Anti-Cancer Drugs最新文献

In this Turkish Oncology Group study, we aimed to evaluate the effectiveness of trastuzumab emtansine (TDM1) in the adjuvant treatment of early-stage human epidermal growth factor receptor-2 (HER2)-positive breast cancer with residual disease using real-life data. A total of 13 Turkish centers participated in the study between September 2019 and October 2024. Patients with early-stage HER2-positive breast cancer who underwent surgery after completing neoadjuvant chemotherapy with HER2-targeted therapies had residual invasive disease in the breast or axillary lymph nodes and received adjuvant TDM1 therapy. The patients' files were retrospectively scanned from the hospitals' archives. The study included 79 female patients. The 36-month median disease-free survival rate was 92%, and the 36-month median overall survival rate was 85%. Neoadjuvant anthracyclines were administered to 93.6% of the patients. All patients received neoadjuvant trastuzumab and 86.1% of patients received neoadjuvant pertuzumab in addition to trastuzumab. Twelve (15.2%) patients developed progression during or after adjuvant TDM1 therapy. The most common adverse events were grade 1 fatigue (34.2%), grade 1 anemia (27.8%), and grade 1 AST increase (25.3%). Toxicity of grade 3 or above developed in five (5%) patients. TDM1 was stopped for one patient due to thrombocytopenia and for two patients due to cardiotoxicity. This study describes the sociodemographic and clinicopathological characteristics of patients with early-stage HER2-positive breast cancer with residual disease after neoadjuvant therapy and provides real-life data on treatment with adjuvant TDM1. The findings support the manageable safety profile of the adjuvant TDM1 regimen with a low discontinuation rate.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare and have among the worst prognoses among all soft tissue sarcomas, with 5-year overall survival rates ranging from 16 to 52%. We report a case of a 50-year-old man with localized dorsal MPNST who developed local recurrence after 1 year and lung metastasis 3 years after diagnosis. He underwent primary tumor resection, two resections for local recurrence, one lung metastasectomy, seven lines of chemotherapy (epirubicin-ifosfamide, cisplatin-etoposide, trabectedin, pazopanib, carboplatin-etoposide, gemcitabine, and ifosfamide), and four courses of stereotactic body radiotherapy for lung metastases. The patient has shown long remission intervals and survival exceeding 7 years, with a good quality of life since the diagnosis of lung metastasis. We conducted a narrative review based on our treatment approach, considering the recent literature and drugs currently available for the treatment of MPNST.

Sunitinib is a small molecule tyrosine kinase inhibitor that is taken by mouth. It works against several kinases, such as vascular endothelial growth factor receptor, c-Kit, and platelet-derived growth factor receptor. We report a case of total disappearance of choroid metastases from renal cell carcinoma after 6 months of sunitinib, with grade 3 hyperbilirubinemia.

CDK4/6 inhibitors are applied for the treatment of breast cancer. The purpose of this study was to explore the effects of palbociclib (PALB) on triple-negative breast cancer. An in vivo assay was applied to determine the effects of PALB on breast cancer. Gene expression was detected using immunohistochemistry. mRNA levels were detected using reverse transcription-quantitative PCR. Protein expression was detected using western blot. The expansion of CD8 + T cell subsets was detected using flow cytometry. We found that PALB treatment promoted the persistence of CD8 + T cells, manifested by the maintenance of stem-like CD8 + T cells and effector T cells. Moreover, PALB downregulated phosphoglycerate dehydrogenase (PHGDH), high levels of which predicted poor prognosis of breast cancer patients. Moreover, overexpression of PHGDH antagonized the effects of PALB and suppressed the persistence of CD8 + T cells. Additionally, PALB enhanced the effects of anti-PD1 immunotherapy and suppressed the tumor growth of breast cancer. In summary, PALB promoted the maintenance of CD8 + memory precursors in breast cancer via downregulating PHGDH.

Objective: The present study aims to evaluate the efficacy of immune checkpoint inhibitor (ICI) rechallenge in combination with metronomic cyclophosphamide, with or without bevacizumab, in patients with metastatic nonsmall cell lung cancer (NSCLC) and to investigate the clinical characteristics associated with the response to the therapy.

