significantly overexpressed in PDAC vs. benign disease. Combined expression of the EV-miR-200 family showed an AUC of 0.823. In an independent validation cohort, application of this model showed a sensitivity, specificity and AUC of 100%, 88%, and 0.97, respectively, for diagnosing PDAC. CONCLUSIONS: This is the first study to validate plasma EV-miR-200 members as a clinically-useful diagnostic biomarker for PDAC. Further validation in larger cohorts and clinical trials is essential. These findings also suggest the potential utility in monitoring response and/or recurrence.

Effects of lactate dehydrogenase A and GLUT1 inhibition on human endothelial cell migration in relation to their intracellular nucleotide pool.

The expression of both lactate dehydrogenase A (LDH-A) and glucose transporter type 1 (GLUT1) is high in pancreatic, thoracic and many other types of cancer. GLUT1 is also highly expressed in endothelial cells (EC), that play an important role in tumor metastasis. We investigated the effect of inhibition of LDH-A by NHI-2 and GLUT1 by PGL14 on cellular migration, a hallmark of metastasis, in relation to changes in intracellular purine nucleotide and nicotinamide adenine dinucleotide pools in a human microvascular endothelial cell line (HMEC-1). HMEC-1 were treated with NHI-2 and PGL14 alone or in combination. Cell migration was tested by the wound healing assay. The intracellular purine nucleotides and NAD+/NADH concentrations were measured using Reversed-Phase High Performance Liquid Chromatography (RP-HPLC). Both NHI-2 at 15 µM and 45 µM and PGL14 at 10 µM and 30 µM inhibited migration by 5 to 28% while the combination led to 46% inhibition. The drugs also decreased intracellular nucleotide pools, but only 45 µM NHI-2 altered energy charge and redox status in HMEC-1 cells. Inhibitors of glycolysis attenuated migration and the energy charge of EC and support further development of LDH-A and GLUT1 inhibitors to target cancer aggressiveness and metastasis.

MicroRNAs as Bile-based biomarkers in pancreaticobiliary cancers (MIRABILE): a cohort study.

BACKGROUND: Biliary obstruction can be due to both malignant and benign pancreaticobiliary disease. Currently, there are no biomarkers that can accurately help make this distinction. MicroRNAs (miRNAs) are stable molecules in tissue and biofluids that are commonly deregulated in cancer. The MIRABILE study aimed to identify miRNAs in bile that can differentiate malignant from benign pancreaticobiliary disease. MATERIALS AND METHODS: There were 111 patients recruited prospectively at endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) for obstructive jaundice, and bile was aspirated for cell-free RNA (cfRNA) extraction and analysis. In a discovery cohort of 78 patients (27 with pancreatic ductal adenocarcinoma (PDAC), 14 cholangiocarcinoma (CCA), 37 benign disease), cfRNA was subjected to small-RNA sequencing. LASSO regression was used to define bile miRNA signatures, and NormFinder to identify endogenous controls. In a second cohort of 87 patients (34 PDAC, 14 CCA, 39 benign disease), RT-qPCR was used for validation. RESULTS: LASSO regression identified 14 differentially-expressed bile miRNAs of which 6 were selected for validation. When comparing malignant and benign pancreaticobiliary disease, bile miR-340 and miR-182 were validated and significantly differentially expressed (P<0.05 and P<0.001, respectively). This generated an AUC of 0.79 (95%CI 0.70-0.88, sensitivity 65%; specificity 82%) in predicting malignant disease. CONCLUSION: Bile collected during biliary drainage contains miRNAs able to differentiate benign from malignant pancreaticobiliary diseases in patients with obstructive jaundice. These bile miRNAs have the potential to increase diagnostic accuracy.

Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic Indicator and Therapeutic Target.

Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new cancer hallmark. Herein, we investigated the largely uncharacterized alternative splicing profile and the key splicing factor SF3B1 in PDAC pancreatic cells and tissues as a potential discovery source of plausible drug targets and new predictive biomarkers of clinical outcome. The research involved a transcriptome-wide analysis, comparing profiles of splicing profiles in PDAC primary cells with normal ductal cells. This revealed more than 400 significant differential splicing events in genes involved in regulation of gene expression, primarily related to mRNA splicing, and metabolism of nucleic acids. PDAC cultures were highly sensitive to the SF3B1 modulators, E7107 and Pladienolide-B, showing IC50s in the low nanomolar range. These compounds induced apoptosis, associated to induction of the MCL-1/S splice variant. and reduced cell migration, associated to RON mis-splicing. In an orthotopic mouse model, E7107 showed promising results. Furthermore, we evaluated SF3B1 expression in specimens from 87 patients and found a significant association of SF3B1 expression with progression-free and overall survival. In conclusion, SF3B1 emerges as both a potential prognostic factor and therapeutic target in PDAC, impacting cell proliferation, migration, and apoptosis. These findings warrant future studies on this new therapeutic strategy against PDAC.

Deciphering the performance of macrophages in tumour microenvironment: a call for precision immunotherapy.

Macrophages infiltrating tumour tissues or residing in the microenvironment of solid tumours are known as tumour-associated macrophages (TAMs). These specialized immune cells play crucial roles in tumour growth, angiogenesis, immune regulation, metastasis, and chemoresistance. TAMs encompass various subpopulations, primarily classified into M1 and M2 subtypes based on their differentiation and activities. M1 macrophages, characterized by a pro-inflammatory phenotype, exert anti-tumoural effects, while M2 macrophages, with an anti-inflammatory phenotype, function as protumoural regulators. These highly versatile cells respond to stimuli from tumour cells and other constituents within the tumour microenvironment (TME), such as growth factors, cytokines, chemokines, and enzymes. These stimuli induce their polarization towards one phenotype or another, leading to complex interactions with TME components and influencing both pro-tumour and anti-tumour processes.This review comprehensively and deeply covers the literature on macrophages, their origin and function as well as the intricate interplay between macrophages and the TME, influencing the dual nature of TAMs in promoting both pro- and anti-tumour processes. Moreover, the review delves into the primary pathways implicated in macrophage polarization, examining the diverse stimuli that regulate this process. These stimuli play a crucial role in shaping the phenotype and functions of macrophages. In addition, the advantages and limitations of current macrophage based clinical interventions are reviewed, including enhancing TAM phagocytosis, inducing TAM exhaustion, inhibiting TAM recruitment, and polarizing TAMs towards an M1-like phenotype. In conclusion, while the treatment strategies targeting macrophages in precision medicine show promise, overcoming several obstacles is still necessary to achieve an accessible and efficient immunotherapy.

Evaluation of the combination of gemcitabine, carboplatin, and lactate dehydrogenase A inhibitor on malignant mesothelioma.

OBJECTIVES: Lactate dehydrogenase A (LDH-A) catalyzes the last step of glycolysis: supplying cells rapidly but inefficiently with ATP. Many tumors, including malignant mesothelioma (MM), have a high expression of LDH-A, which is associated with cancer aggressiveness. We aimed to determine whether the efficacy of the gemcitabine/carboplatin (Gem + Carbo) combination, widely used to treat this disease, could be increased by inhibition of LDH-A (by NHI-2). To this aim, we analyzed the growth inhibition of pleural and peritoneal MM by multiple combinations. METHODS: The 72 h sulforhodamine B assay (SRB) was used to test the cytotoxicity of the combination of gemcitabine (in the range 0.1 - 400 nM) and carboplatin (0.01 - 40 µM) with a fixed concentration of NHI-2 (at IC25). We used pleural (H2452) and primary peritoneal (STO, MESO-II) MM cell lines, cultured at normoxic conditions. RESULTS: NHI-2 did not increase the cytotoxicity of the combination of 100 nM gemcitabine and 10 µM carboplatin in peritoneal MM cell lines. The cell growth inhibition was 10% smaller after the triple combination than the Gem + Carbo treatment. CONCLUSIONS: Inhibition of LDH-A did not increase the efficacy of gemcitabine and carboplatin in MM under normoxic conditions.

The microbial composition of pancreatic ductal adenocarcinoma: A systematic review of 16S rRNA gene sequencing.

