Investigational New Drugs最新文献_第6页

Investigation of the association between therapeutic effectiveness of anamorelin and Glasgow prognostic score in patients with cancer cachexia: a competing risk analysis. 癌症恶病质患者阿纳莫瑞林治疗效果与格拉斯哥预后评分之间关系的研究：竞争风险分析。

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2025-01-09 DOI: 10.1007/s10637-024-01503-6

Kazuhiro Shimomura, Takatsugu Ogata, Akimitsu Maeda, Yukiya Narita, Hiroya Taniguchi, Kenta Murotani, Yutaka Fujiwara, Masahiro Tajika, Kazuo Hara, Kei Muro, Kosaku Uchida

{"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":"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.","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}

引用次数: 0

5-Fluorouracil-methotrexate conjugate enhances the efficacy of 5-fluorouracil in colorectal cancer therapy. 5-氟尿嘧啶-甲氨蝶呤缀合物可提高5-氟尿嘧啶治疗结直肠癌的疗效。

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2024-12-21 DOI: 10.1007/s10637-024-01488-2

Siyuan Zhao, Tiansi Wang, Kourong Shi, Ting Li, Qiuzhen Zhu, Yuan Li, Beiwei Xin, Xin Wu, Wei Fan

{"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":"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.","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}

引用次数: 0

Efficacy and safety of multi-target tyrosine kinase inhibitor AL2846 combined with gemcitabine in pancreatic cancer. 多靶点酪氨酸激酶抑制剂AL2846联合吉西他滨治疗胰腺癌的疗效和安全性

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1007/s10637-024-01485-5

Rui Liu, Zhi Ji, Xia Wang, Jiaqi Xin, Lila Zhu, Shaohua Ge, Le Zhang, Ming Bai, Tao Ning, Yuchong Yang, Hongli Li, Ting Deng, Yi Ba

{"title":"Efficacy and safety of multi-target tyrosine kinase inhibitor AL2846 combined with gemcitabine in pancreatic cancer.","authors":"Rui Liu, Zhi Ji, Xia Wang, Jiaqi Xin, Lila Zhu, Shaohua Ge, Le Zhang, Ming Bai, Tao Ning, Yuchong Yang, Hongli Li, Ting Deng, Yi Ba","doi":"10.1007/s10637-024-01485-5","DOIUrl":"10.1007/s10637-024-01485-5","url":null,"abstract":"Pancreatic cancer patients urgently need new treatments, and we explored the efficacy and safety of combination therapy with AL2846 and gemcitabine in pancreatic cancer patients. This was a single-arm, single-center, open-label phase I/IIa study (NCT06278493). The dose-escalation phase was designed to evaluate the maximum tolerated dose (MTD) of AL2846 combined with gemcitabine. One or two dose levels were chosen for the dose-expansion phase. Treatment continued until disease progression, intolerable toxicity, patient withdrawal, or at the investigators' discretion. The primary study endpoint is to evaluate the safety and MTD of AL2846 combined with gemcitabine. The secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and disease control rate (DCR). Between August 2018 and July 2021, 33 pancreatic cancer patients were enrolled in the study. A total of 15 patients were enrolled in the dose-escalation phase, and the MTD was not determined. Eventually 90 mg and 120 mg of AL2846 were chosen for the dose-expansion phase, in which 11 patients (90 mg) and 7 patients (120 mg) were administered. Treatment-related adverse events (TRAEs) of any grade were reported in 30 (90.91%) patients, and those of grade ≥ 3 were reported in 16 (48.48%) patients. The most frequently reported grade ≥ 3 TRAEs were thrombocytopenia (18.18%), neutropenia (12.12%), elevated γ-glutamyltransferase (6.06%), proteinuria (6.06%), and gastrointestinal hemorrhage (6.06%).The ORR was 6.06%, and the DCR was 72.73%. The median PFS was 3.71 months (95% CI: 3.38-4.11), and the median OS was 5.59 months (95% CI: 4.11-8.71). Gemcitabine and Al2846 combination therapy exhibited tolerable safety, but there was no improvement in efficacy over standard treatment. Further evaluation of this approach is still needed.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"81-92"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931704","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}

