Pancreatic Cancer Therapy Research Articles

Bayesan Model to Predict R Status After Neoadjuvant Therapy in Pancreatic Cancer

Objective: To build a Bayesian approach-based model to predict the success of surgical exploration post-neoadjuvant treatment. Background: Pancreatic cancer (PDAC) is best treated with radical surgery and chemotherapy, offering the greatest chance of survival. Surgery after neoadjuvant treatment (NAT) is indicated in the absence of progression, knowing the limits in accurately predicting resectability with traditional radiology. R Status being a pathological parameter, it can be assessed only after surgery. Method: Patients successfully resected for histologically confirmed PDAC after NAT for BR and LA disease were included, with attention to the predictors of R status from the existing literature. The Bayesian logistic regression model was estimated for predicting the R1 status. The area under curve (AUC) of the average posterior probability of R1 was calculated and results were reported considering the 95% posterior credible intervals for the odds ratios, along with the probability of direction. Results: The final model demonstrated a commendable AUC value of 0.72, indicating good performance. The likelihood of positive margins was associated with older age, higher ASA score, the presence of venous and/or arterial involvement at preoperative radiology, tumor location within the pancreatic body, a lack of tumor size reduction post-NAT, and the persistence of an elevated Ca19.9 value. Conclusions: A Bayesian approach using only preoperative items is firstly used with good performance to predict R Status in pancreatic cancer patients who underwent resection after neoadjuvant therapy.

YKL-06-061 exerts antitumor effect through G1/S phase arrest by downregulating c-Myc and inhibition of metastasis via SIK1 upregulation in pancreatic cancer.

Pancreatic cancer ranks fourth among cancer-related deaths with a low 5-year overall survival rate of less than 13%. At present, treatment of pancreatic cancer is still based on chemotherapy, but the efficacy is limited. Thus, a novel therapeutic agent for pancreatic cancer therapy is urgently needed. A library of compounds was screened, and YKL-06-061, a selective inhibitor of salt-inducible kinases (SIKs), was discovered for its ability of inhibiting the proliferation and metastasis of pancreatic cancer cells in vitro and reducing the growth of xenografts in nude mice in vivo. The results from transcriptome analysis showed that YKL-06-061 influenced the mRNA levels of many genes related to c-Myc and SIK1 signals. Based on this, it was found that YKL-06-061 induced cell cycle arrest at the G1 phase and decreased the levels of c-Myc, CDK4, and cyclin D1 protein. At the same time, YKL-06-061 inhibited invasion and metastasis of cancer cells, increased the levels of SIK1 and E-cadherin protein, and lowered vimentin and ZEB-1. Moreover, YKL-06-061 effectively enhanced the antiproliferation of gemcitabine or doxorubicin in pancreatic cancer cells in a synergistic manner. Collectively, these findings implicate YKL-06-061 as a promising therapeutic agent for patients with pancreatic cancer.

Identification of Prognostic Markers and Potential Therapeutic Targets using Gene Expression Profiling and Simulation Studies in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of less than 10% making it one of the most fatal cancers. A lack of early measures of prognosis, challenges in molecular targeted therapy, ineffective adjuvant chemotherapy, and strong resistance to chemotherapy cumulatively make pancreatic cancer challenging to manage. The present study aims to enhance understanding of the disease mechanism and its progression by identifying prognostic biomarkers, potential drug targets, and candidate drugs that can be used for therapy in pancreatic cancer. Gene expression profiles from the GEO database were analyzed to identify reliable prognostic markers and potential drug targets. The disease's molecular mechanism and biological pathways were studied by investigating gene ontologies, KEGG pathways, and survival analysis to understand the strong prognostic power of key DEGs. FDA-approved anti-cancer drugs were screened through cell line databases, and docking studies were performed to identify drugs with high affinity for ARNTL2 and PIK3C2A. Molecular dynamic simulations of drug targets ARNTL2 and PIK3C2A in their native state and complex with nilotinib were carried out for 100 ns to validate their therapeutic potential in PDAC. Differentially expressed genes that are crucial regulators, including SUN1, PSMG3, PIK3C2A, SCRN1, and TRIAP1, were identified. Nilotinib as a candidate drug was screened using sensitivity analysis on CCLE and GDSC pancreatic cancer cell lines. Molecular dynamics simulations revealed the underlying mechanism of the binding of nilotinib with ARNTL2 and PIK3C2A and the dynamic perturbations. It validated nilotinib as a promising drug for pancreatic cancer. This study accounts for prognostic markers, drug targets, and repurposed anti-cancer drugs to highlight their usefulness for translational research on developing novel therapies. Our results revealed potential and prospective clinical applications in drug targets ARNTL2, EGFR, and PI3KC2A for pancreatic cancer therapy.

