Pancreatic Cancer Therapy Research Articles

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

Aim 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). Methods 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. Results 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). Conclusions 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.

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.

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.

Modulating autophagy to boost the antitumor efficacy of TROP2-directed antibody-drug conjugate in pancreatic cancer

Pancreatic cancer, characterized by a dismal prognosis and limited treatment options, persists as a formidable challenge in oncology. Trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugates have achieved great success in solid tumors such as breast cancer and uroepithelial carcinoma. However, their efficacy against pancreatic cancer was insufficient in clinical trials, necessitating an imperative exploration of underlying mechanisms and new therapeutic strategies. In this study, we indicated that αTROP2-MMAE, an antibody-drug conjugate targeting TROP2, induced apoptosis through the caspase-9/PARP pathway and exerted potent antitumor effects against TROP2-positive pancreatic cancer. Simultaneously, RNA sequencing suggested significant changes in autophagy after αTROP2-MMAE treatment. The formation of autophagosomes and activation of autophagic flux were markedly induced through mechanisms associated with suppressing the activation of the Akt/mTOR pathway. The addition of pharmacological inhibitors of autophagy enhanced the cytotoxicity and apoptosis caused by αTROP2-MMAE, revealing the cytoprotective role of autophagy in TROP2-positive pancreatic cancer. In the subcutaneous xenograft model using BxPC3 cells, the combined administration of αTROP2-MMAE and an autophagy inhibitor elevated the tumor inhibition rate of αTROP2-MMAE from 71.6 % to 99.0 %, resulting in the eradication of tumors in half of the mice. Collectively, our research demonstrated for the first time the cytoprotective role of autophagy in TROP2-targeted antibody-drug conjugate therapy for pancreatic cancer, providing new perspectives for mechanistic exploration and therapeutic strategies in the treatment of pancreatic cancer.

Two‐Step Targeting‐Tunable Semiconducting Nanoswitches Amplify Mitochondrion Damage and PD‐L1 Blockade for Orthotopic Pancreatic Cancer Therapy

AbstractPancreatic cancer is a malignancy tumor with luxuriant extracellular matrix (ECM) and highly immunosuppressive microenvironment and its therapy remains an enormous challenge. A two‐step targeting‐tunable strategy is proposed for orthotopic pancreatic cancer therapy via designing semiconducting nanoswitches (C/SPNT/αP) to amplify the mitochondrion damage and programmed death ligand 1 (PD‐L1) blockade. A mitochondrion‐targeting small nanoparticle (SPNT) consisting of mitochondrial targeting moiety triphenylphosphine (TPP) and semiconducting polymer is embedded with PD‐L1 antibody (αPD‐L1) into sono‐responsive collagen binding peptide (CBP)‐conjugated nanoliposomes to form C/SPNT/αP. In the first targeting step, C/SPNT/αP achieve ECM targeting to observably increase their enrichment into orthotopic pancreatic tumor sites because CBP can effectively bind to collagen in ECM. Upon ultrasound (US) irradiation, C/SPNT/αP mediate a sono‐responsive structural failure via sonodynamic effect for on‐demand releases of SPNT and αPD‐L1. In the second targeting step, SPNT target to mitochondria to induce mitochondrial damage under US irradiation for triggering amplified cell apoptosis and immunogenic cell death (ICD). Moreover, the released αPD‐L1 blocks the immunosuppressive pathway to further boost immunological effect. Such a novel therapeutic regimen can almost completely eradicate orthotopic pancreatic Panc02 and KPC tumors in mouse models. This study presents the first two‐step targeting‐tunable nanomedicine for treatments of deep‐seated orthotopic tumors.

Investigation of interfractional range variation owing to anatomical changes with beam directions based on water equivalent thickness in proton therapy for pancreatic cancer.

