Revealing the impact of modified modules flexibility on gemcitabine prodrug nanoassemblies for effective cancer therapy.

Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine (GEM) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.

Human bone marrow mesenchymal stem cell-derived exosomes loaded with gemcitabine inhibit pancreatic cancer cell proliferation by enhancing apoptosis.

BACKGROUND: Pancreatic cancer remains one of the most lethal malignancies, and has limited effective treatment. Gemcitabine (GEM), a chemotherapeutic agent, is commonly used for clinical treatment of pancreatic cancer, but it has characteristics of low drug delivery efficiency and significant side effects. The study tested the hypothesis that human bone marrow mesenchymal stem cell (MSC)-derived exosomes loaded with GEM (Exo-GEM) would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis. AIM: To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro. METHODS: Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis. Exo-GEM through electroporation, sonication, or incubation, and the loading efficiency was evaluated. The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays. RESULTS: The isolated exosomes had an average size of 76.7 nm. The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation. The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02 µM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells. Moreover, Exo-GEM enhanced the frequency of GEM-induced apoptosis in both cell lines. CONCLUSION: Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis, offering a promising drug delivery system for improving therapeutic outcomes.

Quantum Insights into Partially Molecular Imprinted Microspheres for Anticancer Therapeutics: Experimental and Theoretical Studies.

Drug solubility is a determining factor for controlled release, and solubility-dependent release kinetics can be modified by changing the drug's state in the polymer matrix through partial molecular imprinting (PMI), although research in this area remains limited. This novel PMI approach creates nanocavities within the polymer by partially retaining the imprinting molecule and trapping the drug. Such a method holds promise for developing advanced biomaterial-based drug delivery systems for anticancer therapies. In this study, we developed microspheres designed for anticancer drug delivery utilizing PMI to enhance controlled release properties. Poly(vinyl alcohol) (PVA) microspheres were partially imprinted with aspirin (ASP) to create nanocavities for gemcitabine (GEM) molecules, inducing a polymorphic shift of GEM within the polymer matrix. This novel PMI approach enhanced drug release properties by enabling control over the drug crystallinity and release rate. The PVA-ASP-GEM complex showed zero-order release kinetics, releasing 21.6% of GEM over 48 h, maintaining steady state release profile. In contrast, nonimprinted PVA-GEM microspheres exhibited first-order kinetics with a faster release of 46.85% in the same period. Quantum insights from density functional theory (DFT) calculations revealed the superior stability of the PVA-ASP-GEM complex, with a binding free energy of -56.03 kcal/mol, compared to -29.07 kcal/mol for PVA-GEM. Molecular dynamics (MD) simulations demonstrated that ASP's presence created nanocavities that restricted GEM's movement, further contributing to the controlled release. Experimental validation through differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and Raman spectroscopy confirmed the polymorphic transitions within the PVA-ASP-GEM complex. This PMI-based approach offers a promising method for modulating drug release kinetics and improving the stability of anticancer therapeutics, paving the way for innovative biomaterial-based drug delivery systems.

Exploring epigenetic dynamics unveils a super-enhancer-mediated NDRG1-ß-catenin axis in modulating gemcitabine resistance in pancreatic cancer.

Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/ß-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven ß-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.

Metal Complexation for the Rational Design of Gemcitabine Formulations in Cancer Therapy.

Nanoformulation of chemotherapies represents a promising strategy to enhance outcomes in cancer therapy. Gemcitabine is a chemotherapeutic agent approved by the Food and Drug Administration for the treatment of various solid tumors. Nevertheless, its therapeutic effectiveness is constrained by its poor metabolic stability and pharmacokinetic profile. Nanoformulations of gemcitabine in lipid and polymer nanocarriers usually lead to poor loading capability and an inability to effectively control its release profile due to the physicochemical characteristics of the drug and matrices. Here, we propose metal-gemcitabine complexation with biorelevant metal cations as a strategy to alter the properties of gemcitabine in a noncovalent manner, paving the way for the development of novel nanoformulations. A speciation study on gemcitabine and Mn2+, Zn2+, and Ca2+ was performed with the aim of investigating the extent of the interaction between the drug and the proposed metal cations, and selecting the best conditions of temperature, pH, and drug-to-metal molar ratio that optimize such interactions. Also, a series of density functional theory calculations and spin-polarized ab initio molecular dynamics simulations were carried out to achieve insights on the atomistic modalities of these interactions. Mn2+-gemcitabine species demonstrated the ability to maintain gemcitabine's biological activity in vitro. The scientific relevance of this study lies in its potential to propose metal-gemcitabine as a valuable strategy for developing nanoformulations with optimized quality target product profiles. The work is also clinically relevant because it will lead to improved treatment outcomes, including enhanced efficacy and pharmacokinetics, decreased toxicity, and new clinical possibilities for this potent therapeutic molecule.

