Search Results (750)

Background/Objectives: The TOPAZ-1 phase III trial reported a survival benefit of using durvalumab, an anti-programmed death ligand 1 (anti-PD-L1) antibody, in combination with gemcitabine and cisplatin (GCD) treatment in patients with advanced biliary tract cancer. This retrospective study investigated the efficacy and safety of GCD treatment for advanced biliary tract cancer in real-world conditions. Methods: The study subjects were 52 patients with biliary tract cancer who received GCD therapy between January 2023 and May 2024. The observation parameters included the modified Glasgow Prognostic Score (mGPS), neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), tumor markers (CEA, CA19-9), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: The cohort included 36 men and 16 women, with a median age of 73.0 years. There were 36 cases of cholangiocarcinoma (distal: 10, perihilar: 19, intrahepatic: 7), 13 cases of gallbladder cancer, and 3 cases of ampullary carcinoma. The stages were locally advanced in 30 cases and metastatic in 22 cases. Biliary drainage was performed in 30 cases. There were 38 cases receiving first-line therapy and 14 cases receiving second-line or later treatments. The median values at the start of GCD therapy were ALB 3.7 g/dL, CRP 0.39 mg/dL, NLR 2.4, PLR 162.5, CEA 4.8 ng/mL, and CA19-9 255.9 U/mL. The mGPS distribution was 0:23 cases, 1:18 cases, and 2:11 cases. The treatment outcomes were ORR 25.0% (CR 2 cases, PR 11 cases), DCR 78.8% (SD 28 cases, PD 10 cases, NE 1 case), median PFS 8.6 months, and median OS 13.9 months. The PLR was suggested to be useful for predicting PFS. A decrease in CEA at six weeks after the start of treatment was a significant predictor of PFS and OS. Gallbladder cancer had a significantly poorer prognosis compared to other cancers. The immune-related adverse events included hypothyroidism in two cases, cholangitis in one case, and colitis in one case. Conclusions: The ORR, DCR, and PFS were comparable to those in the TOPAZ-1 trial. Although limited by its retrospective design and small sample size, this study suggests that GCD therapy is an effective treatment regimen for unresectable biliary tract cancer in real-world clinical practice. Full article

Background/Objectives: Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide, with its incidence rising each year. Despite its relatively low incidence, the aggressiveness of pancreatic cancer results in high mortality, with only 12% of patients surviving five years post-diagnosis. Surgical resection remains the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage. The goal of this work is to identify vulnerabilities that can affect the efficacy of treatments and improve the efficacy of therapy. Methods: MAP17 overexpression in pancreatic cancer cell lines, RT-qPCR analysis, xenografts, in vitro and in vivo treatments, analysis of data from pancreatic tumors in transcriptomic patient databases. Results: We studied the prognostic and predictive value of MAP17 (PDZK1IP1) expression in pancreatic cancer, and we found that high MAP17 mRNA expression was associated with poor prognosis. In addition, single-cell analysis revealed that high MAP17 expression was present only in tumor cells. We investigated whether the response to various antitumor agents depended on MAP17 expression. In 2D culture, MAP17-expressing pancreatic cancer cells responded better to gemcitabine and 5-fluorouracil. However, in vivo xenograft tumors with MAP17 expression showed resistance to all treatments. Additionally, MAP17-expressing cells had a high NAD pool, which seems to be effectively depleted in vivo by NAMPT inhibitors, the primary enzyme for NAD biosynthesis. Conclusions: Our findings suggest that MAP17 expression could enhance the prognostic stratification of pancreatic cancer patients. Moreover, the coadministration of NAMPT inhibitors with current treatments may sensitize tumors with high MAP17 expression to chemotherapy and improve the efficacy of chemotherapy. Full article