BACKGROUND: Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), continues to pose a significant clinical and scientific challenge. The most significant finding of recent years is that PDAC tumours harbour their specific microbiome, which differs amongst tumour entities and is distinct from healthy tissue. This review aims to evaluate and summarise all PDAC studies that have used the next-generation technique, 16S rRNA gene amplicon sequencing within each bodily compartment. As well as establishing a causal relationship between PDAC and the microbiome. MATERIALS AND METHODS: This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. A comprehensive search strategy was designed, and 1727 studies were analysed. RESULTS: In total, 38 studies were selected for qualitative analysis and summarised significant PDAC bacterial signatures. Despite the growing amount of data provided, we are not able to state a universal 16S rRNA gene microbial signature that can be used for PDAC screening. This is most certainly due to the heterogeneity of the presentation of results, lack of available datasets and the intrinsic selection bias between studies. CONCLUSION: Several key studies have begun to shed light on causality and the influence the microbiome constituents and their produced metabolites could play in tumorigenesis and influencing outcomes. The challenge in this field is to shape the available microbial data into targetable signatures. Making sequenced data readily available is critical, coupled with the coordinated standardisation of data and the need for consensus guidelines in studies investigating the microbiome in PDAC.

The trend toward more target therapy in pancreatic ductal adenocarcinoma.

INTRODUCTION: Despite the considerable progress made in cancer treatment through the development of target therapies, pancreatic ductal adenocarcinoma (PDAC) continues to exhibit resistance to this category of drugs. As a result, chemotherapy combination regimens remain the primary treatment approach for this aggressive cancer. AREAS COVERED: In this review, we provide an in-depth analysis of past and ongoing trials on both well-known and novel targets that are being explored in PDAC, including PARP, EGFR, HER2, KRAS, and its downstream and upstream pathways (such as RAF/MEK/ERK and PI3K/AKT/mTOR), JAK/STAT pathway, angiogenesis, metabolisms, epigenetic targets, claudin, and novel targets (such as P53 and plectin). We also provide a comprehensive overview of the significant trials for each target, allowing a thorough glimpse into the past and future of target therapy. EXPERT OPINION: The path toward implementing a target therapy capable of improving the overall survival of PDAC is still long, and it is unlikely that a monotherapy target drug will fulfill a meaningful role in addressing the complexity of this cancer. Thus, we discuss the future direction of target therapies in PDAC, trying to identify the more promising target and combination treatments, with a special focus on the more eagerly awaited ongoing trials.

G-Protein Signaling Modulator 2 as a Potential Biomarker in Colorectal Cancer: Integrative Analysis Using Genetic Profiling and Pan-Cancer Studies.

Colorectal cancer (CRC) imposes a significant healthcare burden globally, prompting the quest for innovative biomarkers to enhance diagnostic and therapeutic strategies. This study investigates the G-protein signaling modulator (GPSM) family across several cancers and presents a comprehensive pan-cancer analysis of the GPSM2 gene across several gastrointestinal (GI) cancers. Leveraging bioinformatics methodologies, we investigated GPSM2 expression patterns, protein interactions, functional enrichments, prognostic implications, genetic alterations, and immune infiltration associations. Furthermore, the expression of the GPSM2 gene was analyzed using real-time analysis. Our findings reveal a consistent upregulation of GPSM2 expression in all GI cancer datasets analyzed, suggesting its potential as a universal biomarker in GI cancers. Functional enrichment analysis underscores the involvement of GPSM2 in vital pathways, indicating its role in tumor progression. The prognostic assessment indicates that elevated GPSM2 expression correlates with adverse overall and disease-free survival outcomes across multiple GI cancer types. Genetic alteration analysis highlights the prevalence of mutations, particularly missense mutations, in GPSM2. Furthermore, significant correlations between GPSM2 expression and immune cell infiltration are observed, suggesting its involvement in tumor immune evasion mechanisms. Collectively, our study underscores the multifaceted role of GPSM2 in GI cancers, particularly in CRC, emphasizing its potential as a promising biomarker for prognosis and therapeutic targeting. Further functional investigations are warranted to elucidate its clinical utility and therapeutic implications in CRC management.