Materials and methods: The study included 43 patients with metastatic NSCLC who responded to ICIs for ≥4 months and subsequently experienced disease progression. The patients then underwent ICI rechallenge along with either oral cyclophosphamide daily alone ( n  = 24) or cyclophosphamide and bevacizumab ( n  = 19).

Results: Combining ICI with cyclophosphamide resulted in an objective response rate (ORR) of 16.7%, disease control rate (DCR) of 75.0%, median progression-free survival (PFS) of 5.8 months, and overall survival (OS) of 15.4 months. Oral cyclophosphamide and bevacizumab cohort achieved an ORR of 26.3%, a DCR of 78.9%, a PFS of 6.8 months, and an OS of 17.6 months. No treatment-related adverse events resulted in the discontinuation of the study therapy in either cohort. Multivariate analysis demonstrated that the absence of an objective response to initial ICIs (OS: P  = 0.016), poor Eastern Cooperative Oncology Group Performance Status (ECOG PS) (PFS: P  = 0.017, OS: P  = 0.032), and a neutrophil-to-lymphocyte ratio (NLR) ≥ 3.8 (PFS: P  = 0.004, OS: P  = 0.007) were negative predictors of rechallenge therapy.

Conclusion: The combination showed promising antitumor activity and a well-tolerated safety profile in patients with ICI-pretreated NSCLC. Furthermore, ECOG PS 0-1, objective response, and NLR ≤ 3.8 were predictive of the efficacy of the study therapy.

Pancreatic cancer is one of the most common malignant tumors of the digestive system, with the majority of patients not succumbing to the primary tumor but rather to metastasis. Epithelial-mesenchymal transition (EMT) is abnormally activated in numerous cancers, whereby it promotes tumor cell migration and invasion. Yes-associated protein 1 (YAP1) is commonly overexpressed in various cancer types and plays an oncogenic role. We demonstrated that FV-429, a derivative of the natural flavonoid wogonin, inhibited the invasion and metastasis of pancreatic cancer cells by modulating EMT-related proteins. FV-429 enhances the expression of p-LATS1, thereby promoting the conversion of YAP1 to p-YAP1. Meanwhile, it suppresses the nuclear translocation of YAP1, thereby affecting the expression of E-cadherin and snail1, which, in turn, impacts the EMT. The Hippo-signaling pathway inhibitor TDI-011536 was used to validate these results. In vivo , a mouse model of pancreatic cancer lung metastasis was established using PANC02 cells to validate the antimetastatic effect of FV-429, which confirmed its action through the Hippo/YAP1 pathway. In addition, FV-429 demonstrated high safety and low toxicity. In conclusion, we demonstrated that FV-429 inhibits migration, invasion, and metastasis of human pancreatic cancer cells by affecting the Hippo/YAP1 pathway, suggesting that FV-429 has the potential to be a novel therapeutic agent for pancreatic cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized advanced cancer treatment and prolonged survival; however, they are associated with several immune-related adverse events in up to 60% of patients, affecting various organ systems. A 73-year-old male patient with metastatic melanoma was admitted with left-sided ptosis, diplopia, head drop, and proximal muscle weakness. The patient had been undergoing treatment with nivolumab and ipilimumab, and his symptoms emerged 4 days after receiving the second cycle of the immunotherapy regimen. He was diagnosed as having ICI-related myositis, myasthenia gravis (MG), and myocarditis based on electromyography, muscle biopsy, antibody status, troponin level, and cardiac evaluation. ICIs were withdrawn and the patient was treated with intravenous methylprednisolone, intravenous immunoglobulin, and plasma exchange; however, the patient was treatment-refractory, necessitating long-term immunosuppression with rituximab. Subsequently, he responded well, and nivolumab monotherapy was resumed. The patient has been neurologically stable for 4 months without any recurrence of ICI-related adverse effects. ICI-related myositis, MG, and myocarditis are rare but can be severe and potentially life-threatening. Therefore, early recognition and immediate treatment are crucial for improving prognosis. To the best of our knowledge, this is the only case with nivolumab- and ipilimumab-induced triple overlap syndrome successfully treated with rituximab.

