CDK4/6 inhibition sensitizes MEK inhibition by inhibiting cell cycle and proliferation in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to most chemotherapy drugs, leading to poor chemotherapy efficacy. Recently, Trametinib and Palbociclib have promising prospects in the treatment of pancreatic cancer. This article aims to explore the effects of Trametinib on pancreatic cancer and address the underlying mechanism of resistance as well as its reversal strategies. The GDSC (Genomics of Drug Sensitivity in Cancer) and CTD2 (Cancer Target Discovery and Development) were utilized to screen the potential drug candidate in PDAC cell lines. The dose-increase method combined with the high-dose shock method was applied to induce the Trametinib-resistant PANC-1 and MIA PaCa-2 cell lines. The CCK8 proliferation assay, colony formation assay, flow cytometry, and western blot were conducted to verify the inhibitory effect of Trametinib and Palbociclib. RNA-seq was performed in resistant PDAC cell lines to find the differential expression genes related to drug resistance and predict pathways leading to the reversal of Trametinib resistance. The GDSC and CTD2 database screening revealed that Trametinib demonstrates a significant inhibitory effect on PDAC. We found that Trametinib has a lower IC50 than Gemcitabine in PDAC cell lines. Both Trametinib and Gemcitabine can decrease the proliferation capacity of pancreatic cells, induce cell cycle arrest, and increase apoptosis. Simultaneously, the phosphorylation of the AKT and ERK pathways were inhibited by the treatment of Trametinib. In addition, the RNA-seq of Trametinib-induced resistance PDAC cell lines reveals that the cyclin-dependent kinase (CDK)-RB-E2F regulatory axis and G2/M DNA damage checkpoint might lead the drug resistance. Besides, the combination of Trametinib with Palbociclib could inhibit the proliferation and cell cycle of both resistant cells lines and also restore the sensitivity of drug-resistant cells to Trametinib. Last but not least, the interferon-α and interferon-γ expression were upregulated in resistance cell lines, which might lead to the reversal of drug resistance. The study shows Trametinib has a critical inhibitory effect on PDAC. Besides, the combination of Trametinib with Palbociclib can inhibit the proliferation of PDAC-resistant cells.

Selective epigenetic alterations in RNF43 in pancreatic exocrine cells from high-fat-diet-induced obese mice; implications for pancreatic cancer.

OBJECTIVE: Pancreatic cancer (PC) originates and progresses with genetic mutations in various oncogenes and suppressor genes, notably KRAS, CDKN2A, TP53, and SMAD4, prevalent across diverse PC cells. In addition to genetic mutations/deletions, persistent exposure to high-risk factors, including obesity, induces whole-genome scale epigenetic alterations contributing to malignancy. However, the impact of obesity on DNA methylation in the presymptomatic stage, particularly in genes prone to PC mutation, remains uncharacterized. RESULTS: We analyzed the methylation levels of 197 loci in six genes (KRAS, CDKN2A, TP53, SMAD4, GNAS and RNF43) using Illumina Mouse Methylation BeadChip array (280 K) data from pancreatic exocrine cells obtained from high-fat-diet (HFD) induced obese mice. Results revealed no significant differences in methylation levels in loci between HFD- and normal-fat-diet (NFD)-fed mice, except for RNF43, a negative regulator of Wnt signaling, which showed hypermethylation in three loci. These findings indicate that, in mouse pancreatic exocrine cells, high-fat dietary obesity induced aberrant DNA methylation in RNF43 but not in other frequently mutated PC-related genes.

Blood-Based Multiomics-Guided Detection of a Precancerous Pancreatic Tumor.