Flurbiprofen inhibits cAMP transport by MRP4/ABCC4 increasing the potency of gemcitabine treatment in PDAC cell models.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly malignant cancer with a grim prognosis due to its early metastasis and resistance to current chemotherapies, such as Gemcitabine (GEM). We have previously demonstrated that cAMP exclusion by MRP4 is critical for PDAC cell proliferation, establishing this transporter as a promising prognostic marker and therapeutic target. In search for novel therapeutic options to improve GEM efficacy, we conducted a drug repositioning screening to identify potential inhibitors of cAMP transport by MRP4. Several non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the transport of certain MRP4 substrates. In this study, we assessed the efficacy of sixteen NSAIDs in inhibiting cAMP transport mediated by MRP4, identifying seven potent inhibitors based on their IC50 values. The most potent inhibitors were further tested for their effect on cell proliferation and migration. Flurbiprofen emerged as the most potent inhibitor of both MRP4-mediated cAMP transport and cell proliferation. Overexpression of MRP4 in BxPC-3 cells significantly increased GEM resistance, and co-administration of flurbiprofen with GEM markedly enhanced the latter's potency inhibiting PDAC cells proliferation. These findings position flurbiprofen as a potent inhibitor of cAMP transport by MRP4 and a promising adjunctive therapy to enhance GEM effectiveness in PDAC treatment.

A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer.

BACKGROUND: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC. METHODS: Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH-, 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023. RESULTS: Intravenous P-AscH- increased serum ascorbate levels from micromolar to millimolar levels. P-AscH- added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH- did not negatively impact quality of life or increase the frequency or severity of adverse events. CONCLUSIONS: P-AscH- infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578).

Thrombotic Microangiopathy After Long-Lasting Treatment by Gemcitabine: Description, Evolution and Treatment of a Rare Case.

Thrombotic microangiopathy (TMA) is an uncommon but severe complication that may occur in cancer patients under gemcitabine chemotherapy. Gemcitabine-induced thrombotic microangiopathy (G-TMA) can clinically and biologically present as atypical hemolytic uremic syndrome, with activation of the complement pathway asking the question of the use of eculizumab. We describe here the case of a patient suffering from metastatic cholangiocarcinoma treated by gemcitabine for 4 years leading to the remission of the underlying neoplasia. Despite an impressive response to therapy, she developed thrombopenia, regenerative anemia, and acute kidney injury leading to the suspicion then diagnosis based on the renal biopsy of a very late G-TMA. Spontaneous evolution after treatment interruption was favorable without dialysis requirement. However, in this case where gemcitabine is the only chemotherapy remaining for a mortal underlying condition, we discussed the re-initiation of gemcitabine under eculizumab treatment. This atypical case of TMA illustrates the importance of recognizing, even belatedly, this rare but serious complication of chemotherapy. It asks the question of rechallenging discontinued chemotherapy notably under eculizumab cover, in this population with a high risk of cancer progression.

Telotristat ethyl, a tryptophan hydroxylase inhibitor, enhances antitumor efficacy of standard chemotherapy in preclinical cholangiocarcinoma models.

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5-year survival rate of 5%-15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%-53%) compared to NPT (56%-69%) or GemCis (37%-58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell-derived xenografts (67%-90%). PDX studies revealed TE's marked inhibition of tumour growth (40%-73%) compared to GemCis (80%-86%) or NPT (57%-76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.

Tumor-derived exosome PPP3CB induce gemcitabine resistance by regulating miR-298/STAT3 in pancreatic cancer.

