Investigational New Drugs最新文献

{"title":"Correction to: Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: results of a single-center, multi-arm phase Ib study.","authors":"Kyaw Z Thein, Daniel D Karp, Apostolia Tsimberidou, Jing Gong, Selma Sulovic, Jatin Shah, Denái R Milton, David S Hong, Filip Janku, Lacey McQuinn, Bettzy A Stephen, Rivka Colen, Brett W Carter, Timothy A Yap, Sarina A Piha-Paul, Siqing Fu, Funda Meric-Bernstam, Aung Naing","doi":"10.1007/s10637-024-01493-5","DOIUrl":"https://doi.org/10.1007/s10637-024-01493-5","url":null,"abstract":"","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenging and new opportunities for prodrug technology.","authors":"Helin Li, Xuelian Shen, Yu Chu, Panhong Yuan, Qi Shuai","doi":"10.1007/s10637-025-01515-w","DOIUrl":"https://doi.org/10.1007/s10637-025-01515-w","url":null,"abstract":"<p><p>Research on prodrug technology has opened new avenues for site-directed chemotherapy rather than systemic chemotherapy. This distinctive strategy allows drug delivery to be activated by light-, irradiation-, or ultrasound (US)-tunable chemistries, which have been termed photopharmacology, radiopharmacology, and sonopharmacology, respectively. Prodrugs have emerged as a main strategy for improving pharmacokinetics, reducing side effects, and thus enhancing the therapeutic efficacy of drugs. This review summarizes stimuli-responsive drug release systems and the latest progress in exogenous stimuli-responsive prodrug activation, e.g., light, irradiation, and US, with a focus on the activation of small molecule prodrugs, antibody‒drug conjugates, and prodrug nanosystems. In addition, challenges encountered by Pt drugs and Pt(IV) prodrug nanotherapeutics are summarized and discussed. Moreover, this review presents the current state of precise treatment and discusses the opportunities and challenges for the clinical translation of these strategies.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotective effects of PARP inhibitors for platinum-agent induced cardiotoxicity.","authors":"Jae Hyun Kim, Ja-Young Han, Jae-Hee Kwon, Myeong Gyu Kim","doi":"10.1007/s10637-025-01509-8","DOIUrl":"https://doi.org/10.1007/s10637-025-01509-8","url":null,"abstract":"<p><p>Poly(ADP-ribose) polymerase (PARP) inhibitors may have cardioprotective properties. This study aimed to evaluate the potential cardioprotective effects of PARP inhibitors in patients with epithelial ovarian cancer treated with platinum-based chemotherapeutic agents. A retrospective cohort study was conducted using the Health Insurance Review & Assessment Service claims database from January 2007 to July 2022. Eligible patients were those diagnosed with ovarian, primary peritoneal, or fallopian tube cancer who received platinum-based chemotherapy after 2017. Propensity score matching was employed to adjust for potential confounders, and logistic regression and Cox proportional hazards regression analyses were utilized to estimate the odds ratios, hazard ratios, and 95% confidence intervals (CIs) for the occurrence of cardiac adverse events, including myocardial infarction, cardiomyopathy, and heart failure. A total of 7,253 eligible patients were included in the study, of which 233 (3.2%) used PARP inhibitors. After propensity score matching, no significant cardioprotective effect was observed in the PARP inhibitor-exposed group compared to the non-exposed group (adjusted odds ratio, 0.753; 95% CI 0.275-2.059; adjusted hazard ratio, 0.601; 95% CI 0.228-1.584). Although no statistically significant cardioprotective effect of PARP inhibitors was found in this study, there was a directional trend suggesting that patients with gynecologic malignancies treated with platinum-based chemotherapy could potentially benefit from PARP inhibitors. Further research with larger sample sizes and longer follow-up periods is warranted to elucidate the role of PARP inhibitors in mitigating cardiac adverse events in this patient population.