Over a decade ago, longitudinal multiomics analysis was pioneered for early disease detection and individually tailored precision health interventions. However, high sample processing costs, expansive multiomics measurements along with complex data analysis have made this approach to precision/personalized medicine impractical. Here we describe in a case report, a more practical approach that uses fewer measurements, annual sampling, and faster decision making. We also show how this approach offers promise to detect an exceedingly rare and potentially fatal condition before it fully manifests. Specifically, we describe in the present case report how longitudinal multiomics monitoring (LMOM) helped detect a precancerous pancreatic tumor and led to a successful surgical intervention. The patient, enrolled in an annual blood-based LMOM since 2018, had dramatic changes in the June 2021 and 2022 annual metabolomics and proteomics results that prompted further clinical diagnostic testing for pancreatic cancer. Using abdominal magnetic resonance imaging, a 2.6 cm lesion in the tail of the patient's pancreas was detected. The tumor fluid from an aspiration biopsy had 10,000 times that of normal carcinoembryonic antigen levels. After the tumor was surgically resected, histopathological findings confirmed it was a precancerous pancreatic tumor. Postoperative omics testing indicated that most metabolite and protein levels returned to patient's 2018 levels. This case report illustrates the potentials of blood LMOM for precision/personalized medicine, and new ways of thinking medical innovation for a potentially life-saving early diagnosis of pancreatic cancer. Blood LMOM warrants future programmatic translational research with the goals of precision medicine, and individually tailored cancer diagnoses and treatments.

A 15-Inflammation-Related Gene Signature Predicts the Prognosis of Patients With Pancreatic Ductal Adenocarcinoma.

Chronic inflammation promotes the development of pancreatic ductal adenocarcinoma (PDAC) and PDAC-related inflammatory tumor microenvironment facilitates tumor growth and metastasis. Thus, we aimed to study the association between inflammatory response and prognosis in patients with PDAC. We conducted the whole transcriptomic sequencing using tissue samples collected from patients diagnosed with PDAC (n = 106) recruited from Shandong Cancer Hospital. We first constructed a prognostic signature using 15 inflammation-related genes in The Cancer Genome Atlas (TCGA) cohort (n = 177) and further validated it in an independent International Cancer Genome Consortium (ICGC) cohort (n = 90) and our in-house cohort. PDAC patients with a higher risk score had poorer overall survival (OS) (P < 0.001; HR, 3.02; 95% CI, 1.94-4.70). The association between the prognostic signature and OS remained significant in the multivariable Cox regression adjusting for age, sex, alcohol exposure, diabetes, and stage (P < 0.001; HR, 2.91; 95% CI, 1.73-4.89). This gene signature also robustly predicted prognosis in the ICGC cohort (P = 0.01; HR, 1.94; 95% CI, 1.14-3.30) and our cohort (P < 0.001; HR, 2.40; 95% CI, 1.45-3.97). Immune subtype C3 (inflammatory) was enriched and CD8+ T cells were higher in patients with a lower risk score (P < 0.05). Furthermore, PDAC patients with higher risk scores were more sensitive to chemotherapy, immunotherapy, and PARP inhibitors (P < 0.05). In sum, we identified a novel gene signature that was associated with inflammatory response for risk stratification, prognosis prediction, and therapy guidance in PDAC patients. Future studies are warranted to validate the clinical utility of the signature.

Disruption of the pro-oncogenic c-RAF-PDE8A complex represents a differentiated approach to treating KRAS-c-RAF dependent PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is considered the third leading cause of cancer mortality in the western world, offering advanced stage patients with few viable treatment options. Consequently, there remains an urgent unmet need to develop novel therapeutic strategies that can effectively inhibit pro-oncogenic molecular targets underpinning PDACs pathogenesis and progression. One such target is c-RAF, a downstream effector of RAS that is considered essential for the oncogenic growth and survival of mutant RAS-driven cancers (including KRASMT PDAC). Herein, we demonstrate how a novel cell-penetrating peptide disruptor (DRx-170) of the c-RAF-PDE8A protein-protein interaction (PPI) represents a differentiated approach to exploiting the c-RAF-cAMP/PKA signaling axes and treating KRAS-c-RAF dependent PDAC. Through disrupting the c-RAF-PDE8A protein complex, DRx-170 promotes the inactivation of c-RAF through an allosteric mechanism, dependent upon inactivating PKA phosphorylation. DRx-170 inhibits cell proliferation, adhesion and migration of a KRASMT PDAC cell line (PANC1), independent of ERK1/2 activity. Moreover, combining DRx-170 with afatinib significantly enhances PANC1 growth inhibition in both 2D and 3D cellular models. DRx-170 sensitivity appears to correlate with c-RAF dependency. This proof-of-concept study supports the development of DRx-170 as a novel and differentiated strategy for targeting c-RAF activity in KRAS-c-RAF dependent PDAC.

