cep-9722 and Lung-Neoplasms

NSCLC is a malignant tumor with a high incidence. Ferroptosis presents an essential function in regulating carcinogenesis and tumor progression. However, the ferroptosis-associated prognostic model based on single-cell sequencing of NSCLC remains unexplored. Our study aims to establish a potential predictive model for NSCLC patients and provide available targeted drugs for clinical treatment.. The data on NSCLC patients were collected from TCGA and GEO databases to analyze their gene expression profiles. ConsensusCluster was adopted to divide the patients into different groups based on ferroptosis-related genes. Then, the univariable Cox and LASSO analyses were applied to data analysis and model establishment. Single-cell analysis was used to explore the risk score genes in different cell populations and states. The protein levels of these genes were also investigated through the HPA database. Drug sensitivity was evaluated in CellMiner database. CCK8 and colony formation assays were performed to validate potential drugs' effects on lung cancer cell lines.. A ferroptosis-related prognostic model involving 14 genes in NSCLC patients was established. The risk score model was developed in training set GSE31210 and validated in the test set TCGA. The low-risk score group showed a better prognosis than the high-risk score group. The single-cell analysis revealed that the risk score genes were mainly derived from lung tumor cells. Most risk score genes were more highly expressed in tumor tissue than in normal tissue, according to the HPA database. Besides, these genes were associated with 106 drugs in CellMiner database. Finally, the drug effects on NSCLC cell growth were evaluated by cck8 and colony formation.. We identified an effective ferroptosis-related prognostic model based on single-cell sequencing. The potential prediction model is devoted to exploring clinical therapeutic targets for NSCLC.

Topics: Biomarkers; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Ferroptosis; Humans; Lung Neoplasms; Prognosis

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors may potentiate chemotherapy by hindering DNA damage repair pathways. CEP-9722 is the prodrug of CEP-8983, a selective inhibitor of PARP-1 and PARP-2. Preclinical studies and a prior phase 1 study suggested that CEP-9722 may cause less myelosuppression than has been observed with other oral PARP inhibitors. The primary objective of this study was to determine the maximum-tolerated dose of CEP-9722 in combination with gemcitabine and cisplatin in patients with advanced solid tumors. All patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. Patients who completed one cycle of chemotherapy alone continued chemotherapy in combination with CEP-9722 150, 200, 300, or 400 mg orally twice daily on days 2-7, with dose-limiting toxicity assessed in cycle 2. Patients experiencing clinical benefit could continue treatment until disease progression or unacceptable toxicity. Thirty-two patients enrolled; 18 patients completed cycle 1 and received chemotherapy plus CEP-9722. The median (range) treatment administration with CEP-9722 was five (1-12) cycles. No patient experienced dose-limiting toxicity with CEP-9722 treatment. Grade 3/4 hematologic adverse events included neutropenia (28%) and leukopenia (11%); adverse events led to discontinuation in 33% of patients. One patient achieved complete response, three had partial responses, and 11 had stable disease; however, the relative contribution of CEP-9722 and/or the chemotherapeutic agents cannot be determined from this single-arm design. This study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carbazoles; Cisplatin; Colorectal Neoplasms; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Lung Neoplasms; Lymphoma, Mantle-Cell; Male; Melanoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Phthalimides; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases