Anti-Cancer Drugs最新文献

Mesenchymal-epithelial transition factor (MET) exon 14 skipping alterations are rare mutations in non-small-cell lung cancer, associated with high malignancy and poor prognosis. This article presents a case of a patient diagnosed with advanced left upper lung adenocarcinoma characterized by a MET14 skipping mutation. Following first-line treatment with crizotinib, there was a significant reduction in the size of the primary lesion; however, during the course of treatment, an increase in size and prominence of solid components were observed in the right upper lung lesion. A biopsy and subsequent genetic testing revealed an epidermal growth factor receptor L858R mutation in the right upper lung adenocarcinoma, indicating the presence of multiple primary lung cancers. The patient opted against surgical intervention and local treatments, choosing instead a combination therapy regimen that included almonertinib and crizotinib. This treatment approach led to a significant reduction in the size of the right upper lung lesion. The patient's condition has remained stable without any signs of progression, resulting in an overall survival duration exceeding 53 months.

Multiple cancers are driven by aberrant fibroblast growth factor receptor (FGFR) signaling and vascular endothelial growth factor receptor (VEGFR)-linked angiogenesis. Several therapeutic agents targeting FGFR and VEGFR have been developed and approved for use in solid cancers; however, there is still a high unmet medical need for new agents that have a more powerful antitumor activity and a broader antitumor spectrum. Here, we report the discovery of FH-2001, a novel and potent FGFR/VEGFR dual inhibitor, with additional activity of modulating programmed cell death ligand 1 (PD-L1) gene expression. In biochemical assays, FH-2001 showed potent inhibition of FGFR1, 2, 3, and 4, with half-maximal inhibitory concentration (IC 50 ) of 0.2, 0.2, 0.4, and 2.0 nM, respectively, and VEGFR1, 2, and 3, with IC 50 values of 2.0, 0.3, and 0.5 nM, respectively. FH-2001 significantly suppressed the cell growth of FGFR- or VEGFR-driven cancer cell lines. In representative cell line- and patient-derived tumor xenografts with aberrant FGFR or VEGFR signaling, FH-2001 substantially inhibited tumor growth. Furthermore, FH-2001 demonstrated marked antitumor activities when treated alone or combined with PD-L1 or PD-1 antibody in syngeneic mouse models. Flow cytometric analysis revealed that FH-2001 alone or in combination with anti-PD-L1 increased T and natural killer cells and decreased myeloid cells in the tumor microenvironment. Mechanistically, FH-2001 treatment dramatically reduced c-Myc and PD-L1 mRNA and protein levels in a dose-dependent manner in vitro . Taken together, FH-2001 is a promising dual-target inhibitor of FGFR and VEGFR and also modulates cancer immunity, while its robust antitumor activity positions it as a potentially class-leading anticancer agent.

Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare tumor that is frequently misdiagnosed as other vascular or soft tissue neoplasms and typically follows an indolent course. Due to its locally aggressive and multifocal nature, surgical intervention is often not feasible. Moreover, conventional chemotherapy has shown limited efficacy according to existing literature. Recent advances in genetic profiling have identified a SERPINE1/FOSB gene fusion in PHE, leading to the activation of the mechanistic target of rapamycin (mTOR) pathway. This discovery has highlighted mTOR inhibitors and multityrosine kinase inhibitors as promising therapeutic options. In this report, we present a PHE case with confirmed SERPINE1/FOSB fusion who was initiated on everolimus therapy, along with a review of the current literature.

Tumor metabolism and metabolic reprogramming in cancer cells represent a promising area in oncology research, offering new avenues for therapeutic intervention. While the 'Warburg effect' highlights the reliance of many tumors on aerobic glycolysis, emerging evidence indicates that some cancers also depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, cancer cell survival, tumor progression, metastasis, and drug resistance. We conducted a high-throughput, differential, phenotypic screening followed by a focused medicinal chemistry campaign, leading to the identification of novel, potent OXPHOS inhibitors. These lead compounds selectively target complex I of the mitochondrial electron transport chain, thereby disrupting ATP production and oxygen consumption in cancer cells. In-vitro studies in breast cancer cell lines, along with published data, suggest that MCT4 expression may serve as a biomarker for drug sensitivity. Notably, low MCT4 expression correlated with higher potency in cell growth assays. The identified compounds exhibited favorable drug-like properties, including good pharmacokinetics and oral bioavailability in mice. Daily oral dosing significantly inhibited tumor growth in two in-vivo breast cancer models with low MCT4 expression levels. This efficacy, however, was accompanied by body weight loss, indicating the need to enhance the therapeutic index through optimization or rational combination therapy strategies. These findings highlight the therapeutic potential of targeting mitochondrial OXPHOS in cancers with defined metabolic dependencies, offering a novel approach for exploiting tumor-specific metabolic vulnerabilities for improved cancer treatment.