Background/Objectives: Upper tract urothelial carcinoma (UTUC) is a rare and biologically distinct subset of urothelial malignancies, comprising approximately 5–10% of urothelial cancers. UTUC presents unique diagnostic and therapeutic challenges, with both a higher likelihood of invasive disease at presentation and a less favorable prognosis compared to urothelial carcinoma of the bladder. Current treatment strategies for UTUC are largely derived from bladder cancer studies, underscoring the need for UTUC-directed research. This review provides a comprehensive overview of UTUC, encompassing diagnostic approaches, systemic and intraluminal therapies, surgical management, and future directions. Methods: A narrative review was conducted synthesizing evidence from guideline-based recommendations, retrospective and prospective clinical studies, and ongoing trials focused on UTUC. Results: Neoadjuvant cisplatin-based chemotherapy is increasingly preferred in UTUC due to the risk of postoperative renal impairment that may preclude adjuvant cisplatin use. Surgical management includes kidney-sparing approaches and radical nephroureterectomy (RNU), with selection guided by tumor risk and patient comorbidities. While endoscopic management (EM) preserves renal function, it carries a higher recurrence and surveillance burden; RNU remains standard for high-risk cases. Systemic therapy for advanced and metastatic UTUC mirrors that of bladder urothelial carcinoma. Enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy over chemotherapy in the EV-302 trial, with improved response rate, progression-free survival, and overall survival across subgroups, including UTUC. For patients ineligible for EV, the CheckMate-901 study supported first-line chemoimmunotherapy with gemcitabine, cisplatin, and nivolumab. Further systemic therapy strategies include maintenance avelumab post-chemotherapy (JAVELIN Bladder 100), targeted therapies such as erdafitinib (THOR trial), and trastuzumab deruxtecan (DESTINY-PanTumor02) in FGFR2/3-altered and HER2-positive disease, respectively. Conclusions: Historically, the therapeutic landscape of UTUC has been extrapolated from bladder cancer; however, ongoing research specific to UTUC is deriving more precise regimens involving the use of immune checkpoint inhibitors, antibody–drug conjugates, and biomarker-driven therapies. Full article

Background/Objectives: Bladder cancer is a malignant disease that causes more than 199,922 deaths a year globally, in which ~75% of all newly diagnosed cases are non-muscle-invasive bladder cancer (NMIBC). Despite a number of treatments available, most NMIBC patients with high-grade tumors eventually recur. To add a novel therapy to complement the deficits of the current treatments, this study assesses the antitumor activity and mechanisms of action of intravesical xenogeneic urothelial cell (XUC) treatment as monotherapy and in combination with either chemotherapy or immune checkpoint inhibition (ICI). Methods: The orthotopic NMIBC graft tumor-bearing mice were randomly assigned into different treatment groups, receiving either intravesical XUCs, gemcitabine, anti-programmed death-ligand 1 (PD-L1) antibodies alone or in combination with gemcitabine or anti-PD-1 antibodies. The tumor responses, survival, and immune reactions were analyzed. Results: Intravesical XUC treatment exhibited significantly more antitumor activity to delay tumor progression than the control group and a similar effect to chemotherapy and ICI. In addition, there were significantly higher effects in the combined groups than single treatments. Immune tumor microenvironment and immune cell proliferation, cytotoxicity, and cytokine secretion were also activated by XUC treatment. Moreover, the combined groups have the highest effects. Conclusions: In vivo and ex vivo studies showed increased antitumor efficacy and immune responses by intravesical XUC treatment in single and combined treatments, suggesting a potential utility of this xenogeneic cell immunotherapeutic agent. Intravesical XUC treatment has the potential to address the substantial unmet need in NMIBC therapy as a bladder-sparing treatment option for NMIBC. Full article

The pharmacological treatment of cholangiocarcinoma (CCA) is often hampered by tumor resistance. Improving our understanding of this issue is crucial for developing strategies that can overcome drug refractoriness. We have established and characterized two novel human cell sublines derived from extrahepatic CCA EGI-1 cells that are resistant to cisplatin and 5-fluorouracil (5-FU). Migration and proliferation were analyzed using holographic microscopy. The expression of genes involved in drug uptake and efflux was determined by RT-qPCR. Cross-resistance to commonly used antitumor drugs was assayed using the MTT test. EGI-1 sublines resistant to cisplatin (CR) or 5-FU (FR) exhibited more than a three-fold increase in resistance to cisplatin and 5-FU, respectively, and showed reduced proliferation, migration, and colony-formation rates, along with an altered cell cycle compared to wild-type cells, while retaining tumorigenic capacity. The analysis of the transportome showed downregulation of uptake transporters and upregulation of the export pumps MRP3/4. EGI-1 cells with acquired resistance to 5-FU demonstrated cross-resistance to irinotecan and gemcitabine, while cisplatin-resistant cells showed decreased sensitivity to 5-FU and platinum derivatives. These resistant cell lines offer valuable models for investigating the molecular basis of chemoresistance in CCA, providing a robust platform for the development and evaluation of novel therapeutic strategies. Full article

Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. Escherichia coli expressing long-form cytidine deaminase (CDD_L) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDD_S) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC cells through CDD-mediated degradation. Oral microbes associated with PDAC were selected based on CDD isoforms: Aggregatibacter actinomycetemcomitans carrying CDD_L, Enterococcus faecalis, Streptococcus mutans, Porphyromonas gingivalis, all carrying CDD_S, and Fusobacterium nucleatum lacking CDD. The selected microbes, along with wild-type and CDD-deficient E. coli, were co-incubated with gemcitabine to assess its degradation and PDAC cell proliferation. A. actinomycetemcomitans fully degraded gemcitabine and induced resistance. Surprisingly, CDD_S-expressing oral bacteria partially degraded gemcitabine in a strain-dependent manner. Expressing either CDD_L or CDD_S in CDD-deficient E. coli resulted in equivalent gemcitabine degradation and resistance, indicating that CDD function is independent of isoform length. These findings highlight the role of oral bacteria in gemcitabine resistance and the need for strategies to mitigate microbial-driven resistance in PDAC treatment. Full article

Cancer remains one of the leading causes of death globally, highlighting the urgent need for novel anticancer therapies with higher efficacy and reduced toxicity. Similarly, the rise in multidrug-resistant pathogens and emerging infectious diseases underscores the critical demand for new antimicrobial agents that target resistant infections through unique mechanisms. This study used computational approaches to investigate twenty quinolone–triazole and conazole–triazole hybrid derivatives as antimicrobial and anticancer agents (1–20) with nine reference drugs. By studying their interactions with 6 bacterial DNA gyrase and 10 cancer-inducing target proteins (E. faecalis, M. tuberculosis, S. aureus, E. coli, M. smegmatis, P. aeruginosa and EGFR, MPO, VEGFR, CDK6, MMP1, Bcl-2, LSD1, HDAC6, Aromatase, ALOX15) and comparing them with established drugs such as ampicillin, cefatrizine, fluconazole, gemcitabine, itraconazole, ribavirin, rufinamide, streptomycin, and tazobactam, compounds 15 and 16 emerged as noteworthy antimicrobial and anticancer agents, respectively. In molecular dynamics simulations, compounds 15 and 16 had the strongest binding at −10.6 kcal mol⁻¹ and −12.0 kcal mol⁻¹ with the crucial 5CDQ and 2Z3Y proteins, respectively, exceeded drug-likeness criteria, and displayed extraordinary stability within the enzyme’s pocket over varied temperatures (300–320 K). In addition, we used density functional theory (DFT) to calculate dipole moments and molecular orbital characteristics and analyze the thermodynamic stability of putative antimicrobial and anticancer derivatives. This finding reveals a well-defined, possibly therapeutic relationship, supported by theoretical and future in vitro and in vivo studies. Compounds 15 and 16, thus, emerged as intriguing contenders in the fight against infectious diseases and cancer. Full article

Nucleobase and nucleoside analogs are critical components of antimetabolite chemotherapy treatments used to disrupt DNA replication and induce apoptosis in rapidly proliferating cancer cells. However, the development of resistance to these agents remains a major clinical challenge. This review explores the epigenetic mechanisms that contribute to acquired chemoresistance, focusing on DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These epigenetic alterations regulate key processes such as DNA repair, drug metabolism, cell transport, and autophagy, enabling cancer cells to survive and resist therapeutic pressure. We highlight how dysregulation of DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) modulates expression of transporters (e.g., hENT1, ABCB1), DNA repair enzymes (e.g., Polβ, BRCA1/2), and autophagy-related genes (e.g., CSNK2A1, BNIP3). Furthermore, emerging roles for long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in regulating nucleoside export and DNA damage response pathways underscore their relevance as therapeutic targets. The interplay of these epigenetic modifications drives resistance to agents such as gemcitabine and 5-fluorouracil across multiple tumor types. We also discuss recent progress in therapeutic interventions, including DNMT and HDAC inhibitors, RNA-based therapeutics, and CRISPR-based epigenome editing. Full article

Pancreatic cancer is the third leading cause of cancer-related death in the US. First-line chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC) include FOLFIRINOX or gemcitabine (Gem) with or without paclitaxel (Ptx); however, 5-year survival with these regimens remains poor. Previous work has demonstrated protein arginine methyltransferase 5 (PRMT5) to be a promising therapeutic target in combination with Gem for the treatment of PDAC; however, these findings have yet to be confirmed in relevant preclinical models of PDAC. To test the possibility of PRMT5 as a viable therapeutic target, clinically relevant orthotopic and metastatic patient-derived xenograft (PDX) mouse models of PDAC growth were utilized to evaluate the effect of PRMT5 knockout (KO) or pharmacologic inhibition on treatment with Gem alone or Gem with Ptx. Primary endpoints included tumor volume, tumor weight, or metastatic tumor burden as appropriate. The results showed that Gem-treated PRMT5 KO tumors exhibited decreased growth and were smaller in size compared to Gem-treated wild-type (WT) tumors. Similarly, the Gem-treated PRMT5 KO metastatic burden was lower than the Gem-treated WT metastatic burden. The addition of a PRMT5 pharmacologic inhibitor to Gem and Ptx therapy resulted in a lower final tumor weight and fewer metastatic tumors. The depletion of PRMT5 results in increased DNA damage in response to Gem and Ptx treatment. Thus, PRMT5 genetic depletion or inhibition in combination with Gem-based therapy improved the response in primary and metastatic PDAC in clinically relevant mouse models, suggesting that PRMT5 is a viable therapeutic target for combination therapy in PDAC. Full article