引用次数: 0

Deficiency of myeloid discoidin domain receptor 2 aggravates melanoma lung and bone metastasis. 髓样盘状蛋白结构域受体2缺乏可加重黑色素瘤肺和骨转移。

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2024-12-26 DOI: 10.1007/s10637-024-01496-2

Yue Sun, Liangliang Wei, Hao Liu, Gaoyang Zong, Zhihao Xia, Xiangyang Li, Zhanhai Yin, Dageng Huang, Yan Zhang

{"title":"Deficiency of myeloid discoidin domain receptor 2 aggravates melanoma lung and bone metastasis.","authors":"Yue Sun, Liangliang Wei, Hao Liu, Gaoyang Zong, Zhihao Xia, Xiangyang Li, Zhanhai Yin, Dageng Huang, Yan Zhang","doi":"10.1007/s10637-024-01496-2","DOIUrl":"10.1007/s10637-024-01496-2","url":null,"abstract":"Melanoma, one of the most prevalent cancers worldwide, frequently metastasizes to the lung and bones. Tumor-associated macrophages play essential roles in melanoma metastasis but the underlying mechanism remains obscure. We previously demonstrated that specific knockout of Ddr2, a receptor tyrosine kinase, exacerbates systemic inflammation via modulating macrophage repolarization. To investigate whether myeloid Ddr2 regulates melanoma growth and metastasis, we injected B16BL6 melanoma cells into Ddr2LysM (cKO) mice via subcutaneous neck, tail vein, and left ventricle, respectively. We found that the growth of melanoma cells in cKO mice was significantly retarded, as demonstrated by the subcutaneous transplantation tumor model. Unexpectedly, the melanoma metastasis to the lung or bone was significantly stimulated in cKO mice, indicating the complicated role of Ddr2 in macrophages in melanoma development. Furthermore, Ddr2 in macrophages regulated the migration of B16BL6 cells in the co-culture system. Bioinformatics analysis showed that Ddr2 expression correlates with improved prognostic outcomes in melanoma, and high expression of Ddr2 is protective in melanoma metastasis. Our results enrich the current knowledge of Ddr2 in tumor biology and indicate that more consideration should be taken when applying Ddr2 inhibition as a melanoma treatment strategy.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"50-59"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894717","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}

引用次数: 0

Clinical features, treatment, and prognosis of pembrolizumab -induced Stevens-Johnson syndrome / toxic epidermal necrolysis. 派姆单抗诱导的Stevens-Johnson综合征/中毒性表皮坏死松解症的临床特征、治疗和预后

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2025-01-03 DOI: 10.1007/s10637-024-01499-z