Utility of tumor-informed circulating tumor DNA for detection of minimal residual disease after curative-intent therapy in localized pancreatic cancer

Utility of tumor-informed circulating tumor DNA for detection of minimal residual disease after curative-intent therapy in localized pancreatic cancer

A Mesoporous Silica-Based Nano-Drug Co-Delivery System with Gemcitabine for Targeted Therapy of Pancreatic Cancer.

To investigate the efficacy and safety of the mesoporous silica-based nano-drug co-delivery system with gemcitabine (GEM) in the treatment of pancreatic cancer. Experimental study. Place and Duration of the Study: Wenzhou Central Hospital, Zhejiang Province, China, between July 2022 and November 2023. Ce6@MSN-Fe3O4/GEM@DPM nanoparticles were prepared and structurally characterised, then their drug loading and entrapment efficiency were calculated, and in vitro drug release and cytotoxicity assays were performed. In addition to that, mesoporous silica nanorods were prepared and structurally characterised for cellular uptake, cytotoxicity, and reactive oxygen species detection. The mesoporous silica nanoparticles were spherical in shape and possessed a unique core-shell structure. The prepared nanoparticles had good entrapment efficiency and drug loading, and exibited pharmacotoxic and phototoxic effects on cells. The mesoporous silica nanorods were taken up by pancreatic cancer cells and exbitied cytotoxicity. Mesoporous silica-based nano-drug co-delivery system, which carries GEM, is an effective targeted drug delivery system to provide new research ideas for the treatment of pancreatic cancer. Pancreatic cancer, Gemcitabine, Magnetic nanocomposites, Photodynamic therapy, Targeted drug delivery.

Novel Therapies for Pancreatic Cancer.

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.

Oncolytic virus encoding 4-1BBL and IL15 enhances the efficacy of tumor-infiltrating lymphocyte adoptive therapy in HCC.

Previous studies have found that oncolytic virus (OVs) can improve the efficacy of TIL adoptive therapy in oral cancer, colon cancer, and pancreatic cancer. However, the curative effect in hepatocellular carcinoma (HCC) is still unclear. Therefore, this study aims to explore the therapeutic effect and mechanism of OVs encoding 4-1BBL and IL15 (OV-4-1BBL/IL15) combined with TIL adoptive therapy on HCC. In this study, the role and immunological mechanism of armed OVs combined with TILs were evaluated by flow cytometry and ELISA in patient-derived xenograft and syngeneic mouse tumor models. Co-culturing with TILs can up-regulate the expression of antigen-presenting cell (APC) markers on the surface of OV-infected primary HCC cells, and promote the specific activation ability and tumor-killing ability of TILs. OV-4-1BBL/IL15 combined with TIL adoptive therapy could induce tumor volume reduction and anti-tumor immune memory in patient-derived xenograft and syngeneic mouse tumor models. Furthermore, OV combined with TIL adoptive therapy can endow tumor cells with aAPC characteristics, activate T cells at the same time, and reprogram tumor macrophages into anti-tumor phenotype. OV-4-1BBL/IL15 can stimulate the anti-tumor potential of TIL therapy in HCC, and possess broad clinical application prospects.

First-In-Class Thiosemicarbazone Metal Complexes Targeting the Sigma-2 Receptor (S2R) as an Innovative Strategy against Pancreatic Cancer.