Integrated bioinformatics analysis reveals upregulated extracellular matrix hub genes in pancreatic cancer: Implications for diagnosis, prognosis, immune infiltration, and therapeutic strategies.

BACKGROUND: Pancreatic cancer (PC) stands out as one of the most formidable malignancies and exhibits an exceptionally unfavorable clinical prognosis due to the absence of well-defined diagnostic indicators and its tendency to develop resistance to therapeutic interventions. The primary objective of this present study was to identify extracellular matrix (ECM)-related hub genes (HGs) and their corresponding molecular signatures, with the intent of potentially utilizing them as biomarkers for diagnostic, prognostic, and therapeutic applications. METHODS: Three microarray datasets were sourced from the NCBI database to acquire upregulated differentially expressed genes (DEGs), while MatrisomeDB was employed for filtering ECM-related genes. Subsequently, a protein-protein interaction (PPI) network was established using the STRING database. The created network was visually inspected through Cytoscape, and HGs were identified using the CytoHubba plugin tool. Furthermore, enrichment analysis, expression pattern analysis, clinicopathological correlation, survival analysis, immune cell infiltration analysis, and examination of chemical compounds were carried out using Enrichr, GEPIA2, ULCAN, Kaplan Meier plotter, TIMER2.0, and CTD web platforms, respectively. The diagnostic and prognostic significance of HGs was evaluated through the ROC curve analysis. RESULTS: Ten genes associated with ECM functions were identified as HGs among 131 DEGs obtained from microarray datasets. Notably, the expression of these HGs exhibited significantly (p < 0.05) higher in PC, demonstrating a clear association with tumor advancement. Remarkably, higher expression levels of these HGs were inversely correlated with the likelihood of patient survival. Moreover, ROC curve analysis revealed that identified HGs are promising biomarkers for both diagnostic (AUC > 0.75) and prognostic (AUC > 0.64) purposes. Furthermore, we observed a positive correlation between immune cell infiltration and the expression of most HGs. Lastly, our study identified nine compounds with significant interaction profiles that could potentially act as effective chemical agents targeting the identified HGs. CONCLUSION: Taken together, our findings suggest that COL1A1, KRT19, MMP1, COL11A1, SDC1, ITGA2, COL1A2, POSTN, FN1, and COL5A1 hold promise as innovative biomarkers for both the diagnosis and prognosis of PC, and they present as prospective targets for therapeutic interventions aimed at impeding the progression PC.

The causal effects of immune cells on pancreatic cancer: A 2­sample Mendelian randomization study.

Leveraging publicly available genetic datasets, we conducted a comprehensive 2-sample Mendelian randomization (MR) analysis to explore the causal links between 731 immunophenotypes and the risk of pancreatic cancer (PC). To ensure the robustness of our findings, extensive sensitivity analyses were performed, evaluating stability, heterogeneity, and potential horizontal pleiotropy. Our analysis pinpointed 24 immunophenotypes significantly associated with the risk of PC. Notably, phenotypes such as CD4+ CD8dim %leukocyte (OR = 0.852, 95% CI = 0.729-0.995, P = .0430) and HLA DR+ CD4+ AC (OR = 0.933, 95% CI = 0.883-0.986) in TBNK were inversely correlated with PC risk. Conversely, phenotypes like CD28 on CD45RA- CD4 non-Treg (OR = 1.155, 95% CI = 1.028-1.297, P = .016) and CD25 on activated Treg (OR = 1.180, 95% CI = 1.014-1.374, P = .032) in Treg cells, among others, exhibited a positive correlation. These insights offer a valuable genetic perspective that could guide future clinical research in this area.