Purpose: Due to resistance to gemcitabine (GEM), patients with pancreatic cancer (PC) usually have poor prognosis and low survival rate. The purpose of our research was to explore the impact of exosome PPP3CB on GEM resistance in PC, and concurrently analyze the regulatory role of the miR-298/STAT3 signaling pathway. Methods: Exosomes isolated from PC cells were verified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting (WB). The interaction between PPP3CB and miR-298 was verified using dual-luciferase reporter gene assay, followed by evaluation of cell growth and death using CCK8 assay, EdU staining, and flow cytometry. Results: Increased PPP3CB expression was observed in GEM-resistant PC cells. Exosomes from PC cells and GEM-resistant PC cells were successfully extracted by ultra-high speed centrifugation. Confocal microscopy showed internalization of fluorescein amide (FAM)-labeled GEM-resistant exosomes by PC cells. PPP3CB enhanced the proliferation of GEM-resistant PC cells and inhibited their apoptosis, whereas down-regulation of PPP3CB promoted the death of PC cells and inhibited the proliferation of GEM-resistant PC cells, and enhance the susceptibility of PC cells to GEM. Additionally, PPP3CB positively regulated STAT3 expression in PC cells by down-regulating miR-298, thus promoting the growth and inhibiting the death of PC cells. Conclusion: PC cell-derived exosome PPP3CB enhances STAT3 expression by downregulating miR-298, stimulating cell growth, and suppressing cell death, thereby increasing the resistance of PC cells to GEM.

20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters.

INTRODUCTION: Gemcitabine (GEM) is the first-line drug for pancreatic ductal adenocarcinoma (PDAC), but drug resistance severely restricts its chemotherapeutic efficacy. Laminin subunit γ2 (LAMC2) plays a crucial role in extracellular matrix formation in the development of GEM-resistance. However, the biological function of LAMC2 in GEM resistance and its molecular mechanisms are still unclear. 20(S)-Ginsenoside Rh2 (Rh2), one of the principal active components isolated from Ginseng Radix et Rhizoma, possesses strong anti-tumor effects. However, the effects of Rh2 on overcoming GEM resistance and its action mechanisms remain to be elucidated. OBJECTIVES: This study aimed to determine the efficacy of Rh2 on overcoming GEM resistance and to explore its underlying molecular mechanisms. METHODS: Clinical study, Western blotting, publicly available databasesand bioinformatic analyses were performed to investigate the protein expression of LAMC2 in the GEM-resistant PDAC patients and the acquired GEM-resistant PDAC cells. Then, the effects of Rh2 on overcoming the GEM resistance in PDAC were evaluated both in vitro and in vivo. Stable silencing or overexpression of LAMC2 in the GEM-resistant PDAC cells were established for validating the role of LAMC2 on Rh2 overcoming the GEM resistance in PDAC. RESULTS: The protein expression of LAMC2 was markedly increased in the GEM-resistant PDAC patient biopsies compared to the sensitive cases. The protein expression of LAMC2 was significantly higher in the acquired GEM-resistant PDAC cells than that in their parental cells. Rh2 enhanced the chemosensitivity of GEM in the GEM-resistant PDAC cells, and inhibited the tumor growth of Miapaca-2-GR cell-bearing mice and Krastm4TyjTrp53tm1BrnTg (Pdx1-cre/Esr1*) #Dam/J (KPC) mice. Rh2 effectively reversed the GEM resistance in Miapaca-2-GR and Capan-2-GR cells by inhibiting LAMC2 expression through regulating the ubiquitin-proteasome pathway. Knockdown of LAMC2 enhanced the chemosensitivity of GEM and the effects of Rh2 on overcoming the GEM resistance in PDAC cells and the orthotopic PDAC mouse model. Conversely, LAMC2 overexpression aggravated the chemoresistance of GEM and abolished the effects of Rh2 on overcoming GEM resistance via modulating ATP-binding cassette (ABC) transporters leading to the active GEM efflux. CONCLUSIONS: LAMC2 plays an important role in the GEM resistance in PDAC, and Rh2 is a potential adjuvant for overcoming the chemoresistance of GEM in PDAC.

Thermosensitive Liposomes for Gemcitabine Delivery to Pancreatic Ductal Adenocarcinoma.

