Search Results (125)

Background and Objectives: Combining osimertinib (OSI) with pemetrexed (PEM) can enhance antitumor efficacy; however, the benefit is schedule-dependent. Our previous pharmacodynamic (PD) study showed that concurrent PEM + OSI is limited by OSI-induced G1 arrest, attenuating early PEM cytotoxicity. In contrast, sequential PEM→OSI allows PEM to fully induce S-phase arrest and DNA damage but elicits a pro-survival EGFR rebound; subsequent OSI suppresses this rebound and promotes apoptosis of damaged cells, yielding strong synergy. Here, we investigated whether pharmacokinetic (PK) drug–drug interactions (DDIs) contribute to this synergy and predicted the relative advantage of PEM→OSI versus PEM + OSI under clinically relevant conditions using a PK/PD approach. Method and Results: Potential PK-DDIs were assessed at cellular uptake, plasma exposure, and intratumoral distribution levels. No meaningful PK-DDIs were observed, supporting a primary PD-driven synergy. We integrated mouse PK with in vitro/in vivo PD data to build a mechanistic Quantitative System Pharmacology (QSP)–PK–PD model linking drug disposition to folate biology, Epidermal Growth Factor Receptor (EGFR) signaling, and tumor growth inhibition. The model recapitulated schedule dependence and explained PEM→OSI superiority: PEM initiates damage and EGFR compensatory rebound, after which OSI suppresses EGFR signaling and enhances apoptosis. In contrast, concurrent PEM + OSI induced G1 arrest, reduced the pool of damaged apoptosis-susceptible cells, and weakened the synergy. Global sensitivity analysis identified intrinsic OSI sensitivity and the pro-apoptotic protein Bim as key determinants; reduced OSI sensitivity or Bim activity diminished the advantage of the sequential strategy. The simulations indicated that OSI can start 48 h after PEM exposure (no extended drug holiday is needed) and that the PEM→OSI benefit remains robust across heterogeneity, including BIM-deletion polymorphisms and inter-individual variability in tumor drug sensitivity. Conclusions: This mechanism-based QSP–PK–PD framework connects whole-body PK to core PD processes, explains schedule-dependent synergy, and supports optimization of sequencing intervals and identification of likely responders. Full article

Background/Objectives: The aberrant epigenetic landscape of cancer cells has attracted wide attention, motivating the search for new epigenetically active drugs both for anticancer therapy and for overcoming the drug resistance promoted by epigenetic changes. The use of epi-drugs in cancer therapy requires consideration of the influence of applied treatment on epigenetic regulation of gene expression. Therefore, it is reasonable to screen epigenetically active compounds among the drugs widely used in clinical oncology. Methods: We applied the HeLa TI cell-based assay to analyze the epigenetic activity of 40 drugs including 22 chemotherapeutic, 2 immunotherapeutic, 13 targeted, and 3 palliative agents. Reactivation of the epigenetically silenced GFP reporter gene integrated into the genome of HeLa TI cells was assessed using flow cytometry. Results: Statistically significant increases in the proportions of GFP-positive cells were demonstrated for the alkylating agent chlorambucil; the antimetabolites cytarabine, fluorouracil, gemcitabine, and pemetrexed; the platinum-based compounds cisplatin, and oxaliplatin; the topoisomerase inhibitor topotecan; and the antimicrotubule agents docetaxel, vincristine, and eribulin. Epigenetic activity was also detected for the targeted-therapy agents AZD8055, wortmannin, and cetuximab, as well as for the corticosteroid dexamethasone. Thus, epigenetic activity was revealed for 15 drugs widely used in cancer therapy, which possess different modes of action. Conclusions: Our findings show that many anticancer therapy agents modulate the epigenetic landscape of cancer cells, providing a rationale for expanding their therapeutic applications and enhancing the efficacy of combination strategies by overcoming epigenetically driven chemoresistance. Full article