PAFAH1B3 is a KLF9 target gene that promotes proliferation and metastasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Uncontrolled cell proliferation, invasion and migration of pancreatic cancer cells are the fundamental causes of death in PDAC patients. Our previous studies showed that KLF9 inhibits the proliferation, invasion and migration of pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In this study, we found that platelet-activating factor acetylhydrolase IB3 (PAFAH1B3) is highly expressed in pancreatic cancer tissues and cells. In vitro and in vivo studies showed that overexpression of PAFAH1B3 promoted the proliferation and invasion of pancreatic cancer cells, while downregulation of PAFAH1B3 inhibited these processes. We found that KLF9 expression is negatively correlated with PAFAH1B3 expression in pancreatic cancer tissues and cells. Western blotting revealed that KLF9 negatively regulates the expression of PAFAH1B3 in pancreatic cancer tissues and cells. Rescue experiments showed that overexpression of PAFAH1B3 could partially attenuate the suppression of pancreatic cancer cell proliferation, invasion and migration induced by KLF9 overexpression. Finally, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out, and the results showed that KLF9 directly binds to the promoter of PAFAH1B3 and inhibits its transcriptional activity. In conclusion, our study indicated that KLF9 can inhibit the proliferation, invasion, migration and metastasis of pancreatic cancer cells by inhibiting PAFAH1B3.

A senescence restriction point acting on chromatin integrates oncogenic signals.

We identify a senescence restriction point (SeRP) as a critical event for cells to commit to senescence. The SeRP integrates the intensity and duration of oncogenic stress, keeps a memory of previous stresses, and combines oncogenic signals acting on different pathways by modulating chromatin accessibility. Chromatin regions opened upon commitment to senescence are enriched in nucleolar-associated domains, which are gene-poor regions enriched in repeated sequences. Once committed to senescence, cells no longer depend on the initial stress signal and exhibit a characteristic transcriptome regulated by a transcription factor network that includes ETV4, RUNX1, OCT1, and MAFB. Consistent with a tumor suppressor role for this network, the levels of ETV4 and RUNX1 are very high in benign lesions of the pancreas but decrease dramatically in pancreatic ductal adenocarcinomas. The discovery of senescence commitment and its chromatin-linked regulation suggests potential strategies for reinstating tumor suppression in human cancers.

Activated NAD+ biosynthesis pathway induces olaparib resistance in BRCA1 knockout pancreatic cancer cells.

PARP inhibitors have been developed as anti-cancer agents based on synthetic lethality in homologous recombination deficient cancer cells. However, resistance to PARP inhibitors such as olaparib remains a problem in clinical use, and the mechanisms of resistance are not fully understood. To investigate mechanisms of PARP inhibitor resistance, we established a BRCA1 knockout clone derived from the pancreatic cancer MIA PaCa-2 cells, which we termed C1 cells, and subsequently isolated an olaparib-resistant C1/OLA cells. We then performed RNA-sequencing and pathway analysis on olaparib-treated C1 and C1/OLA cells. Our results revealed activation of cell signaling pathway related to NAD+ metabolism in the olaparib-resistant C1/OLA cells, with increased expression of genes encoding the NAD+ biosynthetic enzymes NAMPT and NMNAT2. Moreover, intracellular NAD+ levels were significantly higher in C1/OLA cells than in the non-olaparib-resistant C1 cells. Upregulation of intracellular NAD+ levels by the addition of nicotinamide also induced resistance to olaparib and talazoparib in C1 cells. Taken together, our findings suggest that upregulation of intracellular NAD+ is one of the factors underlying the acquisition of PARP inhibitor resistance.

ABCD1 as a Novel Diagnostic Marker for Solid Pseudopapillary Neoplasm of the Pancreas.