To assess the interfractional anatomical range variations (ARVs) with beam directions and their impact on dose distribution in intensity modulated proton therapy, we analyzed water equivalent thickness (WET) from 10 patients with pancreatic cancer. The distributions of the interfractional WET difference ($\Delta{\mathrm{WET}}^{\theta }$) across 360° were visualized using polar histograms. Interfractional ARVs were evaluated using the mean absolute error and ΔWET pass rate, indicating the percentage of $\Delta \mathrm{WE}{\mathrm{T}}^{\theta }$ < thresholds. The impact on dose distribution in proton therapy was evaluated based on two treatment plans for 40Gy(RBE)/5 fractions: 'Plan A', using two beam angles, in which the target was closest to the body surface among four perpendicular directions; and 'Plan B', using two beam angles with small ARVs. Analysis revealed individual variations in angular trends of interfractional ARVs. Three distinct trends were identified: Group 1 exhibited small ARVs around posterior directions; Group 2 exhibited small ARVs except ~60°; Group 3 demonstrated minimal ARVs only ~90°. In dose evaluation, while 150° and 210° were selected in Plan B for 9 out of 10 patients, for the remaining patient, 60° and 90° were chosen. Comparing dose volume histogram parameters for all patients, Plan B significantly reduced target coverage loss while maintaining organ-at-risk sparing comparable to Plan A. These results demonstrated that selecting beam angles with small interfractional ARVs for each patient enhances the robustness of dose distribution, reducing target coverage loss.

The complement C3a/C3aR pathway is associated with treatment resistance to gemcitabine-based neoadjuvant therapy in pancreatic cancer

Gemcitabine is a standard first-line drug for pancreatic cancer chemotherapy. Nevertheless, gemcitabine resistance is common and significantly limits its therapeutic efficacy, impeding advancements in pancreatic cancer treatment. In this study, through a comprehensive analysis of gemcitabine-resistant cell lines and patient samples, 39 gemcitabine resistance-associated risk genes were identified, and two distinct gemcitabine response-related phenotypes were delineated. Through a combination of bioinformatics analysis and in vivo and in vitro experiments, we identified the C3a/C3aR signaling pathway as a pivotal player in the development of gemcitabine resistance in pancreatic cancer. We found that activation of the C3a/C3aR signaling pathway promoted the proliferation, migration and gemcitabine resistance of pancreatic cancer cells, while the C3aR antagonist SB290157 effectively counteracted these effects by impeding the activation of the C3a/C3aR pathway. Our study reveals the fundamental role of complement C3a in the progression of pancreatic cancer, suggesting that complement C3a may serve as a promising biomarker in pancreatic cancer.

C-Myc inhibition and p21 modulation contribute to unsymmetrical bisacridines-induced apoptosis and senescence in pancreatic cancer cells.

Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer. The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting. Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs. UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies.

Targeting the CSF1/CSF1R signaling pathway: an innovative strategy for ultrasound combined with macrophage exhaustion in pancreatic cancer therapy.

Pancreatic cancer (PC) is a highly aggressive and lethal malignancy characterized by a complex tumor microenvironment (TME) and immunosuppressive features that limit the efficacy of existing treatments. This paper reviews the potential of combining ultrasound with macrophage exhaustion in the treatment of pancreatic cancer. Macrophages, particularly tumor-associated macrophages (TAMs), are crucial in pancreatic cancer progression and immune escape. Prolonged exposure to the immunosuppressive TME leads to macrophage exhaustion, reducing their anti-tumor ability and instead promoting tumor growth. The CSF1/CSF1R signaling pathway is key in macrophage recruitment and functional regulation, making it an effective target for combating macrophage exhaustion. Ultrasound technology not only plays a significant role in diagnosis and staging but also enhances therapeutic efficacy by guiding radiofrequency ablation (RFA) and percutaneous alcohol injection (PEI) in combination with immunomodulators. Additionally, ultrasound imaging can monitor the number and functional status of TAMs in real-time, providing a basis for optimizing treatment strategies. Future studies should further investigate the combined use of ultrasound and immunomodulators to refine treatment regimens, address challenges such as individual variability and long-term effects, and offer new hope for pancreatic cancer 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 the U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy. However, limited indications hinder their further application. Bromodomain-containing protein 4 (BRD4) repression 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 (with the ability to induce PARP1 degradation) was employed in combination with the BRD4 inhibitor, JQ1, and their synergistic effect in HR-proficient pancreatic cancer was confirmed via various methods. Moreover, compared with the JQ1 and PARPi olaparib combination, it was revealed that 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.