Zhaoquan Wu, Xiting Li, Rui Huang, Binsheng He, Chunjiang Wang

{"title":"Clinical features, treatment, and prognosis of pembrolizumab -induced Stevens-Johnson syndrome / toxic epidermal necrolysis.","authors":"Zhaoquan Wu, Xiting Li, Rui Huang, Binsheng He, Chunjiang Wang","doi":"10.1007/s10637-024-01499-z","DOIUrl":"10.1007/s10637-024-01499-z","url":null,"abstract":"The understanding of pembrolizumab-induced Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) primarily derives from case reports, leaving specific clinical features largely unknown. This study aims to investigate the clinical characteristics associated with pembrolizumab-induced SJS/TEN and to encourage the judicious use of pembrolizumab. Retrieve reports on pembrolizumab induced SJS/TEN before September 30, 2024 for retrospective analysis. Twenty-four (57.1%) and 18 (42.9%) patients were enrolled, with a median age of 65 years (range 32, 81). The median time to onset of SJS/TEN was 15 days (range 2, 180), and the median cycle was 1 cycle (range 1, 9). The most prevalent skin symptoms included erythema (66.7%), rash (64.3%), bullae/blisters (50.0%), and epidermal detachment (42.9%). Skin biopsy findings primarily revealed epidermal necrosis (42.9%), keratinocyte necrosis (35.7%), subepidermal bulla/blister (19.0%), and perivascular inflammatory cell infiltration (47.6%). Following the cessation of the drug and subsequent treatment, 85.7% of patients showed symptom improvement, while 14.3% succumbed to the condition. SJS/TEN represents a rare but potentially fatal adverse reaction to pembrolizumab. Clinicians should consider SJS/TEN in patients presenting with fever, erythematous rash, or mucosal involvement. Timely identification and management of SJS/TEN can significantly reduce morbidity and mortality.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"74-80"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921615","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}

引用次数: 0

Immunotherapy in thymic epithelial tumors: an attractive dilemma. 胸腺上皮肿瘤的免疫治疗：一个吸引人的困境。

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1007/s10637-024-01497-1

Nahed Damaj, Dany Nassar, Bilal Chamaa, Joseph Kattan

{"title":"Immunotherapy in thymic epithelial tumors: an attractive dilemma.","authors":"Nahed Damaj, Dany Nassar, Bilal Chamaa, Joseph Kattan","doi":"10.1007/s10637-024-01497-1","DOIUrl":"10.1007/s10637-024-01497-1","url":null,"abstract":"Thymomas and thymic carcinomas are the most prevalent tumors that develop in the thymus's epithelial tissue. Thymomas are malignant tumors that develop from the epithelial cells of the thymus and frequently include mixed populations of lymphocytes. In contrast, thymic carcinomas are also tumors of the thymic epithelium, but they are characterized by a lack of lymphocytes, exhibit more aggressive behavior, and are associated with a poorer prognosis. Surgical intervention is the primary approach for managing resectable cases, while advanced, unresectable tumors are treated with platinum-based chemotherapy. The recurrence of the disease can happen months to years after initial treatment. Some patients do benefit from biologic therapies, but there is still a significant need for new treatment options. Immune checkpoint inhibitors have proven safe and clinically effective, improving survival in various cancers. However, their use in thymic cancers is currently limited to treating recurrent thymic carcinoma due to potential immune toxicity risks. This manuscript reviews the current applications of immunotherapy for thymic epithelial tumors and discusses strategies to enhance safety and expand treatment options for patients with these cancers.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"69-73"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921617","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}

引用次数: 0

Comprehensive study of gene fusions in sarcomas. 肉瘤基因融合综合研究。

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2024-12-16 DOI: 10.1007/s10637-024-01486-4

Nan Chen, Qin Zhang, Lei Sun, Xia You, Siqi Chen, Dongsheng Chen, Fengkun Yang

{"title":"Comprehensive study of gene fusions in sarcomas.","authors":"Nan Chen, Qin Zhang, Lei Sun, Xia You, Siqi Chen, Dongsheng Chen, Fengkun Yang","doi":"10.1007/s10637-024-01486-4","DOIUrl":"10.1007/s10637-024-01486-4","url":null,"abstract":"Sarcomas, including bone sarcomas and soft tissue sarcomas (STSs), are a heterogeneous group of mesenchymal malignancies. Recent advancements in next-generation sequencing (NGS) have enabled the identification of novel chromosomal translocations and fusion genes, which play a critical role in sarcoma subtypes. Our study focuses on gene fusions in sarcomas among Chinese patients, comparing their genomic profiles to those of Western populations. We analyzed 1048 sarcoma samples from Chinese patients using a panel of over 500 genes, identifying 481 gene fusions in 329 patients. The most common fusions included EWSR1, HMGA2, and SS18, with notable subtype-specific fusions such as EWSR1-FLI1 in Ewing sarcoma and NAB2-STAT6 in solitary fibrous tumors. In comparison to Chinese and Western populations, variations in fusion spectrum exist, potentially necessitating distinct treatment strategies; however, further validation of these fusions is warranted. Our findings highlight the importance of gene fusions as diagnostic markers and potential therapeutic targets. Actionable fusions, including kinase-related fusions like ALK, NTRK3, and BRAF, were detected in 67 patients (6.4%) and may guide precision therapies. Additionally, we observed the frequent co-occurrence of genomic alterations, particularly in cell cycle regulators such as CDK4 and MDM2. Genomic profiling of sarcomas offers valuable insights into their molecular drivers and can support personalized therapeutic approaches. Further research is needed to validate these findings and optimize treatment strategies for sarcoma patients.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"3-17"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828555","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}