The diagnosis of solid pseudopapillary neoplasm of the pancreas (SPN) can be challenging due to potential confusion with other pancreatic neoplasms, particularly pancreatic neuroendocrine tumors (NETs), using current pathological diagnostic markers. We conducted a comprehensive analysis of bulk RNA sequencing data from SPNs, NETs, and normal pancreas, followed by experimental validation. This analysis revealed an increased accumulation of peroxisomes in SPNs. Moreover, we observed significant upregulation of the peroxisome marker ABCD1 in both primary and metastatic SPN samples compared with normal pancreas and NETs. To further investigate the potential utility of ABCD1 as a diagnostic marker for SPN via immunohistochemistry staining, we conducted verification in a large-scale patient cohort with pancreatic tumors, including 127 SPN (111 primary, 16 metastatic samples), 108 NET (98 nonfunctional pancreatic neuroendocrine tumor, NF-NET, and 10 functional pancreatic neuroendocrine tumor, F-NET), 9 acinar cell carcinoma (ACC), 3 pancreatoblastoma (PB), 54 pancreatic ductal adenocarcinoma (PDAC), 20 pancreatic serous cystadenoma (SCA), 19 pancreatic mucinous cystadenoma (MCA), 12 pancreatic ductal intraepithelial neoplasia (PanIN) and 5 intraductal papillary mucinous neoplasm (IPMN) samples. Our results indicate that ABCD1 holds promise as an easily applicable diagnostic marker with exceptional efficacy (AUC=0.999, sensitivity=99.10%, specificity=100%) for differentiating SPN from NET and other pancreatic neoplasms through immunohistochemical staining.

Identification of Pancreatic Cancer Germline Risk Variants With Effects That Are Modified by Smoking.

PURPOSE: Pancreatic cancer (PC) is a deadly disease most often diagnosed in late stages. Identification of high-risk subjects could both contribute to preventative measures and help diagnose the disease at earlier timepoints. However, known risk factors, assessed independently, are currently insufficient for accurately stratifying patients. We use large-scale data from the UK Biobank (UKB) to identify genetic variant-smoking interaction effects and show their importance in risk assessment. METHODS: We draw data from 15,086,830 genetic variants and 315,512 individuals in the UKB. There are 765 cases of PC. Crucially, robust resampling corrections are used to overcome well-known challenges in hypothesis testing for interactions. Replication analysis is conducted in two independent cohorts totaling 793 cases and 570 controls. Integration of functional annotation data and construction of polygenic risk scores (PRS) demonstrate the additional insight provided by interaction effects. RESULTS: We identify the genome-wide significant variant rs77196339 on chromosome 2 (per minor allele odds ratio in never-smokers, 2.31 [95% CI, 1.69 to 3.15]; per minor allele odds ratio in ever-smokers, 0.53 [95% CI, 0.30 to 0.91]; P = 3.54 × 10-8) as well as eight other loci with suggestive evidence of interaction effects (P < 5 × 10-6). The rs77196339 region association is validated (P < .05) in the replication sample. PRS incorporating interaction effects show improved discriminatory ability over PRS of main effects alone. CONCLUSION: This study of genome-wide germline variants identified smoking to modify the effect of rs77196339 on PC risk. Interactions between known risk factors can provide critical information for identifying high-risk subjects, given the relative inadequacy of models considering only main effects, as demonstrated in PRS. Further studies are necessary to advance toward comprehensive risk prediction approaches for PC.

Optimization of a mouse model of pancreatic cancer to simulate the human phenotypes of metastasis and cachexia.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) presents with a high mortality rate. Two important features of PDAC contribute to this poor outcome. The first is metastasis which occurs in ~ 80% of PDAC patients. The second is cachexia, which compromises treatment tolerance for patients and reduces their quality of life. Although various mouse models of PDAC exist, recapitulating both metastatic and cachectic features have been challenging. METHODS: Here, we optimize an orthotopic mouse model of PDAC by altering several conditions, including the subcloning of parental murine PDAC cells, implantation site, number of transplanted cells, and age of recipient mice. We perform spatial profiling to compare primary and metastatic immune microenvironments and RNA sequencing to gain insight into the mechanisms of muscle wasting in PDAC-induced cachexia, comparing non-metastatic to metastatic conditions. RESULTS: These modifications extend the time course of the disease and concurrently increase the rate of metastasis to approximately 70%. Furthermore, reliable cachexia endpoints are achieved in both PDAC mice with and without metastases, which is reminiscent of patients. We also find that cachectic muscles from PDAC mice with metastasis exhibit a similar transcriptional profile to muscles derived from mice and patients without metastasis. CONCLUSION: Together, this model is likely to be advantageous in both advancing our understanding of the mechanism of PDAC cachexia, as well as in the evaluation of novel therapeutics.