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress of KRAS G12C inhibitors in the treatment of refractory colorectal cancer and strategies for drug resistance response.","authors":"Peiyuan Yang, Yongchao Li","doi":"10.1007/s10637-025-01514-x","DOIUrl":"https://doi.org/10.1007/s10637-025-01514-x","url":null,"abstract":"<p><p>Colorectal cancer is the third most prevalent cancer in the world. Early screening and detection of tumours, active surgical radical treatment, postoperative adjuvant chemotherapy, targeted therapy, and immunotherapy are performed based on pathological staging and immunohistochemistry. Even with these measures, the 5-year survival rate of colorectal cancer is only 65%, and a considerable number of patients still experience tumour recurrence or even metastasis. The KRAS G12C mutation accounts for 3 to 4% of refractory colorectal cancer (advanced or metastatic colorectal cancer), and it was once believed that KRAS did not have a drug target until the emergence of KRAS G12C inhibitors provided targeted treatment for KRAS-mutated colorectal cancer. However, KRAS G12C inhibitors only produce moderate efficacy, and resistance occurs after a short remission. The mechanism of drug resistance in tumour cells is complex and diverse, and existing research has limited understanding of it. This review aims to elucidate the clinical trial progress of KRAS G12C inhibitors in refractory colorectal cancer, the research progress of drug resistance mechanisms, and the combined treatment strategies for drug resistance.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC6 inhibition through WT161 synergizes with temozolomide, induces apoptosis, reduces cell motility, and decreases β-catenin levels in glioblastoma cells.","authors":"Leilane Sales Oliveira, João Marcos Oliveira-Silva, Hebreia Oliveira Almeida-Souza, Mario Machado Martins, Carolina Berraut Chiminazo, Rafael Fonseca, Carlos Vinicius Expedito de Souza, Alexandre Ferro Aissa, Luciana Machado Bastos, Marisa Ionta, Graziela Domingues de Almeida Lima, Angel Mauricio Castro-Gamero","doi":"10.1007/s10637-025-01508-9","DOIUrl":"https://doi.org/10.1007/s10637-025-01508-9","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) accounts for 70% of all primary malignancies of the central nervous system. Current treatment strategies involve surgery followed by chemotherapy with temozolomide (TMZ); however, the median survival after treatment is approximately 15 months. Many GBM cases develop resistance to TMZ, resulting in a poor prognosis for patients, which underscores the urgent need for novel therapeutic approaches. One promising avenue is the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates α-tubulin and is increasingly recognized as a potential pharmacological target in cancer. In GBM specifically, HDAC6 overexpression has been linked to poor prognosis and chemoresistance. In this study, we demonstrate that HDAC6 protein levels are elevated in GBM and evaluate the effects of the novel selective HDAC6 inhibitor, WT161, on U251, U87, and T98G cells to assess its potential to revert the malignant phenotype. Our results show a significant increase in acetylated α-tubulin levels, suppression of cell growth, cell cycle arrest at the G2/M phase, and decreased clonogenicity of 2D-cultured GBM cells. Additionally, WT161 acted synergistically with TMZ, induced apoptosis and enhanced TMZ-induced apoptosis. Notably, HDAC6 inhibition resulted in reduced cell migration and invasion, associated with decreased β-catenin levels. When cultured in 3D conditions, WT161-treated T98G spheroids were sensitized to TMZ and exhibited reduced migration. Finally, HDAC6 inhibition altered the metabolome, particularly affecting metabolites associated with lipid peroxidation. In conclusion, our data reveal, for the first time, the efficacy of the selective HDAC6 inhibitor WT161 in a preclinical GBM setting.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of fruquintinib plus capecitabine as first-line treatment in patients with metastatic colorectal cancer ineligible for intravenous chemotherapy: a two-stage, single-armed, phase II study.","authors":"Xin Wang, Zhigang Bai, Wei Deng, Xinfeng Wang","doi":"10.1007/s10637-025-01510-1","DOIUrl":"https://doi.org/10.1007/s10637-025-01510-1","url":null,"abstract":"<p><p>Fruquintinib has been recommended for treating refractory metastatic colorectal cancer. This single-arm, phase II study explored for the first time whether fruquintinib combined with capecitabine could be used as a first-line treatment for patients with metastatic colorectal cancer who are intolerant to intravenous chemotherapy. From December 8, 2021, to December 31, 2024, 17 patients were included in