A meta-analysis and systematic review of randomized controlled trials in combination gemcitabine with erlotinib in the pancreatic cancer.

Previous studies have demonstrated the efficacy and safety of combining gemcitabine and erlotinib (Gem-Erlo) for the treatment of pancreatic cancer (PaC). However, there is a limited number of clinical studies and multiple prospective randomized controlled trials (RCTs) have yielded inconsistent conclusions. The question of whether Gem-Erlo has significant advantages over conventional chemotherapy in the treatment of PaC has been controversial. In order to provide valuable insights for PaC treatment, this study conducted a meta-analysis based on the current evidence from RCTs. We searched several databases including PubMed/Medline, Web of Science, Cochrane Library, and Embase, as well as relevant conference abstracts from the beginning of their inception to July 2023. We used the patient/population, intervention, comparison, outcomes and study design (PICOS) principle to screen the literature. After title, abstract and full text filtering, we extract the data from each study to assess the risk of bias by examining the quality of the literature. We used a meta-analysis with random effects model to synthesize and summarize the results regarding objective response rate (ORR), disease control rate (DCR), median progression-free survival (median PFS), median overall survival (median OS) and 1-year survival rate. Seven RCTs were included, involving 2,152 PaC patients treated with either Gem-Erlo or gemcitabine alone. The results showed that Gem-Erlo significantly improved DCR [odds ratio (OR) =1.74; 95% confidence interval (CI): 1.03 to 2.92; P=0.04]; but did not significantly improve median OS [standardized mean difference (SMD) =-0.20; 95% CI: -1.46 to 1.06; P=0.75], median PFS (SMD =-0.97; 95% CI: -4.01 to 2.07; P=0.53), ORR (OR =1.29; 95% CI: 0.84 to 1.97), or 1-year survival rate (OR =1.18; 95% CI: 0.88 to 1.57). In addition, sensitivity analysis of the median OS showed the Gem-Erlo group significantly prolonged the median OS compared to the gemcitabine alone group [weighted mean difference (WMD) =-1.74; 95% CI: -1.87 to -1.62; P<0.001]. The most common adverse events (AEs) were rash, diarrhea, fatigue, neutropenia and thrombocytopenia in both groups, but the Gem-Erlo group is more often than the gemcitabine alone (OR =1.40, 95% CI: 1.19 to 1.65; P<0.001), and all AEs were within the acceptable range for patients. Gem-Erlo can improve DCR when compared to gemcitabine. There was no statistically significant improvement in median PFS, median OS, ORR and 1-year survival rate. However, sensitivity analysis showed a statistical difference in the median OS. Our study indicated that Gem-Erlo had better efficacy than gemcitabine alone in PaC therapy. The occurrence of AEs is under the acceptable range for patients.

Feasibility and safety of endoscopic ultrasound-guided diffusing alpha emitter radiation therapy for advanced pancreatic cancer: Preliminary data

Abstract Background and study aims Pancreatic cancer is a devastating disease with limited locoregional treatment options. Diffusing alpha-emitter radiation therapy (Alpha DaRT), a novel cancer treatment using alpha-particle interstitial radiotherapy, may help address this challenge. The aim of this study was to evaluate the feasibility and safety of endoscopic ultrasound (EUS)-guided Alpha DaRT for advanced pancreatic cancer. Patients and methods Patients with inoperable locally advanced or metastatic pancreatic adenocarcinoma were treated with EUS-guided Alpha DaRT insertion. The Alpha DaRT sources were delivered into pancreatic tumors using a standard EUS needle with a novel proprietary applicator. Adverse events (AEs) were assessed based on the Common Terminology Criteria for Adverse Events version 5.0. Tumor response was evaluated by imaging 4 to 6 weeks post treatment. Results The first five patients were treated between March and September 2023. The procedure was technically successful in all cases, with Alpha DaRT sources inserted into the target tumor. Estimated gross tumor volume coverage ranged from 8% to 44%. Fourteen AEs were reported among three patients. Four were serious AEs, none of which was associated with the treatment, but rather, with disease progression or medical assistance in dying. Only two AEs (mild) were deemed possibly related to the study device. At the 35-day visit, two patients had progressive disease and three had stable disease, with one of the latter showing partial response 2 months post procedure. Conclusions Preliminary results from this first-in-human trial indicate that EUS-guided Alpha DaRT treatment for unresectable pancreatic cancer is feasible and safe, with no device-associated serious AEs. Further investigation of this promising novel modality is underway.