Immunotherapy has significantly reshaped the management of malignant pleural mesothelioma (MPM), offering new therapeutic opportunities after decades in which platinum–pemetrexed chemotherapy represented the only systemic option. However, clinical benefit remains markedly heterogeneous, with outcomes strongly influenced by histologic subtype, patient characteristics, and real-world treatment conditions. Evidence from monotherapy trials has been inconsistent, whereas combination approaches—particularly nivolumab plus ipilimumab—have demonstrated improved survival compared with chemotherapy, mainly in non-epithelioid tumors. Nevertheless, real-world data consistently show lower efficacy and higher toxicity than registrational studies, especially among elderly and unselected populations. Recent translational work has highlighted the relevance of the tumor microenvironment and recurrent genomic alterations such as BAP1, NF2, and CDKN2A in shaping immune activity and potentially modulating response to immune checkpoint inhibitors. Transcriptomic signatures and circulating biomarkers—including soluble mesothelin-related peptide—have shown prognostic associations but no validated predictive value. Overall, current evidence suggests that sensitivity to immunotherapy in MPM arises from a complex interplay of genomic, immunologic, and clinical factors, and that no biomarker is yet suitable for guiding treatment decisions. Prospective studies integrating molecular and immune profiling will be essential to refine patient selection and advance toward a more rationally personalized use of immunotherapy Full article

SATB2 (special AT-rich binding protein 2) functions as a chromatin-associated epigenetic regulator that modulates gene expression, in part by serving as a transcriptional cofactor. This study assessed whether SATB2 overexpression is sufficient to promote in vitro transformation of human mesothelial cells and whether SATB2 suppression in mesothelioma cancer stem cell (CSC)–enriched populations is associated with altered chemoresistance. SATB2 expression was high in human malignant pleural mesothelioma (MPM) cell lines but absent in Met5A mesothelial cells. Ectopic SATB2 expression in Met5A cells was associated with acquisition of malignant and stem cell–like phenotypes, including increased expression of stem cell markers and pluripotency-associated factors, as well as anchorage-independent growth in soft agar and spheroid formation in suspension culture. In contrast, Met5A cells transduced with an empty vector did not form colonies or mesospheres. SATB2 overexpression in Met5A cells was also associated with increased motility, migration, and invasion, accompanied by induction of epithelial–mesenchymal transition (EMT)–related transcription factors relative to empty vector controls. Conversely, shRNA-mediated SATB2 knockdown in an MPM cell line attenuated proliferation, EMT-associated features, and CSC-like characteristics. Chromatin immunoprecipitation assays identified SATB2 occupancy at promoter regions of Bcl2, XIAP, KLF4, c-Myc, NANOG, and SOX2, consistent with a role in transcriptional regulation of genes linked to transformation, pluripotency, cell survival, proliferation, and EMT. In CSC-enriched cells, SATB2 inhibition was associated with increased sensitivity to cisplatin and pemetrexed, concomitant with reduced OCT4 and SOX2 expression. Collectively, these findings support SATB2 as a candidate therapeutic target in MPM and suggest that SATB2 suppression may enhance chemotherapy response when combined with standard agents. Full article

Background: Thymic epithelial tumors (TETs), including thymic carcinomas and thymomas, are rare malignancies originating in the mediastinum. Therapeutic options remain limited for patients experiencing disease progression following platinum-based chemotherapy. High tumor mutational burden (TMB) is uncommon in thymic malignancies but may predict response to immunotherapy. We report a patient with TMB-high TET who participated in the KOSMOS-II study in South Korea and achieved a durable response to atezolizumab without developing immune-related adverse events (irAEs). Case presentation: A 73-year-old woman who had been treated for thymoma 20 years ago presented with a left neck mass. A biopsy of the neck mass confirmed recurrent thymoma, type B3, and her disease progressed despite platinum-based chemotherapy and subsequent pemetrexed treatment. TMB-high thymoma is very rare, but based on the next-generation sequencing (NGS) results, she was diagnosed with TMB-high (20.3 mutations/Mb) thymoma. As TMB-based immunotherapy is not approved in Korea, she was enrolled in the KOSMOS-II study and initiated on atezolizumab following molecular tumor board review. She achieved stable disease after three cycles and has remained progression-free for 14 months, completing 20 cycles without significant irAEs. Notably, her underlying myasthenia gravis did not worsen during treatment. Conclusions: This case demonstrates a favorable outcome with biomarker-directed ICI treatment in recurrent thymoma with limited treatment options, highlighting the importance of appropriate molecular markers to predict drug response. Although TMB-based immunotherapy is FDA-approved in the U.S., it remains unavailable in Korea, underscoring the need to explore flexible access pathways, including the potential use of immunotherapy beyond current indications, to improve treatment options for patients with life-threatening conditions. Full article