Mesenchymal stem cells (MSCs) have recently shown great promise as potential anticancer drug delivery carriers. MSCs exhibit tropism to inflammatory sites, such as tumor beds, and resistance to chemotherapeutics. The aim of this study was to examine the efficacy of gemcitabine (GEM) conjugated with flurbiprofen (FLU) as a potential agent enhancing the GEM cytotoxic effect. Pancreatic cancer cell lines (PCCs), including PANC-1, AsPC-1, and BxPC-3, were studied meticulously. Moreover, the usefulness of bone-marrow-derived mesenchymal stem cells (BM-MSCs) treated with GEM and FLU, and the conditioned media from above these cells (CM) as elements supporting the in vitro action of GEM, inducing apoptosis, necrosis, and inhibiting the cell cycle, was tested. The results showed that CM-GEM exhibited higher cytotoxicity towards the selected PCCs compared to GEM alone. Furthermore, the obtained data revealed lower sensitivity of these cells to treatment, which promotes the utilization of BM-MSCs as potential drug carriers. Based on the presented findings, it seems that applying FLU in the antiproliferative effect of GEM might be regarded as an effective strategy in the therapy of pancreatic cancer, especially in the inhibition of proliferation and induction of cancer cell death. Full article

Background/Objectives: Drug resistance and severe side effects caused by gemcitabine (Gem) and cisplatin (CDDP) are common. This study aimed to investigate the combined effects of CU4c and Gem or CDDP on lung cancer cells in vitro and in nude mouse xenograft models. Methods: Antiproliferative activity and drug interaction were evaluated using MTT and Chou–Talalay methods, respectively. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. The expression levels of proteins were evaluated by Western blot analysis. The HDAC-inhibitory activity of CU4c was confirmed in vitro, in silico, and in A549 cells. Results: CU4c inhibited the proliferation of A549 cells in a dose- and time-dependent manner but had little effect on the growth of noncancerous Vero cells. CU4c synergistically enhanced the antiproliferative activities of CDDP (at 24 h) and Gem (at 48 and 72 h) against A549 cells. Combined CU4c and CDDP notably inhibited A549 proliferation by triggering cell cycle arrest at S and G2/M phases at 24 h with elevated levels of p21 and p53 proteins. Combined CU4c and Gem induced cell cycle arrest at both the S and G2/M phases at 48 h via upregulating the expression of the p21 protein. CU4c enhanced the apoptotic effects of CDDP and Gem by increasing the Bax/Bcl-2 ratio, pERK1/2, and Ac-H3 levels. Combined CU4c and Gem significantly reduced tumor growth while minimizing visceral organ damage in animal study. Conclusions: These results suggest that CU4c enhances the anticancer activity of CDDP and Gem and reduces the toxicity of Gem in animal studies. Full article

The adsorption of the drug gemcitabine on nucleobases was investigated using a dispersion-corrected density functional theory (DFT) study. The planar structure of complexes is more stable than those with stacked and buckle-angled configurations. The complexes were found to possess at least two intermolecular hydrogen bonds. The binding energy and interaction energy are both negative, with the highest values observed for the gemcitabine–guanine and the lowest in the gemcitabine–thymine complex. The complex formation was found to be an enthalpy-driven process. Pyrimidine nucleobases have a lower enthalpy of formation than purine nucleobases. The computed HOMA and NICS values on the gemcitabine–nucleobase complexes show a substantial increase compared to the pristine nucleobases. An MESP analysis of the complexes shows a directional interaction and electron density shift between the gemcitabine and the nucleobases. A QTAIM analysis indicates that the intermolecular hydrogen bonds have a partial covalent character. The computed bond energy demonstrates that intermolecular NH⋅⋅⋅N bonds are more potent than other bonds. An energy decomposition analysis using the DLPNO−CCSD(T) method indicates that the complexes exhibit a substantial electrostatic attraction, and dispersion contributes the least towards the system stability. The intermolecular bonds are stronger than the intramolecular bonds in the drug–nucleobase complexes. The strength of intramolecular bonds is determined by the deformation of the gemcitabine ring during the complex formation. Full article