Glutathione peroxidase 4 (GPX4) plays a pivotal role in regulating ferroptosis and maintaining redox homeostasis, making it a critical target in drug-resistant cancers. Recent studies suggest that allosteric inhibition of GPX4 could overcome resistance mechanisms. This study aimed to identify natural products with potential allosteric inhibition of GPX4 using computational approaches. A comprehensive virtual screening was conducted on a curated library of 125 415 natural compounds derived from the COlleCtion of Open Natural ProdUcTs (COCONUT) database. Structure-based virtual screening and molecular docking were performed against the allosteric site of GPX4 (PDB ID: 7U4N) using UCSF DOCK6. The top candidates were evaluated through binding free energy calculations [molecular mechanics Poisson-Boltzmann surface area (MM-PBSA)] and 100 ns molecular dynamics simulations using the AMBER20 package. Pharmacokinetic and toxicity profiles were assessed through absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Five natural compounds - quercetin, zeatinriboside, ribofuranosylmakaluvic acid C, tecleanatalensine B, and scopolamine - exhibited superior binding affinities (docking scores ranging from -4.01 to -4.95 kcal/mol) compared with the cocrystallized ligand (-3.15 kcal/mol), with significant interactions at the key Cys66 residue of GPX4. MM-PBSA analysis revealed highly favorable binding free energies (up to -37.94 kcal/mol), indicating stable ligand-protein complexes. Molecular dynamic simulations confirmed structural stability, with minimal root mean square deviation and root mean square fluctuations. ADMET profiling suggested favorable solubility, absorption, low toxicity, and good drug-likeness. This study highlights the potential of natural products as allosteric inhibitors of GPX4. The identified compounds demonstrated strong and stable interactions with the GPX4 allosteric site and possessed desirable pharmacokinetic properties, warranting further in-vitro and in-vivo investigations for potential development as anticancer agents targeting drug-resistant cancers.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare subtype of inflammatory myofibrosarcoma. Anlotinib has demonstrated efficacy in the treatment of sarcoma. Nevertheless, to our knowledge, its use in EIMS has not been reported. Herein, we present a case of pulmonary EIMS. The patient underwent two courses of chemotherapy with doxorubicin combined with ifosfamide; however, the treatment was switched to anlotinib due to leukocytopenia. After 11 months of treatment with anlotinib, the tumor was in partial remission. Subsequently, the patient developed an acute myocardial infarction, which resulted in the discontinuation of anlotinib. Four months after discontinuation, the tumor progressed and anlotinib therapy was resumed. Following treatment for 5 months, tumor assessment indicated partial remission until March 2024. During this period, the patient experienced an adverse effect (i.e. ostealgia), which led to two reductions in the dosage of anlotinib. This case report provides a novel strategy for treating EIMS.

Despite significant advancements in vaccination, screening, and therapeutic strategies have substantially reduced cervical cancer incidence, effective treatment for this disease remains a major clinical challenge. This study reveals that APG-115, a murine double minute 2 (MDM2) inhibitor, upregulates the transcription and expression of MDM2, p53, and p21, effectively inhibiting cell proliferation and inducing apoptosis in cervical cancer cells. Mechanistically, APG-115 suppresses the activation of the AKT and ERK signaling pathways and reduces the expression of antiapoptotic proteins BCL-2, BCL-xL, and MCL-1, while promoting the expression of pro-apoptotic proteins BAK, BAX, and BIM. Notably, the combination of APG-115 with bortezomib enhances p53 and p21 expression, synergistically induces cell apoptosis. In the cervical cancer xenograft models, APG-115 and bortezomib significantly downregulated the expression of Ki67 and BCL-2 while markedly increasing p21 protein levels, effectively suppressing tumor growth and inducing apoptosis. The combination further amplified the effects on Ki67, BCL-2, and p21 expression, leading to enhanced tumor growth inhibition. In summary, this study demonstrates that APG-115 exerts antitumor effects in cervical cancer, and its combination with bortezomib further enhances this inhibitory effect, probably through maximal activation of p53 and inhibition of BCL-2, suggesting a potential application of APG-115 in the treatment of cervical cancer.

Hepatocellular carcinoma is the main primary liver cancer. Due to the high recurrence rate and potential resistance to treatments, there is an urgent need to find more effective and targeted therapies. Combinational therapies and using advanced drug delivery methods are promising approaches. Niosomes are one of the popular types of nanoparticles in modern drug delivery systems and have recently attracted more attention. They are biodegradable, nonimmunogenic, and more stable carriers than liposomes. They can release anticancer drugs in an efficient and controlled manner. The aim of this study was to synthesize and characterize the physicochemical properties of linoleic acid (LA)-loaded niosomes and evaluate their anticancer effects on a hepatoma cell. We synthesized LA-loaded niosomes using a thin-film hydration method and characterized their size, polydispersity index (PDI), and zeta potential. The morphology of niosomes was evaluated by scanning electron microscopy. Finally, the viability, migration capacity, and colonization potential of Hep-3B hepatoma cells treated with 150 μM LA-loaded niosomes were investigated and compared to the control groups. The niosomes had a mean size of 266.9 nm, PDI of 0.271, and zeta potential of -26.1 mV. The LA-loaded niosomes released LA sustainably at 37 °C for 72 h. MTS assay indicated that the LA-loaded niosomes were more toxic than free LA. Hep-3B hepatoma cells treated with LA-loaded niosomes showed a remarkable decline in the migration ability and colony-formation capacity. Therefore, the use of LA-loaded niosomes in combination with conventional protocols may be a promising approach to target cancer cells.

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) have been widely documented. Diabetic ketoacidosis (DKA), a severe irAEs, has not been previously reported in patients with nasopharyngeal carcinoma (NPC). This case report describes the development of DKA during maintenance immunotherapy with tislelizumab in a patient with recurrent NPC. A 41-year-old female patient with recurrent NPC (rT3N0M0, 8 th edition of AJCC staging) experienced DKA during her 13 th session of maintenance treatment with the ICI tislelizumab. After urgent consultation with an endocrinologist, immune-related DKA was diagnosed, and immune checkpoint inhibitor-related diabetes was confirmed. Prompt treatment with hypoglycemic agents, fluid infusion, and correction of water-electrolyte and acid-base balance was administered. The patient's blood glucose was stabilized within 6 days, and she was discharged without complications. This is the first reported case of DKA in a patient with NPC receiving tislelizumab maintenance immunotherapy. Clinicians should enhance their understanding and monitoring of adverse events in patients treated with ICIs, focusing on early diagnosis and appropriate intervention.