Pancreatic cancer, with its increasing incidence and lowest 5-year survival rate, is predicted to become the second leading cause of cancer deaths by 2030. Current clinical trials have shown limited improvement, highlighting the need for new therapies. The sigma-2 receptor (S2R), with roles in tumor progression, is a target for novel thiosemicarbazones (TSCs). FA4 has shown potent activity against pancreatic cancer in vivo. We synthesized complexes of FA4 with Cu(II) and Pt(II), and compared their efficacy with complexes of the non-S2R-targeting TSC 1. TSC-Cu exhibited over 50-fold higher in vitro cytotoxicity than TSCs-Pt, which was less active than TSCs. FA4-Cu induced apoptotic cell death via ER and mitochondrial stress showing more potent activity than FA4. This in vitro effect was replicated in the preclinical PANC-1 model, where FA4-Cu was more potent than FA4, 1, and 1-Cu. These results support further exploration of FA4-Cu as a potential therapy for pancreatic cancer.

Is there a place for surgery in oligometastatic ductal carcinoma of the pancreatic head?

Background: New chemotherapy regimens (gemcitabine / nab-paclitaxel, FOLFIRINOX) have improved overall survival rates in ductal carcinoma, which has renewed the interest in surgical treatment for isolated liver metastases. Aim: To identify the role of surgery in ductal carcinoma of the pancreatic head with liver oligometastases. Methods: We retrospectively analyzed the data from 490 patients with morphologically verified ductal carcinoma of the pancreatic head in two specialized centers, who had undergone pancreatoduodenectomy (PD) from January 2011 to April 2024. In 21 patients, PD was performed simultaneously with liver resection (liver oligometastases were found during the surgery). Results: In the postoperative period after PD with liver resection, compared to that after PD without liver resection, intra-abdominal abscesses were more frequent (4/21 (19.0%) versus 10/469 (2.2%), p = 0.002) and relaparotomy was performed more often by 9.8% [95 confidence interval (CI, Miettinen-Nurminen score method) 0.21–30.3] (3/21 (14.3%) versus 21/469 (4.5%), p = 0.077). The postoperative death rates were comparable (1/21 (4.8%) versus 19/469 (4.1%), p = 0.8). The median overall survival of the patients after PD with liver resection was 11 (95% CI: 6–16) months, and overall 1-, 2-, and 3-year survival rates were 39.2, 16.8 and 7.2%, respectively. In the patients after PD with liver resection without any adjuvant chemotherapy (n = 5), the median overall survival was 6 (95% CI: 5–7) months, and in those with chemotherapy, 13 (95% CI: 6–16) months (p = 0.006). The overall three-year survival of the patients after PD with liver resection and adjuvant chemotherapy was 11.5%. In the patients after PD with liver resection R0, the median overall survival was 13 (95% CI: 6–32) months, with R1 resection 6 (95% CI: 6–7), and with R2 resection 6 (95% CI: 6–7) months (p = 0.021). The median overall survival of patients after PD with liver resection for G1 tumors was 17 (95% CI: 6–32) months. Conclusion: Surgery as a component of combination therapy for oligometastatic pancreatic head cancer can be considered in a certain category of patients with high tumor differentiation grade and mandatory preliminary assessment of the feasibility of R0 surgery and systemic chemotherapy.

Trends and Outcomes of Neoadjuvant Chemotherapy for Clinical Stage T1 Pancreatic Cancer.