Treatment of pancreatic ductal adenocarcinoma with gemcitabine is limited by an increased desmoplasia, poor vascularization, and short plasma half-life. Heat-sensitive liposomes modified by polyethylene glycol (PEG; PEGylated liposomes) can increase plasma stability, reduce clearance, and decrease side effects. Nevertheless, translation of heat-sensitive liposomes to the clinic has been hindered by the low loading efficiency of gemcitabine and by the difficulty of inducing hyperthermia in vivo. This study was designed to investigate the effect of phospholipid content on the stability of liposomes at 37 °C and their release under hyperthermia conditions; this was accomplished by employing a two-stage heating approach. First the liposomes were heated at a fast rate, then they were transferred to a holding bath. Thermosensitive liposomes formulated with DPPC: DSPC: PEG2k (80:15:5, mole%) exhibited minimal release of carboxyfluorescein at 37 °C over 30 min, indicating stability under physiological conditions. However, upon exposure to hyperthermic conditions (43 °C and 45 °C), these liposomes demonstrated a rapid and significant release of their encapsulated content. The encapsulation efficiency for gemcitabine was calculated at 16.9%. Additionally, fluorescent analysis during the removal of unencapsulated gemcitabine revealed an increase in pH. In vitro tests with BxPC3 and KPC cell models showed that these thermosensitive liposomes induced a heat-dependent cytotoxic effect comparable to free gemcitabine at temperatures above 41 °C. This study highlights the effectiveness of the heating mechanism and cell models in understanding the current challenges in developing gemcitabine-loaded heat-sensitive liposomes.

Knockdown of cullin 3 inhibits progressive phenotypes and increases chemosensitivity in cholangiocarcinoma cells.

Cholangiocarcinoma (CCA) is an extremely aggressive malignancy arising from the epithelial cells lining the bile ducts. It presents a substantial global health issue, with the highest incidence rates, ranging from 40­100 cases/100,000 individuals, found in Southeast Asia, where liver fluke infection is endemic. In Europe and America, incidence rates range from 0.4­2 cases/100,000 individuals. Globally, mortality rates range from 0.2­2 deaths/100,000 person­years and are increasing in most countries. Chemotherapy is the primary treatment for advanced CCA due to limited options from late­stage diagnosis, but its efficacy is hindered by drug­resistant phenotypes. In a previous study, proteomics analysis of drug­resistant CCA cell lines (KKU­213A­FR and KKU­213A­GR) and the parental KKU­213A line identified cullin 3 (Cul3) as markedly overexpressed in drug­resistant cells. Cul3, a scaffold protein within CUL3­RING ubiquitin ligase complexes, is crucial for ubiquitination and proteasome degradation, yet its role in drug­resistant CCA remains to be elucidated. The present study aimed to elucidate the role of Cul3 in drug­resistant CCA cell lines. Reverse transcription­quantitative PCR and western blot analyses confirmed significantly elevated Cul3 mRNA and protein levels in drug­resistant cell lines compared with the parental control. Short interfering RNA­mediated Cul3 knockdown sensitized cells to 5­fluorouracil and gemcitabine and inhibited cell proliferation, colony formation, migration and invasion. In addition, Cul3 knockdown induced G0/G1 cell cycle arrest and suppressed key cell cycle regulatory proteins, cyclin D, cyclin­dependent kinase (CDK)4 and CDK6. Bioinformatics analysis of CCA patient samples using The Cancer Genome Atlas data revealed Cul3 upregulation in CCA tissues compared with normal bile duct tissues. STRING analysis of upregulated proteins in drug­resistant CCA cell lines identified a highly interactive Cul3 network, including COMM Domain Containing 3, Ariadne RBR E3 ubiquitin protein ligase 1, Egl nine homolog 1, Proteasome 26S Subunit Non­ATPase 13, DExH­box helicase 9 and small nuclear ribonucleoprotein polypeptide G, which showed a positive correlation with Cul3 in CCA tissues. Knocking down Cul3 significantly suppressed the mRNA expression of these genes, suggesting that Cul3 may act as an upstream regulator of them. Gene Ontology analysis revealed that the majority of these genes were categorized under binding function, metabolic process, cellular anatomical entity, protein­containing complex and protein­modifying enzyme. Taken together, these findings highlighted the biological and clinical significance of Cul3 in drug resistance and progression of CCA.