Current evidence for neoadjuvant therapy in resectable pancreatic cancer

Current evidence for neoadjuvant therapy in resectable pancreatic cancer

Prescribing of pancreatic enzyme therapy for malabsorption in unresectable pancreatic cancer: Cross-sectional survey across New Zealand and Australia

ObjectiveTo investigate the practices of clinicians prescribing pancreatic enzyme replacement therapy (PERT) for unresectable pancreatic cancer in Aotearoa New Zealand and Australia. MethodsA mixed media advertising campaign was used to recruit appropriate clinicians to complete a questionnaire that collected demographic data, information regarding prescribed medication, and awareness of PERT guidelines. ResultsThe study recruited 161 clinicians, with 93 and 68 respondents from Aotearoa New Zealand and Australia respectively. Most respondents from both countries were experienced gastrointestinal surgeons and dietitians. Aotearoa New Zealand clinicians and dietitians used faecal elastase more frequently to diagnose PEI than other groups. Clinicians had a tendency to under-prescribe PERT, and to advise incorrectly on the timing of the medication. The majority of clinicians from Aotearoa New Zealand and Australia were not aware of any best practice clinical guidelines for PERT (70 % and 77 %, respectively). ConclusionThis study suggests clinicians are over-reliant on faecal elastase to diagnose PEI and are uncertain about the correct dose and timing of PERT for optimal patient benefit in those with unresectable pancreatic cancer. Most clinicians were not aware of best practice guidelines.

Folate-Functionalized Chitosan-PLGA Nanoparticles: A Novel approach for targeted osthole delivery in pancreatic cancer

Efficient drug delivery systems targeting cancer cells are crucial for enhancing cancer therapy. In this study, we developed PLGA nanoparticles coated with folate-conjugated chitosan (osthole-PLGA-NPs/CS-FA) to deliver osthole to cancer cells and investigated its inhibitory and molecular signaling mechanisms in the PANC-1 pancreatic cancer cell line. Field emission scanning electron microscopy (FESEM) revealed that osthole-PLGA-NPs/CS-FA had a spherical structure with a uniform size distribution. Dynamic light scattering (DLS) analysis showed an average size of 171.76 nm, a dispersion index 0.26, and a surface charge of + 33.08 mV, indicating stability and uniform dispersion. Fourier-transform infrared (FTIR) spectrum analysis confirmed the successful incorporation of osthole into the PLGA nanoparticles, with an encapsulation efficiency of 93.12 %. These physicochemical properties suggest efficient cellular uptake and targeted delivery. The antioxidant potential of osthole-PLGA-NPs/CS-FA was evaluated using the ABTS assay, showing concentration-dependent inhibition of free radicals with an IC50 value of 172.95 μg/mL. The anticancer properties were assessed using the MTT assay, demonstrating a significant and concentration-dependent cytotoxic effect on PANC-1 cells (IC50 = 31.2 μg/mL) with minimal impact on normal human foreskin fibroblast (HFF) cells. DAPI staining and flow cytometry analyses confirmed a concentration-dependent increase in apoptosis in PANC-1 cells. The nanoparticles induced upregulation of Bax and downregulation of Bcl2, indicating activation of the intrinsic mitochondrial apoptotic pathway. The anti-angiogenic activity of osthole-PLGA-NPs/CS-FA was evaluated using the chick chorioallantoic membrane (CAM) assay. The results showed significant inhibition of angiogenesis in a concentration-dependent manner, starting at 40 μg/mL and increasing up to 120 μg/mL. In conclusion, osthole-PLGA-NPs/CS-FA nanoparticles exhibit promising potential for targeted pancreatic cancer therapy by enhancing cellular uptake, inducing apoptosis, and inhibiting angiogenesis.