Neoadjuvant chemotherapy (NC) for early pancreatic ductal adenocarcinoma (PDAC) remains controversial. We investigate the adoption of NC and its impact on survival in clinical T1 (cT1) PDAC. National Cancer Database (2006-2017) was reviewed for cT1 PDAC. Patients receiving NC and surgery were compared with patients undergoing upfront surgery (US). A total of 5886 patients were included. NC use increased from 4.8% in 2006 to 18.8% in 2017. The NC group (n = 618) versus the US group (n = 5268) had: younger age (66 years vs. 68 years), smaller tumor size (2 cm vs. 2.2 cm), more pancreas head tumors (77% vs. 70.6%), lower lymph-vascular invasion (25.9% vs. 40.6%), and less lymph node positivity (43.6% vs. 54.5%), p < 0.001. Factors associated with receipt of NC were: younger age, recent year of diagnosis, and treatment at an academic program. In the NC group versus the US group, median OS was 35.2 months versus 28.3 months, p < 0.001. Factors associated with improved survival included: well differentiated pathology, R0 surgical margins, and receipt of chemotherapy. In cT1 PDAC, chemotherapy is associated with improved survival. In a surgery-first approach, only 59% of patients receive adjuvant chemotherapy. These data suggest consideration of neoadjuvant therapy for early pancreatic cancer.

Select Endocrine Disorders and Exosomes in Early PDAC Diagnosis.

Disturbances in carbohydrate metabolism are suggested to be the early symptoms of pancreatic ductal adenocarcinoma (PDAC). The accumulated data suggests that endocrine function-related biomarkers may represent a breakthrough in the early detection of PDAC. Factors which may predispose one to the development of PDAC are insulin resistance and hyperinsulinemia. Elevated insulin levels induce the onset of carcinogenesis by altering the differentiation and function of islet cells through stimulating growth factors, including insulin-like growth factors (IGFs). Impaired β cell function, along with the impact of PDAC-released factors (e.g., adrenomedullin (ADM), IGF-1, and macrophage inhibitory factor (MIF) on pancreatic islets, may contribute to the induction of diabetes associated with PDAC. Recently, exosomes have attracted worldwide attention due to their role in varied features of cell function, particularly in cancer progression. Exosomes comprise of small extracellular vesicles produced by almost all cells. These vesicles contain a vast array of biomolecules, including proteins and microRNAs. Exosomes participate in cancer growth and promote angiogenesis. They promote tumorigenesis and metastasis, and are associated with the acquisition of cancer cells resistant to chemotherapy. Data have been accumulating recently on the role of exosomes in the rapid recognition, prognosis and potential therapy of pancreatic cancer.

Investigation of the efficacy of siRNA-mediated KRAS gene silencing in pancreatic cancer therapy.

Pancreatic carcinoma is an aggressive cancer that progresses without many symptoms. The difficulty of early diagnosis and an inadequate response to traditional treatments also cause the survival rate of pancreatic cancer to be low. Current research is focusing on methods of diagnosis and treatment, such as gene therapy, to increase survival rates. Small interfering ribonucleic acid (siRNA) has emerged as a promising advanced therapeutic strategy for cancer treatment. This study sought to silence the KRAS gene in the human pancreatic carcinoma cell line using a complex of small interfering ribonucleic acid (siRNA) and gold nanoparticles (AuNP). In this study, 25 nM siRNA and gold nanoparticles at 0.5 mg/ml, 0.25 mg/ml, and 0.125 mg/ml concentrations were used to silence the KRAS gene in the CAPAN-1 cell line. Real-time PCR analysis, agarose gel electrophoresis, and double staining were carried out, and xCelligence real-time cell analysis (RTCA) was used to measure proliferation. The PCR analysis revealed crossing point (CP) values of actin beta (ACTB) ranging from 33.04 to 35.98, which was in the expected range for all samples. The interaction between the gold nanoparticle/siRNA complex in the double staining analysis revealed that the most effective concentration of gold nanoparticle was 0.125 mg/ml. The WST-1 technique showed that siRNA/AuPEI cells in application groups had a viability rate of over 90%, indicating no toxicity or side effects. The xCELLigence RTCA®showed that at hour 72, there was a significant difference in proliferation in the 0.5 mg/mL PEI/AuNP-siRNA, 0.25 mg/mL PEI/AuNP-siRNA, and 0.125 mg/mL PEI/AuNP-siRNA application groups compared to the control and siRNA groups (p<0.05). By hour 96, all three groups were statistically different from the control and siRNA groups in terms of proliferation (p<0.05). The results of this analysis suggest that the AuPEI/siRNA complex can be effectively used to silence the target gene, but more studies are needed to verify these results.