Gliomas, arising from supportive glial cells in the central nervous system, present significant challenges in oncology due to their varying aggressiveness and poor prognosis, particularly in high-grade forms. Understanding the molecular pathways involved in glioma progression is essential for developing effective treatment strategies. This study aimed to develop a fatty acid metabolism (FAM)-related gene signature to better predict poor prognosis in glioma patients, thereby facilitating more targeted therapeutic approaches. We employed the Least Absolute Shrinkage and Selection Operator regression analysis to identify a gene signature associated with FAM from The Cancer Genome Atlas and Chinese Glioma Genome Atlas RNA-seq datasets. Survival analyses, including Kaplan-Meier and Cox regression analyses, were conducted to assess the prognostic value of the identified genes. A total of seven FAM-related genes were associated with survival outcomes in isocitrate dehydrogenase-1 wild-type glioblastoma. The constructed gene signature effectively stratified patients into high-risk and low-risk groups, with high-risk patients demonstrating significantly poorer survival. PTGR1 emerged as the core gene, closely linked to malignant progression and poor prognosis. The FAM-related gene signature developed in this study provides a reliable tool for predicting poor outcomes in glioma patients. PTGR1, identified as a pivotal gene within this signature, may serve as a potential target for future therapeutic interventions, offering promising avenues for enhancing patient survival.

The overexpression of CAV1 in many cancers is linked to chemotherapy resistance, but the exact mechanisms by which CAV1 contributes to resistance in nasopharyngeal carcinoma (NPC) are not fully known. Our research aims to elucidate the potential pathways by which CAV1 contributes to chemotherapy resistance in NPC, providing a basis for developing strategies to overcome resistance. A docetaxel-resistant NPC cell line was established, and CAV1 expression was analyzed in the cell line and the resistant variant using western blot. The sensitivity of the resistant cell line to docetaxel was assessed via cell counting kit-8, colony formation assays, and flow cytometry. Flow cytometry was used to measure lipid reactive oxygen species levels, while kits were employed to determine Fe 2+ and malondialdehyde concentrations. The Ubibrowser database helped identify ubiquitination enzymes that interact with CAV1. The binding relationship between UCHL1 and CAV1 was studied using co-immunoprecipitation and immunofluorescence, which also evaluated the deubiquitination activity of UCHL1 on CAV1. CAV1 is overexpressed in NPC tissues and cells, correlating with adverse patient prognoses. In docetaxel-resistant cells, CAV1 expression is elevated compared to standard NPC cells. Silencing CAV1 increased the sensitivity of these resistant cells to docetaxel. Additionally, treatment with the ferroptosis inducer erastin could counteract the effects of CAV1 overexpression on drug resistance. UCHL1 interacted with CAV1 and inhibited its ubiquitin-mediated degradation pathway. By deubiquitinating CAV1, UCHL1 stabilizes and increases its expression, which inhibits ferroptosis and enhances the resistance of NPC cells to docetaxel.

Tumor-associated macrophages play a critical role in regulating the progression of lung adenocarcinoma (LUAD). Platelet-derived protein thrombospondin-2 (THBS2) has been identified as a tumor marker and is known to be overexpressed in LUAD. However, the specific role of THBS2 in M2 macrophage polarization within LUAD remains unclear. We conducted bioinformatics analyses to assess the clinical significance of THBS2 expression in LUAD, which was subsequently validated using quantitative PCR. We examined the relationship between THBS2 expression and M2 macrophage infiltration. A coculture system of LUAD cells and M0 macrophages was established to investigate the influence of THBS2 on macrophage infiltration and polarization through immunofluorescence and ELISA. We explored the impact of THBS2 on fatty acid metabolism (FAM) using oil red O staining and relevant kits and elucidated the role of THBS2 in regulating M2 macrophage polarization and LUAD proliferation through cell counting kit-8 (CCK-8) and colony formation assays. Western blot was employed to assess expression changes of Bax and Bcl-2. THBS2 was highly expressed in LUAD and was associated with poor prognosis in patients. In-vitro experiments demonstrated that silencing THBS2 significantly inhibited macrophage infiltration and polarization. THBS2 primarily activated FAM pathways, inducing M2 macrophage polarization and promoting LUAD cell proliferation. THBS2 enhanced LUAD proliferation by regulating FAM to induce M2 macrophage polarization. These findings provide a theoretical basis for targeting THBS2 as a novel therapeutic strategy in LUAD.