Background/objective: Carboplatin, pemetrexed, and pembrolizumab are established as a key first-line regimen for metastatic non-small cell lung cancer, although selecting the optimal therapy for each patient remains challenging in real-world clinical practice. This retrospective multicenter study compared the efficacy and safety of two atezolizumab-based combination regimens, ACnP (carboplatin, nab-paclitaxel, atezolizumab) and ABCP (carboplatin, paclitaxel, bevacizumab, atezolizumab), in patients with non-small cell lung cancer in real-world clinical practice. Methods: A total of 91 patients treated between May 2018 and December 2023 at six Japanese hospitals were analyzed: 40 received ACnP and 51 received ABCP. Patient characteristics, treatment outcomes, and adverse events were compared, with subgroup analyses adjusted by inverse probability of treatment weighting using propensity scores. Results: The objective response rates were 55.0% with ACnP and 45.1% with ABCP. Median progression-free survival was 5.5 months for ACnP and 6.9 months for ABCP, while median overall survival was 16.2 and 18.3 months, respectively. Subgroup analyses showed significantly improved progression-free survival with ABCP in patients with brain metastases, liver metastases, EGFR-positive tumors, PD-L1-positive tumors, and impaired renal function (CCr < 45 mL/min). ABCP also conferred overall survival benefits in patients with brain and liver metastases. However, ACnP was associated with a lower incidence of neutropenia, peripheral neuropathy, and skin rash. Conclusions: These findings suggest that ABCP may offer superior efficacy in specific non-small cell lung cancer subgroups, while ACnP remains a valuable option for patients requiring a more tolerable safety profile. Full article

Background: Combining pemetrexed (PEM) with Osimertinib (OSI) improves outcomes in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), but optimal scheduling remains undefined. Sequential PEM → OSI strategies may outperform concurrent administration; however, the critical dosing interval determining synergy has not been explored. Methods: PEM pharmacodynamics were divided into an OSI-antagonized early phase (S-phase arrest and DNA damage accumulation) and OSI-synergized late phase (DNA damage peak, apoptosis initiation, and feedback EGFR activation). Time-course profiling of cell cycle, DNA damage, apoptosis, and EGFR pathways was evaluated under monotherapy or sequential combination regimens to elucidate the mechanisms underlying synergistic/antagonistic effects. Results: OSI antagonizes PEM’s early phase via G1 arrest but potently enhances late-phase apoptosis through Rad51/thymidylate synthase suppression, Bim upregulation, and inhibition of EGFR signaling. The 48 h interval PEM → OSI uniquely enabled complete early-phase execution and aligned OSI exposure with late-phase initiation, yielding robust synergy across OSI-sensitive cell lines. In contrast, the 24 h interval PEM → OSI sequence demonstrated synergy only in PEM-sensitive PC9 cells. Both concurrent PEM + OSI and OSI → PEM sequence induced attenuated DNA damage and apoptotic signaling. Conclusions: The 48 h interval PEM → OSI sequence maximizes efficacy by temporally segregating antagonistic and synergistic interactions. This pharmacodynamically optimized regimen represents a promising strategy for clinical translation. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide. Advances in screening, diagnosis, and management have transformed clinical practice, particularly with the integration of immunotherapy and target therapies. Methods: A systematic literature search was carried out for the period between October 2016 to September 2024. Phase II and III randomized trials evaluating ICI monotherapy, ICI–chemotherapy combinations, and dual ICI regimens in patients with advanced NSCLC were included. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). Results: PD-1-targeted therapies demonstrated superior OS compared to PD-L1-based regimens, with cemiplimab monotherapyranking highest for OS benefit (posterior probability: 90%), followed by sintilimab plus platinum-based chemotherapy (PBC) and pemetrexed—PBC. PFS atezolizumab plus bevacizumab and PBC, and camrelizumab plus PBC were the most effective regimens. ICI–chemotherapy combinations achieved higher ORRs but were associated with greater toxicity. The most favorable safety profiles were observed with cemiplimab, nivolumab, and avelumab monotherapy, while atezolizumab plus PBC and sugemalimab plus PBC carried the highest toxicity burdens. Conclusions: In PD-L1-unselected advanced NSCLC, PD-1 blockade—particularly cemiplimab monotherapy—and rationally designed ICI–chemotherapy combinations represent the most efficacious treatment strategies. Balancing efficacy with safety remains critical, especially in the absence of predictive biomarkers. These findings support a patient-tailored approach to immunotherapy and highlight the need for further biomarker-driven and real-world investigations to optimize treatment selection. Full article