Enhancing Pancreatic Cancer Therapy with Targeted CD133-Exosome Delivery of PD-L1 siRNA: A Preclinical Investigation.

This study assessed the anticancer potential of genetically modified exosomes engineered to express CD133-binding peptides on their surface and carry PD-L1 siRNA for the treatment of murine model of metastatic pancreatic cancer. CD133-targeting exosomes (tEx) were generated by harvesting conditioned media from adipose-derived stem cells (ASCs) that had undergone transformation using pDisplay vectors encoding CD133-binding peptide sequences. Subsequently, siPD-L1-loaded CD133-targeting Exosomes, referred to as tEx(s), were created by incorporating PD-L1 siRNA into the tEx using Exofect kit. tEx(s) demonstrated superior targetability compared to other materials, including Ex, Ex(p), and tEx. This was substantiated by higher Total Radiant Efficiency (TRE) observed in metastatic liver and pancreatic tissues following intravenous administration of tEx(s) (P < 0.05). Furthermore, the intravenous delivery of tEx(s) resulted in the most pronounced upregulation of pro-apoptotic markers (BIM and c-caspase 3) and the least downregulation of the anti-apoptotic markers (Mcl-1 and Bcl-xL) which has been demonstrated in various methods, including RT-PCR, Western blot analysis, and immunohistochemistry in the metastatic lesions in the livers (P < 0.05). PD-L1 siRNA-loaded CD133-targeting exosomes demonstrated remarkable anticancer efficacy, characterized by specific binding to CD133-positive pancreatic cancer cells and suppression of PD-L1 expression within these cells.

Targeted intervention in nerve-cancer crosstalk enhances pancreatic cancer chemotherapy.

Nerve-cancer crosstalk has gained substantial attention owing to its impact on tumour growth, metastasis and therapy resistance. Effective therapeutic strategies targeting tumour-associated nerves within the intricate tumour microenvironment remain a major challenge in pancreatic cancer. Here we develop Escherichia coli Nissle 1917-derived outer membrane vesicles conjugated with nerve-binding peptide NP41, loaded with the tropomyosin receptor kinase (Trk) inhibitor larotrectinib (Lar@NP-OMVs) for tumour-associated nerve targeting. Lar@NP-OMVs achieve efficient nerve intervention to diminish neurite growth by disrupting the neurotrophin/Trk signalling pathway. Moreover, OMV-mediated repolarization of M2-like tumour-associated macrophages to an M1-like phenotype results in nerve injury, further accentuating Lar@NP-OMV-induced nerve intervention to inhibit nerve-triggered proliferation and migration of pancreatic cancer cells and angiogenesis. Leveraging this strategy, Lar@NP-OMVs significantly reduce nerve infiltration and neurite growth promoted by gemcitabine within the tumour microenvironment, leading to augmented chemotherapy efficacy in pancreatic cancer. This study sheds light on a potential avenue for nerve-targeted therapeutic intervention for enhancing pancreatic cancer therapy.

The Combined Effect of Hypoxia Activation and Radiosensitization by a Multifunctional Nanoplatform System Enhances the Therapeutic Efficacy of Chemoradiotherapy in Pancreatic Cancer