The high FKBP1A expression in WBCs as a potential screening biomarker for pancreatic cancer.

Given the limitation of current routine approaches for pancreatic cancer screening and detection, the mortality rate of pancreatic cancer cases is still critical. The development of blood-based molecular biomarkers for pancreatic cancer screening and early detection which provide less-invasive, high-sensitivity, and cost-effective, is urgently needed. The goal of this study is to identify and validate the potential molecular biomarkers in white blood cells (WBCs) of pancreatic cancer patients. Gene expression profiles of pancreatic cancer patients from NCBI GEO database were analyzed by CU-DREAM. Then, mRNA expression levels of three candidate genes were determined by quantitative RT-PCR in WBCs of pancreatic cancer patients (N = 27) and healthy controls (N = 51). ROC analysis was performed to assess the performance of each candidate gene. A total of 29 upregulated genes were identified and three selected genes were performed gene expression analysis. Our results revealed high mRNA expression levels in WBCs of pancreatic cancer patients in all selected genes, including FKBP1A (p < 0.0001), PLD1 (p < 0.0001), and PSMA4 (p = 0.0002). Among candidate genes, FKBP1A mRNA expression level was remarkably increased in the pancreatic cancer samples and also in the early stage (p < 0.0001). Moreover, FKBP1A showed the greatest performance to discriminate patients with pancreatic cancer from healthy individuals than other genes with the 88.9% sensitivity, 84.3% specificity, and 90.1% accuracy. Our findings demonstrated that the alteration of FKBP1A gene in WBCs serves as a novel valuable biomarker for patients with pancreatic cancer. Detection of FKBP1A mRNA expression level in circulating WBCs, providing high-sensitive, less-invasive, and cost-effective, is simple and feasible for routine clinical setting that can be applied for pancreatic cancer screening and early detection.

hsa_circ_0007919 promotes pancreatic cancer metastasis by modulating Sp1-mediated THBS1 transcription.

CircRNAs are abnormally expressed in various cancers and play an important role in the occurrence and development of cancers. However, their biological functions and the underlying molecular mechanisms in pancreatic cancer (PC) metastasis are incompletely understood. Differentially expressed circRNAs were identified by second-generation transcriptome sequencing in three pairs of PC tissues and adjacent tissues. The expression and prognostic significance of hsa_circ_0007919 were evaluated by qRT-PCR and Kaplan-Meier survival curves. Gain- and loss-of-function assays were conducted to detect the role of hsa_circ_0007919 in PC metastasis in vitro. A lung metastasis model and IHC experiments were conducted to confirm the effects of hsa_circ_0007919 on tumor metastasis in vivo. Mechanistically, RNA immunoprecipitation and chromatin immunoprecipitation assays were conducted to explore the interplay among hsa_circ_0007919, Sp1, and the THBS1 promoter. hsa_circ_0007919 was significantly upregulated in PC tissues and cells and was correlated with lymph node metastasis, TNM stage, and poor prognosis. Knockdown of hsa_circ_0007919 significantly suppressed the migration and invasion of PC cells in vitro and inhibited tumor metastasis in vivo. However, overexpression of hsa_circ_0007919 exerted the opposite effects. Mechanistically, hsa_circ_0007919 could recruit the transcription factor Sp1 to inhibit THBS1 transcription, thereby facilitating PC metastasis. hsa_circ_0007919 can promote the metastasis of PC by inhibiting THBS1 expression. hsa_circ_0007919 may be a potential therapeutic target in PC.

Olaparib not cost-effective as maintenance therapy for platinum-sensitive, BRCA1/2 germline-mutated metastatic pancreatic cancer.