Pleural malignancies represent a clinically devastating group of oncological disorders, most commonly arising from metastatic disease, with lung and breast cancers being the most frequent primary sites. Malignant pleural mesothelioma is a primary malignancy of the pleura and occurs less often than metastatic pleural disease. Pleural malignancies often present with malignant pleural effusion, which typically indicates advanced-stage disease and is associated with poor overall prognosis. Treatment of pleural malignancies includes both palliative and definitive approaches. Palliative interventions primarily aim to relieve symptoms and improve quality of life. Definitive treatments include systemic chemotherapy, targeted therapy, and immunotherapy, depending on the type and molecular profile of the underlying tumor. In mesothelioma, platinum-based chemotherapy in combination with pemetrexed remains the cornerstone of treatment, while the combination of nivolumab and ipilimumab is recommended as first-line therapy for unresectable disease. For metastatic disease, systemic therapy is typically tailored to the primary tumor’s characteristics. Intrapleural administration of chemotherapeutic agents is one of the therapeutic strategies and hyperthermic intrathoracic chemotherapy and pressurized intrathoracic aerosol chemotherapy are the most recent innovations that are under active investigation. This review provides an up-to-date synthesis of systemic chemotherapy strategies for pleural malignancies, their integration with targeted and immune-based therapies, and recent advances in intrapleural chemotherapy modalities. It also explores existing knowledge gaps and outlines directions for future research and potential changes in clinical practice. Full article

Previous studies have demonstrated that Candida spp. isolates exposed in vitro to the folic acid antagonist methotrexate may develop multidrug cross-resistance to azole antifungals. The aim of this study was to determine whether systemic therapy with antineoplastic antifolates—pemetrexed or methotrexate—constitutes a risk factor for colonization or infection with fluconazole-resistant yeasts. The study group comprised 44 cancer patients who received high-dose systemic antifolate therapy, while the control group consisted of 48 patients without prior exposure to either methotrexate or pemetrexed. Oral swabs and relevant clinical data were collected from all participants. In total, 109 fungal strains representing 13 species were isolated, identified, and subsequently tested for fluconazole susceptibility. Fluconazole-resistant isolates were identified in 4 out of 44 (9.1%) antifolate-treated patients and in 3 out of 48 (6.3%) control patients. Our findings suggest that, although this phenomenon occurs in vitro, systemic antineoplastic antifolate therapy does not induce azole resistance among endogenous yeast species in vivo. Full article

Reactive oxygen species (ROS) generated by cold atmospheric plasma (CAP) cause irreversible damage to cancer cell DNA, RNA, mitochondria, and antioxidant defense systems, leading to apoptosis. Plasma-induced disruption of the antioxidant defense system of cancer cells by cystine uptake via xC⁻ antiporter has been widely studied, while folate uptake by cancer cells via high expression of hSLC19A1, which generates Nicotinamide Adenine Dinucleotide Phosphate (NADPH) via one-carbon metabolism, is also an important component of the antioxidant defense mechanism of cancer cells. Disrupting folate transport in cancer cells is an important potential pathway for synergizing with pemetrexed (PMX) to induce apoptosis in cancer cells, which is of great research value. In this paper, classical molecular dynamics simulations were employed to study the effect of plasma oxidation of hSLC19A1 on the uptake of 5-Methyltetrahydrofolate (5-MTHF), which is the predominant dietary and circulatory folate, and the antifolate chemotherapeutic agent PMX by cancer cells. The results showed that the channel radius of hSLC19A1 for transporting 5MTHF after oxidation became narrower and the conformation tended to be closed, which was unfavorable for the transport of 5-MTHF; hydrogen bonding and hydrophobic interactions between hSLC19A1 and 5-MTHF decreased, the predicted docking affinity decreased, and the binding energy decreased from −28.023 kcal/mol to −16.866 kcal/mol, while that with PMX was stable around −28 kcal/mol, suggesting that the oxidative modification reduced the binding capacity of hSLC19A1 and 5-MTHF while barely affecting the transport of PMX, which contributed to weakening the antioxidant defense system of cancer cells and synergizing with PMX to induce apoptosis in cancer cells. Our simulations provide theoretical insights for CAP-induced apoptosis in cancer cells at the microscopic level and help promote the further development of cold atmospheric plasma in the field of cancer therapy. Full article