引用次数: 0

Targeting MYC for the treatment of breast cancer: use of the novel MYC-GSPT1 degrader, GT19630. 靶向MYC治疗乳腺癌：使用新型MYC- gspt1降解物GT19630。

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2025-01-28 DOI: 10.1007/s10637-024-01504-5

Minhong Tang, John Crown, Michael J Duffy

{"title":"Targeting MYC for the treatment of breast cancer: use of the novel MYC-GSPT1 degrader, GT19630.","authors":"Minhong Tang, John Crown, Michael J Duffy","doi":"10.1007/s10637-024-01504-5","DOIUrl":"10.1007/s10637-024-01504-5","url":null,"abstract":"Background: Since MYC is one of the most frequently altered driver genes involved in cancer formation, it is a potential target for new anti-cancer therapies. Historically, however, MYC has proved difficult to target due to the absence of a suitable crevice for binding potential low molecular weight drugs.Objective: The aim of this study was to evaluate a novel molecular glue, dubbed GT19630, which degrades both MYC and GSPT1, for the treatment of breast cancer.Methods: The antiproliferative potential of GT19630 was evaluated in 14 breast cancer cell lines representing the main molecular subtypes of breast cancer. In addition, we also investigated the effects of GT19630 on apoptosis, cell cycle progression, cell migration, and degradation of the negative immune checkpoint protein, B7-H3.Results: GT19630 inhibited cell proliferation, blocked cell cycle progression, promoted apoptosis, and decreased cell migration at low nanomolar concentrations in breast cancer cell lines. By contrast, previously described MYC inhibitors such as specific MYC-MAX antagonists affected these processes at micromolar concentrations. Consistent with the ability of MYC to promote immune evasion, we also found that GT19630 degraded the negative immune checkpoint inhibitor, B7-H3.Conclusions: We conclude that the novel molecular glue, GT19630, is a potent mediator of endpoints associated with cancer formation/progression. Its ability to degrade B7-H3 suggests that GT19630 may also promote host immunity against cancer. To progress GT19630 as a therapy for breast cancer, our finding should now be confirmed in an animal model system.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"167-179"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Linifanib alone and in combination with metronomic chemotherapy is active on cutaneous T-cell lymphoma cells by targeting the AKT/mTOR signaling pathway. 利尼法尼单用和联合节律化疗通过靶向AKT/mTOR信号通路对皮肤t细胞淋巴瘤细胞有活性。

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2025-01-17 DOI: 10.1007/s10637-024-01501-8

Marta Banchi, Maria Christina Cox, Arianna Bandini, Paola Orlandi, Costanza Tacchi, Fabio Stefanelli, Silvio Chericoni, Guido Bocci

{"title":"Linifanib alone and in combination with metronomic chemotherapy is active on cutaneous T-cell lymphoma cells by targeting the AKT/mTOR signaling pathway.","authors":"Marta Banchi, Maria Christina Cox, Arianna Bandini, Paola Orlandi, Costanza Tacchi, Fabio Stefanelli, Silvio Chericoni, Guido Bocci","doi":"10.1007/s10637-024-01501-8","DOIUrl":"10.1007/s10637-024-01501-8","url":null,"abstract":"Cutaneous T-cell lymphomas (CTCLs) are a rare and heterogeneous subset of skin-localized, non-Hodgkin lymphomas. Our aim was to evaluate the in vitro antitumor activity of the multi-kinase inhibitor linifanib, either alone or in combination with metronomic vinorelbine (mVNR) or etoposide (mETO), on CTCL cells. In vitro proliferation assay and Luminex analysis showed that long-term, daily exposure of linifanib significantly inhibited the proliferation of the human CTCL cell line HH, in a concentration-dependent manner (IC50 = 48.4 ± 20.4 nM) and the phosphorylation of AKT/mTOR signaling pathway. The concomitant exposure of linifanib plus mVNR or mETO resulted in a strong synergism, with combination index values < 1. Linifanib significantly increased the VNR and ETO intracellular concentrations in HH cells, evaluated by UPLC-HRMS technology, and strongly reduced the ABCB1 and ABCG2 gene expression in HH. In conclusion, we reported a striking antitumor activity of daily, long-term linifanib and a clear synergistic effect when administered in combination with mCHEMO on CTCL cells, as a promising base for future clinical approaches in T-cell lymphomas.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"135-146"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005378","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}

引用次数: 0

Lenvatinib plus immunotherapy versus lenvatinib monotherapy in lenvatinib-insensitive patients with unresectable hepatocellular carcinoma: a retrospective study. Lenvatinib联合免疫治疗与Lenvatinib单药治疗对Lenvatinib不敏感的不可切除肝细胞癌患者：一项回顾性研究

IF 3 3区医学

Investigational New Drugs Pub Date : 2025-02-01 Epub Date: 2025-01-07 DOI: 10.1007/s10637-024-01502-7

Zeyu Yu, Bin Leng, Ran You, Chendong Wang, Lingfeng Diao, Qingyu Xu, Guowen Yin

{"title":"Lenvatinib plus immunotherapy versus lenvatinib monotherapy in lenvatinib-insensitive patients with unresectable hepatocellular carcinoma: a retrospective study.","authors":"Zeyu Yu, Bin Leng, Ran You, Chendong Wang, Lingfeng Diao, Qingyu Xu, Guowen Yin","doi":"10.1007/s10637-024-01502-7","DOIUrl":"10.1007/s10637-024-01502-7","url":null,"abstract":"Purpose: The combination therapy of lenvatinib and immunotherapy as first-line treatment remains controversial in unresectable hepatocellular carcinoma (uHCC). This research aimed to compare the efficacy and safety of lenvatinib monotherapy (L) and combination therapy of lenvatinib and immune checkpoint inhibitor (LI) in lenvatinib-insensitive patients with uHCC.Methods: Two hundred fifty-five uHCC patients were enrolled in this study. Patients were classified into two groups: (1) Lenvatinib monotherapy (L); (2) Combination therapy (LI). Patients who remained stable disease (SD) but did not achieve complete response (CR) or partial response (PR) or progression disease (PD) for at least 3 months after receiving lenvatinib monotherapy were defined as lenvatinib-insensitive. Overall survival (OS) and progression-free survival (PFS), baseline characteristics, and safety were compared between groups.Results: The LI group had longer OS (15.9 months vs. 11.9 months, P = 0.001) and PFS (12.6 months vs. 7.3 months, P < 0.001) than the L group. ECOG PS was an independent prognostic factor affecting OS and Up-to-seven was an independent prognostic factor affecting PFS. The frequency of grade ≥ 3 treatment-related adverse events (TRAEs) was not significantly different.Conclusions: Our study demonstrated that the combination therapy (LI) had longer OS and PFS than the lenvatinib monotherapy (L) in lenvatinib-insensitive patients with uHCC.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"43 1","pages":"93-100"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0