OBJECTIVE: To assess the cost-effectiveness and budget impact of olaparib as a maintenance therapy in platinum-responsive, metastatic pancreatic cancer patients harboring a germline BRCA1/2 mutation, using the Swiss context as a model. METHODS: Based on data from the POLO trial, published literature and local cost data, we developed a partitioned survival model of olaparib maintenance including full costs for BRCA1/2 germline testing compared to FOLFIRI maintenance chemotherapy and watch-and-wait. We calculated the incremental cost-effectiveness ratio (ICER) for the base case and several scenario analyses and estimated 5-year budget impact. RESULTS: Comparing olaparib with watch-and wait and maintenance chemotherapy resulted in incremental cost-effectiveness ratios of CHF 2,711,716 and CHF 2,217,083 per QALY gained, respectively. The 5-year costs for the olaparib strategy in Switzerland would be CHF 22.4 million, of which CHF 11.4 million would be accounted for by germline BRCA1/2 screening of the potentially eligible population. This would amount to a budget impact of CHF 15.4 million (USD 16.9 million) versus watch-and-wait. CONCLUSIONS: Olaparib is not a cost-effective maintenance treatment option. Companion diagnostics are an equally important cost driver as the drug itself.

MicroRNAs in Pancreatic Cancer: Advances in Biomarker Discovery and Therapeutic Implications.

Pancreatic cancer remains a formidable malignancy characterized by high mortality rates, primarily attributable to late-stage diagnosis and a dearth of effective therapeutic interventions. The identification of reliable biomarkers holds paramount importance in enhancing early detection, prognostic evaluation, and targeted treatment modalities. Small non-coding RNAs, particularly microRNAs, have emerged as promising candidates for pancreatic cancer biomarkers in recent years. In this review, we delve into the evolving role of cellular and circulating miRNAs, including exosomal miRNAs, in the diagnosis, prognosis, and therapeutic targeting of pancreatic cancer. Drawing upon the latest research advancements in omics data-driven biomarker discovery, we also perform a case study using public datasets and address commonly identified research discrepancies, challenges, and limitations. Lastly, we discuss analytical approaches that integrate multimodal analyses incorporating clinical and molecular features, presenting new insights into identifying robust miRNA-centric biomarkers.

Protein Arginine Methyltransferases in Pancreatic Ductal Adenocarcinoma: New Molecular Targets for Therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease with a low 5-year overall survival rate. It is the third-leading cause of cancer-related deaths in the United States. The lack of robust therapeutics, absence of effective biomarkers for early detection, and aggressive nature of the tumor contribute to the high mortality rate of PDAC. Notably, the outcomes of recent immunotherapy and targeted therapy against PDAC remain unsatisfactory, indicating the need for novel therapeutic strategies. One of the newly described molecular features of PDAC is the altered expression of protein arginine methyltransferases (PRMTs). PRMTs are a group of enzymes known to methylate arginine residues in both histone and non-histone proteins, thereby mediating cellular homeostasis in biological systems. Some of the PRMT enzymes are known to be overexpressed in PDAC that promotes tumor progression and chemo-resistance via regulating gene transcription, cellular metabolic processes, RNA metabolism, and epithelial mesenchymal transition (EMT). Small-molecule inhibitors of PRMTs are currently under clinical trials and can potentially become a new generation of anti-cancer drugs. This review aims to provide an overview of the current understanding of PRMTs in PDAC, focusing on their pathological roles and their potential as new therapeutic targets.

Advancements in medical treatment for pancreatic neuroendocrine tumors: A beacon of hope.

This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors (pan-NETs), emphasizing tailored approaches for specific subtypes. Cytoreductive surgery and somatostatin analogs (SSAs) play pivotal roles in managing tumors, while palliative options such as molecular targeted therapy, peptide receptor radionuclide therapy, and chemotherapy are reserved for SSA-refractory patients. Gastrinomas, insulinomas, glucagonomas, carcinoid tumors and VIPomas necessitate distinct thera-peutic strategies. Understanding the genetic basis of pan-NETs and exploring immunotherapies could lead to promising avenues for future research. This review underscores the evolving landscape of pan-NET treatment, offering renewed hope and improved outcomes for patients facing this complex disease.

Genetic Signature of Human Pancreatic Cancer and Personalized Targeting.

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.