BackgroundPancreatic cancer is a highly malignant tumor, which is still a major global health problem. Chemotherapy and radiotherapy are regularly used in adjuvant therapy for pancreatic cancer but their therapeutic efficacy is limited. MethodsIn the present study, nanoparticle（MSN-AuNPs） was used as a drug carrier loaded with tirapazamine(TPZ) and hyaluronic acid (HA) to synthesize a multifunctional nanoplatform HA@TPZ-MSN-AuNPs (HTMA) for hypoxia activation and radiotherapy sensitization, which can be combined with radiotherapy therapy and synergistically enhance the therapeutic effect in pancreatic cancer. The anti-tumor performance of the nano platform was verified by in vivo and in vitro experiments. ResultFirst, the HA@TPZ-MSN-AuNPs (HTMA) was successfully synthesized. Drug release experiments showed that acidic environment and hyaluronidase promoted drug release in the nanoplatform. In vitro experiments, CCK-8, live-dead staining, clonal formation assay and flow cytometry confirmed the combined anti-tumor effect of hypoxia activation and radiotherapy sensitization with HTMA. In the drug uptake experiment, the nanoplatform showed the function of targeting and binding pancreatic cancer cells. In vivo, HTMA demonstrated good antitumor properties and good biocompatibility. ConclusionsThe nanoplatform had a good targeting effect and synergistic anti-tumor effect. The combination of hypoxia activation and radiotherapy sensitization is a promising strategy for the treatment of pancreatic cancer.

Deciphering the role of NcRNAs in Pancreatic Cancer immune evasion and drug resistance: a new perspective for targeted therapy.

Pancreatic cancer (PC) is a very aggressive digestive system tumor, known for its high mortality rate, low cure rate, low survival rate and poor prognosis. In particular, pancreatic ductal adenocarcinoma (PADC), which accounts for more than 90% of PC cases, has an overall 5-year survival rate of only 5%, which is an extremely critical situation. Early detection and effective treatment of PC is extremely difficult, which leads many patients to despair. In the current medical context, targeted therapy, as an important strategy for cancer treatment, is expected. However, the problems of immune escape and drug resistance in PC have become two major obstacles that are difficult to be overcome by targeted therapy. How to break through these two difficulties has become a key issue to be solved in the field of PC therapy. In recent years, non-coding RNAs (ncRNAs) have continued to heat up in the field of cancer research. NcRNAs play a pivotal role in gene regulation, cell differentiation, development, and disease processes, and their important roles in the genesis, development, and therapeutic response of PC have been gradually revealed. More importantly, ncRNAs have many advantages as therapeutic targets, such as high specificity and low side effects, making them a new favorite in the field of PC therapy. Therefore, the aim of this paper is to provide new ideas and methods for the targeted therapy of PC by reviewing the mechanism of action of four major ncRNAs (circRNAs, lncRNAs, miRNAs, siRNAs) in both immune escape and drug resistance of PC. It is expected that an effective way to overcome immune escape and drug resistance can be found through in-depth study of ncRNA, bringing a ray of hope to PC patients.

Enhancing therapeutic efficacy in homologous recombination-proficient pancreatic cancer via the combination of PARP1-PROTAC and a BRD4 inhibitor

Currently, poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved by U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy. However, limited indications hinder their further application. Repression of bromodomain-containing protein 4 (BRD4) can block the homologous recombination (HR) repair pathway and has the potential to enhance the response to PARPi in HR-proficient pancreatic cancer therapy. In addition, proteolysis targeting chimeras (PROTACs) can hijack E3 ligase within the cell to ubiquitinate degradation-targeted proteins effectively and quickly, thus enhancing the therapeutic effect on tumors. In the present study, the LB23 compound, which induces PARP1 degradation, was employed in combination with the BRD4 inhibitor JQ1, confirming their synergistic effect in HR-proficient pancreatic cancer through various methods. Moreover, compared to the JQ1 and PARPi olaparib combination, PARP1-PROTAC and JQ1 had more notable synergistic effects. Further research into the synergistic mechanism demonstrated that combination therapy enhanced DNA damage and suppressed DNA repair by inducing cell cycle arrest and cell apoptosis. The present study therefore provides the experimental data for this type of combination therapy, which is expected to be an innovative approach for the treatment of HR-proficient pancreatic cancer.