Background/Objectives: Neutrophil cells’ lysis forms the extracellular traps (NETs) to counter the foreign body during insults to the body. Peptidyl arginine deiminase (PAD) participates in this process and is then released into the extracellular fluid with the lysed cell components. In some diseases, patients with abnormal function of PADs, especially PAD 4, tend to form autoantibodies against the abnormal citrullinated proteins that are the result of PAD activity on arginine side chains. Those antibodies, which are highly distinct in RA, are distinctly anti-citrullinated protein antibodies (ACPA). This study used an in-silico drug repurposing approach of FDA-approved medications to identify potential alternative medications that can inhibit this process and address solutions to the current limitations of existing therapies. Methods: We utilized Maestro Schrödinger as a computational tool for preparing and docking simulations on the PAD 4 enzyme crystal structure that is retrieved from RCSB Protein Data Bank (PDB ID: 4X8G) while the docked FDA-approved medications are obtained from the Zinc 15 database. The protein was bound to GSK 199—an investigational compound—as a positive control for the docked molecules. Preparation of the protein was performed by Schrödinger Protein Preparation Wizard tool. Binding pocket determination was performed by Glide software (Schrödinger Release 2021–3:Schrödinger, LLC., New York, NY, USA, 2021). and validation of molecular docking was carried out through the redocking of GSK 199 and superimposition. After that, standard and induced fit docking were performed. Results/Conclusions: Among the four obtained hits Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol, which showed the highest XP scores providing favorable binding interactions. The induced-fit docking (IFD) results displayed the strong binding affinities of Ioversol, Pemetrexed, Leucovorin, Chlordiazepoxide in the order IFD values −11.617, −10.599, −10.521, −9.988, respectively. This research investigates Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol as potential repurposing agents in the treatment of rheumatoid arthritis (RA) as they are identified as PAD4 inhibitors. Full article

Background: In unresectable pleural mesothelioma, pemetrexed+cisplatin as first line is considered the standard of care, but novel treatments have been recently proposed. Methods: Our objective was to compare, albeit indirectly, the results of randomized controlled trials on overall survival (OS). The IPDfromKM method was employed for reconstruct individual patient data (IPD) from the graphs of Kaplan–Meier curves. Cox statistics was run to estimate hazard ratios (HRs). Results: After a literature search on Medline (via PubMed) and Scopus databases, six randomized controlled trials were identified in which five new treatments (nivolumab plus ipilimumab, bevacizumab plus pemetrexed plus cisplatin, chemotherapy plus pembrolizumab, ONCOS-102 plus pemetrexed plus cisplatin/carboplatin and cediranib plus pemetrexed+cisplatin with maintenance with cediranib) were evaluated. In five trials, pemetrexed plus cisplatin was the standard of care given to the control arms. Nivolumab plus ipilimumab, bevacizumab plus pemetrexed plus cisplatin and chemotherapy plus pembrolizumab showed a significantly better OS compared with controls. ONCOS-102 plus pemetrexed plus cisplatin/carboplatin did not significantly improve OS. In contrast, OS worsened with cisplatin alone and with cediranib plus pemetrexed+cisplatin with maintenance with cediranib. Discussion: Our analysis indicates that, in patients with unresectable pleural mesothelioma, three of the five novel treatments provided a significant survival benefit compared with the standard of care. Further research is needed to confirm the OS benefit found in our analysis with some treatments, whereas cisplatin alone and cediranib plus pemetrexed+cisplatin with maintenance with cediranib do not seem to deserve further research. Full article

Background. The Hippo pathway is the most frequently altered signaling in pleural mesothelioma (PM). Epithelioid PM (ePM) is associated with better outcome than non-epithelioid subtypes, but its prognosis can be heterogeneous. Here, we tried to stratify ePM using the expression levels of the Hippo-TEAD network. Methods. Thirty patients with ePM were included in this study. Tumors were stratified using the expression levels of 74 genes belonging to the Hippo-TEAD network and using the non-negative matrix factorization algorithm. Results were validated using ePM cases from the TCGA cohort. Alterations associated with the molecular subgroups were investigated using mutation and copy number alteration data from TCGA. Results. Two groups of ePM (i.e., HP1 and HP2) were identified and validated using TCGA data. HP2 comprises about one-third of tumors. These tumors are frequently high-grade (73% vs. 35%), have higher levels of downstream Hippo effectors (i.e., YAP1, WWTR1 and TEADs), lower levels of VSIR—which encodes for VISTA—and poorer PFS and OS. HP2 tumors commonly harbor homodeletions in Hippo core suppressors (25% vs. 3%), while no specific gene mutation or copy number alterations of Hippo genes was associated with the two groups. Conclusions. ePM can be stratified in prognostic subtypes based on the expression levels of the Hippo-TEAD network. Higher levels of downstream Hippo effectors are associated with poor response to platinum-pemetrexed doublet and worse OS. The stratification of ePM based on the activation of the YAP/TAZ-TEAD axis is an intriguing approach in the light of the inhibitors of this signaling that are currently under investigation. Full article