Economic evaluation of NALIRIFOX vs. nab-paclitaxel and gemcitabine regimens for first-line treatment of metastatic pancreatic ductal adenocarcinoma from U.S. perspective.

BACKGROUND: The cost-effectiveness of NALIRIFOX as a potential new standard of care for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) has yet to be established. Our objective was to evaluate the cost-effectiveness of NALIRIFOX vs. nab-paclitaxel and gemcitabine in this indication from the perspective of U.S. public payers. METHODS: A partitioned survival model was constructed from the perspective of U.S. public payers, drawing on baseline patient characteristics and vital clinical data from the NAPOLI-3 trial. Costs and utilities were sourced from publicly accessible databases and literature. A lifetime horizon was applied, with an annual discount rate of 3%. We calculated and compared cumulative costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). To evaluate the model's robustness, sensitivity analyses, scenario analyses, and subgroup analyses were carried out. Additionally, a price simulation for the costly liposomal irinotecan was conducted to inform the pricing strategy at the given willingness to pay (WTP) threshold. RESULTS: In the base-case analysis, NALIRIFOX provided an additional 0.29 QALYs with an ICER of $206,340.69 /QALY compared to nab-paclitaxel and gemcitabine, indicating it is not cost-effective at a $150,000/QALY threshold. Sensitivity analysis showed the model was most sensitive to the costs of liposomal irinotecan, capecitabine, and post-progression care. Probabilistic sensitivity analysis indicated a 17.66% probability of NALIRIFOX being cost-effective at $150,000/QALY, rising to 47.48% at $200,000/QALY. Pricing simulations suggested NALIRIFOX could become cost-effective at $150,000/QALY if the price of irinotecan liposome drops to $53.24/mg (a 14.8% reduction). CONCLUSIONS: NALIRIFOX may not be cost-effective at its current price as a first-line treatment for patients with mPDAC in the long term. The cost of liposomal irinotecan has the greatest impact. It may become cost-effective only if its cost is reduced by 14.8%, with a WTP threshold of $150,000 /QALY.

Efficacy, safety and differential outcomes of immune-chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort.

BACKGROUND: Combined Immuno-chemotherapy consisting of gemcitabine, cisplatin and the programmed death-ligand one inhibitor durvalumab (GCD) is the new standard of care for patients with biliary tract cancers (BTC) based on positive results of the TOPAZ-1 study. OBJECTIVE: We here evaluated the efficacy and safety of GCD for BTC in a German multicenter real-world patient cohort. METHODS: Patients with BTC treated with GCD from 9 German centers were included. Clinicopathological baseline parameters, overall survival (OS), response rate and adverse events (AEs) were retrospectively analyzed. The prognostic impact was determined by Kaplan-Meier analyses and Cox regression models. RESULTS: A total of 165 patients treated with GCD between 2021 and 2024 were included in the study. Median OS and median progression-free survival were 14 months (95% CI 10.3-17.7) and 8 months (95% CI 6.8-9.2), respectively. The best overall response rate was 28.5% and disease control rate was 65.5%. While extrahepatic and intrahepatic BTC showed similar outcomes, mOS was significantly shorter in patients with gall bladder cancer (GB-CA) with 9 months (95% CI 5.5-12.4; p = 0.02). In univariate analyses age ≥70 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥1, status post cholecystectomy, GB-CA and high baseline CRP values were significantly associated with OS. ECOG PS ≥ 1 and GB-CA remained independent prognostic factors for OS in multivariable cox regression analysis. AEs have been reported in 130 patients (78.8%), including 149 grade 3-4 AEs (25.5%). One patient died of severe infectious pneumonia. Immune-related (ir)AEs occurred in 17 patients (10.3%), including 9 grade 3-4 irAEs (2.2%), which led to treatment interruption in 4 patients. CONCLUSIONS: Immuno-chemotherapy in patients with BTC was feasible, effective and safe in a real-life scenario. Our results were comparable to the phase 3 clinical trial results (TOPAZ-1). Reduced efficacy was noted in patients with GB-CA and/or a reduced performance status that warrants further investigation.

Randomized phase 2 study of valproic acid combined with simvastatin and gemcitabine/nab-paclitaxel-based regimens in untreated metastatic pancreatic adenocarcinoma patients: the VESPA trial study protocol.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models. METHODS/DESIGN: VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples. CONCLUSIONS: VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024. TRIAL REGISTRATION: EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.

Comparative Effectiveness of Bacillus Calmette-Guérin and Sequential Intravesical Gemcitabine and Docetaxel for Treatment-naïve Intermediate-risk Non-muscle-invasive Bladder Cancer.

BACKGROUND AND OBJECTIVE: Sequential intravesical gemcitabine/docetaxel (Gem/Doce) has emerged as a potential alternative to bacillus Calmette-Guérin (BCG) for the treatment of non-muscle-invasive bladder cancer (NMIBC). Our aim was to determine the comparative effectiveness of BCG and Gem/Doce for patients with intermediate-risk (IR) NMIBC, composed mainly of high-grade (HG) Ta disease. METHODS: Patients with IR-NMIBC who received either BCG or Gem/Doce during 2013-2023 were included. Maintenance BCG (as per the Southwest Oncology Group protocol) and monthly Gem/Doce maintenance for 1 yr were offered to patients with no evidence of recurrence after induction. Routine surveillance with cystoscopy was performed according to the American Urological Association guidelines. The Kaplan-Meier method was used to assess high-grade and any-grade recurrence-free survival (RFS). Cox regression analysis was performed to find predictors of recurrence. KEY FINDINGS AND LIMITATIONS: Of 483 patients, 127 had IR-NMIBC; 66 patients received BCG and 61 received Gem/Doce. Median age was 69 yr (interquartile range [IQR] 61-76) for the BCG group and 72 yr (IQR 62-76) for the Gem/Doce group. Median follow-up was 53.1 mo (IQR 25.3-71.2) for the BCG group and 20.2 mo (IQR 8.28-33.1) for the Gem/Doce group. The 2-yr high-grade RFS rates for primary high-grade tumors for BCG versus Gem/Doce groups were 81% versus 61%, with corresponding any-grade RFS rates of 60% versus 41%. Induction with Gem/Doce predicted any-grade recurrence (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.1-3.2) and high-grade recurrence for primary high-grade tumors (HR 3.4 95% CI 1.27-9.13), while receipt of maintenance therapy decreased the risk of any-grade recurrence (HR 0.4, 95% CI 0.22-0.72). This study is limited by its retrospective design. CONCLUSIONS AND CLINICAL IMPLICATIONS: For patients with IR-NMIBC, BCG was associated with superior any-grade RFS and high-grade RFS for primary high-grade tumors. Maintenance therapy was associated with better RFS when receiving Gem/Doce. Standardization and longer maintenance therapy protocols should be considered for Gem/Doce treatment. PATIENT SUMMARY: We compared outcomes for patients who received two different in-bladder treatments for intermediate-risk bladder cancer. Bacillus Calmette-Guérin (BCG) led to better outcomes than gemcitabine + docetaxel (Gem/Doce). Monthly maintenance therapy improved recurrence-free survival for patients who received Gem/Doce. We conclude that maintenance therapy is essential for patients receiving Gem/Doce to avoid bladder cancer recurrence after treatment.

G3BP2 promotes tumor progression and gemcitabine resistance in PDAC via regulating PDIA3-DKC1-hENT in a stress granules-dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC-1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC-1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC's resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC.

Safety of pressurized intraperitoneal aerosolized chemotherapy in biliary cancer patients with peritoneal metastases.

Biliary tract cancers are a rare diagnosis with a rising incidence. Up to 20% of patients have peritoneal metastases, resulting in symptoms of ascites, abdominal pain and potential bowel obstruction. A standard of care systemic treatment comprises gemcitabine, cisplatin and durvalumab (gem/cis/durva). However, the clinical benefit among patients with peritoneal metastases remains unknown. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy directly to the peritoneal space, which could potentially improve efficacy with minimal systemic toxicity. We describe the design of a Phase I study investigating PIPAC with nab-paclitaxel plus systemic gem/cis/durva among biliary tract cancer patients with peritoneal metastases who have not received prior systemic treatment. The primary end point is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva.Clinical Trial Registration: NCT05285358 (ClinicalTrials.gov).

[Box: see text].