the effect analysis who respectively received capecitabine and fruquintinib at a starting dose of 825 mg/m² twice a day and 4 mg every day (2 weeks followed by 1-week rest) and recorded changes in safety and quality of life; the dosage can be appropriately adjusted according to the protocol to make it tolerable for the patients. The median age was 76 years old; the study achieved a disease control rate of 88.2%, an overall response rate of 17.6%, and a median progression-free survival of 16.3 months (95% CI 9.7-22.9); the overall survival had not been reached. The median quality of life scores and self-assessment of health scores change, respectively, from 42 (IQR 34, 47) to 45 (IQR 41, 57) and from 5 (IQR 4.25, 6.75) to 4 (IQR 3.00, 6.00). There were only 3 events of grade ≥ 3 TRAEs, including one rare case of aortic dissection. Fruquintinib combined with capecitabine has initially shown ideal disease control, safety, and convenience, especially as a first-line treatment for elderly frail patients with metastatic colorectal cancer. Further phase III study is planned to refine this combination. Clinical Trial Number: NCT04866108.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DYNC2H1 mutation as a potential predictive biomarker for immune checkpoint inhibitor efficacy in NSCLC and melanoma.","authors":"Lu Yang, Yanlong Feng, Xuewen Liu, Qin Zhang, Yaqin Liu, Xing Zhang, Ping Li, Dongsheng Chen","doi":"10.1007/s10637-024-01495-3","DOIUrl":"https://doi.org/10.1007/s10637-024-01495-3","url":null,"abstract":"<p><p>Dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) is reported to play a potential role in cancer immunotherapy. However, the association between DYNC2H1 mutation and the clinical benefit of immunotherapy in non-small cell lung cancer (NSCLC) and melanoma remains to be elucidated. We collected data from three public immune checkpoint inhibitor (ICI)-treated NSCLC cohorts (n = 137 in total) and seven ICI-treated melanoma cohorts (n = 418 in total) to explore the potential of DYNC2H1 mutation as a predictive biomarker. The clinical outcomes, including the objective response rate (ORR) and progression-free survival (PFS), of patients with DYNC2H1 mutations are significantly better than those of patients with wild-type DYNC2H1. Multivariate Cox regression analysis confirmed that DYNC2H1 mutation was an independent predictive factor for ICI efficacy in NSCLC and melanoma. In addition, DYNC2H1 mutation exhibited no prognostic value for NSCLC or melanoma. Tumour mutational burden (TMB) and tumour neoantigen burden (TNB) were significantly higher in patients with DYNC2H1 mutation than in those with wild-type DYNC2H1 in both NSCLC and melanoma cohort. The analysis of immune-related genes and immune cell enrichment revealed an association between DYNC2H1 mutation and increased immune infiltration, revealing a potential mechanism underlying the predictive role of DYNC2H1 mutation in immunotherapy efficacy. In conclusion, DYNC2H1 mutation serves as a predictive biomarker of ICI efficacy in NSCLC and melanoma.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical features, diagnosis, and treatment of pembrolizumab induced autoimmune encephalitis.","authors":"Li Zou, Xianlin Rao, Xiyue Zhao","doi":"10.1007/s10637-025-01511-0","DOIUrl":"https://doi.org/10.1007/s10637-025-01511-0","url":null,"abstract":"<p><p>Pembrolizumab has shown links to autoimmune encephalitis (AE), yet the exact clinical characteristics remain unclear. This study examines the clinical features of pembrolizumab-induced AE to enhance diagnostic accuracy and therapeutic strategies. Reports on pembrolizumab-induced AE were gathered via a searchable database, culminating on November 30, 2024. The median age at onset among the 34 patients was 68 years (range 47-82), with males constituting 67.6%. The average onset period for AE was 6 months (range 0.3-25) after the initial dose, with an average of 6 cycles (range 1-17). Commonly reported symptoms included confusion (38.2%), fever (35.3%), and decreased consciousness (32.4%). Cerebrospinal fluid analysis revealed elevated protein (55.9%), leukocytosis (70.6%), and normal blood glucose levels (38.2%). Antineuronal antibodies were found to be negative in 41.2% of cases and positive in 35.3%. Magnetic resonance imaging indicated T2/FLAIR hypersignal in 32.4% of cases, while the electroencephalogram revealed slow waves (11.8%) and diffuse slowing (11.8%). Following treatment with steroids, intravenous immunoglobulin, and plasmapheresis, 82.4% of patients experienced symptom improvement or recovery, though 5.9% succumbed to AE. Oncologists must consider the risk of AE when prescribing pembrolizumab. Early diagnosis and intervention for AE are crucial. Further research is needed to define the optimal treatment approach.