Platinum resistance represents an urgent medical need in the management of ovarian cancer. The activity of the combinations of onvansertib, an inhibitor of polo-like kinase 1, with gemcitabine or carboplatin was tested using patient-derived xenografts of high-grade serous ovarian carcinoma resistant to cisplatin (DDP). Two PDX models were selected from our xenobank: one with acquired resistance to DDP (#266R) and the other (#315) with intrinsic DDP resistance. Tumor-bearing mice were randomized to receive vehicle, single onvansertib, gemcitabine and carboplatin, and their combinations. Onvansertib/gemcitabine and onvansertib/carboplatin combinations were well tolerated. In the #266R model, single drug treatments were completely inactive, while the combinations of onvansertib/gemcitabine and onvansertib/carboplatin resulted in a significant increase in survival compared to controls and single drugs (p < 0.001 versus control, onvansertib, gemcitabine and carboplatin). Similar efficacy was observed in the s.c. #315 PDX model; indeed, onvansertib and carboplatin monotherapies were inactive, gemcitabine monotherapy was marginally active, while both combinations were highly active. The molecular mechanism underlying the efficacy of the combinations suggests a higher induction of DNA damage which seems plausible considering that, in both cases, gemcitabine and carboplatin, respectively, interfere with DNA metabolism and induce alkylation damage. The results suggest that the combinations of onvansertib/gemcitabine and onvansertib/carboplatin are safe and were shown to be of therapeutic value in the platinum-resistant setting of ovarian carcinoma, strongly supporting their clinical translatability. Full article

Intrahepatic cholangiocarcinoma (iCCA) is a malignancy with limited treatment options in advanced stages. Recently, targeted therapies against fibroblast growth factor receptor 2 (FGFR2) fusions have emerged as a promising approach for selected patients. Tasurgratinib, a selective FGFR1–3 inhibitor, was approved in Japan in 2024 for second-line treatment of FGFR2 fusion-positive biliary tract cancer. We report the case of a 55-year-old female with advanced iCCA harboring an FGFR2-BICC1 fusion, who experienced a rapid clinical response to tasurgratinib following disease progression on gemcitabine, cisplatin, and durvalumab (GCD). Following the failure of GCD therapy, treatment with oral tasurgratinib was initiated at 140 mg/day and subsequently reduced to 105 mg/day due to Grade 2 diarrhea. Within weeks, imaging and tumor markers indicated a partial response, accompanied by a reduction in ascites, and improved performance status. The response sustained for several months without evidence of disease progression. Notably, no substantial clinical hyperphosphatemia or anorexia was observed during treatment. This is the first report to describe the real-world clinical efficacy of tasurgratinib in an iCCA patient with FGFR2-BICC1 fusion. Our findings suggest that tasurgratinib can provide a rapid and durable response with manageable toxicity in molecularly selected patients who have progressed on standard therapies. Full article

The prognostic and predictive role of the human equilibrative nucleoside transporter 1 (hENT-1) has emerged in different cancer types, including intrahepatic cholangiocarcinoma (iCCA), but the mechanisms regulating its expression are poorly understood. Here, we investigated the link between p53 status and hENT-1 regulation in 38 iCCA patients and cell line models; the predictive role of p53 status in response to adjuvant gemcitabine was also investigated. A positive association between mutant p53 cells and hENT-1 expression was observed in iCCA tissue samples; furthermore, patients receiving adjuvant gemcitabine and expressing mutant p53 cells > 4% in tumor tissue had a longer disease-free survival (DFS) than patients expressing mutant p53 cells ≤ 4% (median 18.5 vs. 6 months, p = 0.0229). In iCCA cell line models, transient knockdown of mutant p53 resulted in a decrease in hENT-1 mRNA and protein expression; similarly, restoration of wild-type p53 function induced a significant reduction in hENT-1 mRNA and protein expression. Overall, these findings support a role of p53 status in the regulation of hENT-1 expression, suggesting an opposite effect (activating versus repressive) of mutant and wild-type p53 protein. Furthermore, although the present study should be considered as preliminary, our findings suggest a predictive role of p53 status in iCCA patients treated with gemcitabine, thus deserving future investigations in additional cohorts of cancer patients. Full article