Advancements in Pancreatic Cancer Treatment: A Comprehensive Review of Current Therapies and Future Directions

Pancreatic cancer still has a 5-year survival rate in the single digits, making it one of the most aggressive and deadly cancers. The therapy of pancreatic cancer presents considerable hurdles because of its late diagnosis, fast development, and resistance to traditional therapies, even with advancements in oncological research. This study offers a thorough summary of the various treatment options available today, including as radiation therapy, chemotherapy, surgery, and the newly recognized roles of immunotherapy and targeted medicines. We examine the most recent advancements in personalized medicine and molecular profiling, which are starting to challenge established therapy paradigms and provide fresh hope for bettering patient outcomes. The study also outlines ongoing clinical trials that attempt to address the shortcomings of current therapy, such as the toxicity and limited efficacy of chemotherapeutic drugs. This study aims to provide a comprehensive overview of the pancreatic cancer therapy landscape by analyzing both conventional and cutting-edge treatments. It also identifies promising directions for future research and clinical practice.

NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy in pancreatic cancer.

Resistance to KRAS therapy in pancreatic ductal adenocarcinoma (PDAC) involves cellular plasticity, particularly the epithelial-to-mesenchymal transition (EMT), which poses challenges for effective targeting. Chronic pancreatitis, a known risk factor for PDAC, elevates TGFβ levels in the tumor microenvironment (TME), promoting resistance to KRAS therapy. Mechanistically, TGFβ induces the formation of a novel protein complex composed of SMAD3, SMAD4, and the nuclear factor NFAT5, triggering EMT and resistance by activating key mediators such as S100A4. Inhibiting NFAT5 attenuates pancreatitis-induced resistance to KRAS inhibition and extends mouse survival. Additionally, TGFβ stimulates PDAC cells to secrete CCL2, recruiting macrophages that contribute to KRAS bypass through paracrine S100A4. Our findings elucidate the role of TGFβ signaling in EMT-associated KRAS therapy resistance and identify NFAT5 as a druggable target. Targeting NFAT5 could disrupt this regulatory network, offering a potential avenue for preventing resistance in PDAC.

Functionalized Nanomaterials In Pancreatic Cancer Theranostics And Molecular Imaging.

Pancreatic cancer (PC) is one of the most fatal malignancies in the world. This lethality persists due to lack of effective and efficient treatment strategies. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive epithelial malignancy which has a high incidence rate and contributes to overall cancer fatalities. As of 2022, pancreatic cancer contributes to about 3 % of all cancers globally. Over the years, research has characterised germline predisposition, the origin cell, precursor lesions, genetic alterations, structural alterations, transcriptional changes, tumour heterogeneity, metastatic progression, and the tumour microenvironment, which has improved the understanding of PDAC carcinogenesis. By using molecular-based target therapies, these fundamental advancements support primary prevention, screening, early detection, and treatment. The focus of this review is the use of targeted nanoparticles as an alternative to conventional pancreatic cancer treatment due to the various side effects of the latter. The principles of nanoparticle based cancer therapy is efficient targeting of tumour cells via enhanced permeability and retention (EPR) effects and decrease the chemotherapy side effects due to their non-specificity. To increase the efficiency of existing therapies and modify target nanoparticles, several molecular markers of pancreatic cancer cells have been identified. Thus pancreatic cancer cells can be detected using appropriately functionalized nanoparticles with specific signalling molecules. Once cancer has been identified, these nanoparticles can kill the tumour by inducing hyperthermia, medication delivery, immunotherapy or gene therapy. As potent co-delivery methods for adjuvants and tumor-associated antigens; nanoparticles (NPs) have demonstrated significant promise as delivery vehicles in cancer therapy. This ensures the precise internalization of the functionalized nanoparticle and thus also activates the immune system effectively against tumor cells. This review also discusses the immunological factors behind the uptake of functionalized nanoparticles in cancer therapies. Theranostics, which combine imaging and therapeutic chemicals in a single nanocarrier, are the next generation of medicines. Pancreatic cancer treatment may be revolutionised by the development of a tailored nanocarrier with diagnostic, therapeutic, and imaging capabilities. It is extremely difficult to incorporate various therapeutic modalities into a single nanocarrier without compromising the individual functionalities. Surface modification of nanocarriers with antibodies or proteins will enable to attain multifunctionality which increases the efficiency of pancreatic cancer therapy.