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-Fluorouracil-methotrexate conjugate enhances the efficacy of 5-fluorouracil in colorectal cancer therapy.","authors":"Siyuan Zhao, Tiansi Wang, Kourong Shi, Ting Li, Qiuzhen Zhu, Yuan Li, Beiwei Xin, Xin Wu, Wei Fan","doi":"10.1007/s10637-024-01488-2","DOIUrl":"10.1007/s10637-024-01488-2","url":null,"abstract":"<p><p>To extend the short half-life of fluorouracil (Fu), enhance its tumor targeting, improve efficacy, and reduce side effects, providing a new approach for colorectal cancer treatment. Fluorouracil was hydroxylated and conjugated with methotrexate to form a 5-fluorouracil-methotrexate conjugate (MF). This was complexed with sulfobutyl ether-β-cyclodextrin (MF-SEBCD) using a stirring method to create an injectable formulation. In vitro studies assessed the conversion of MF-SEBCD in plasma and its antitumor activity. In vivo studies examined antitumor activity, preliminary safety, pharmacokinetics, and tissue distribution. MF was synthesized with a 25% yield and purity above 95%. The water solubility of MF increased by 92-fold with MF-SEBCD preparation. In vitro, MF-SEBCD effectively converted into Fu in plasma and showed strong antitumor activity, with IC50 values of 0.51, 1.29, and 1.26 µM for MC38, HT29, and 4T1 cells, respectively. In vivo, MF-SEBCD achieved a tumor inhibition rate of 57.08%. Pharmacokinetic studies showed that MF-SEBCD extended Fu's half-life to 47 min, nearly double that of Fu injection. Tissue distribution analysis confirmed improved tumor targeting. MF-SEBCD effectively prolongs Fu's half-life, enhances tumor targeting, increases antitumor efficacy, and reduces side effects, offering a promising approach for colorectal cancer treatment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"30-41"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the association between therapeutic effectiveness of anamorelin and Glasgow prognostic score in patients with cancer cachexia: a competing risk analysis.","authors":"Kazuhiro Shimomura, Takatsugu Ogata, Akimitsu Maeda, Yukiya Narita, Hiroya Taniguchi, Kenta Murotani, Yutaka Fujiwara, Masahiro Tajika, Kazuo Hara, Kei Muro, Kosaku Uchida","doi":"10.1007/s10637-024-01503-6","DOIUrl":"10.1007/s10637-024-01503-6","url":null,"abstract":"<p><p>Anamorelin, a highly selective ghrelin receptor agonist, enhances appetite and increases lean body mass in patients with cancer cachexia. However, the predictors of its therapeutic effectiveness are uncertain. This study aimed to investigate the association between the Glasgow prognostic score (GPS), used for classifying the severity of cancer cachexia, the therapeutic effectiveness of anamorelin, and the feasibility of early treatment based on cancer types. A retrospective analysis included patients with gastric, pancreatic, colorectal, and non-small-cell lung cancer treated with anamorelin between May 2021 and July 2022. The endpoints were the response rate for increased appetite within 3 weeks of treatment initiation and the time to treatment failure (TTF) due to therapeutic failure of anamorelin. Multivariate logistic regression model and Fine and Gray's model were used for analysis. Of the 137 patients in this analysis, 51% of patients had a GPS of 0 or 1, and 49% of those had a GPS of 2. Patients with a GPS of 2 showed a lower response for increased appetite than those with a GPS of 0 or 1 (adjusted odds ratio 0.29 [95% CI 0.12-0.72], P = 0.007). Additionally, TTF was shorter in patients with a GPS of 2 with a GPS of 0 or 1 (adjusted subdistribution hazard ratio 2.22 [95% CI 1.22-4.03], P = 0.009). Anamorelin could be more effective in improving appetite and prolonging the duration of treatment effect in patients with a GPS of 0 or 1 than those with a GPS of 2.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"118-125"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}