Investigational New Drugs最新文献

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Targeting multiple receptor tyrosine kinases with sitravatinib: A Phase 1b study in advanced renal cell carcinoma and castrate-resistant prostate cancer. 利用西曲替尼靶向多种受体酪氨酸激酶:晚期肾细胞癌和阉割耐药前列腺癌的 1b 期研究。
IF 3 3区 医学
Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-21 DOI: 10.1007/s10637-024-01465-9
Shubham Pant, Byoung Chul Cho, Christos E Kyriakopoulos, Alexander Spira, Nizar Tannir, Theresa L Werner, Xiaohong Yan, Saskia Neuteboom, Richard Chao, Sanjay Goel
{"title":"Targeting multiple receptor tyrosine kinases with sitravatinib: A Phase 1b study in advanced renal cell carcinoma and castrate-resistant prostate cancer.","authors":"Shubham Pant, Byoung Chul Cho, Christos E Kyriakopoulos, Alexander Spira, Nizar Tannir, Theresa L Werner, Xiaohong Yan, Saskia Neuteboom, Richard Chao, Sanjay Goel","doi":"10.1007/s10637-024-01465-9","DOIUrl":"10.1007/s10637-024-01465-9","url":null,"abstract":"<p><p>Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n = 38, CRPC n = 10) received ≥ 1 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, P = 0.015 (null hypothesis [ORR ≤ 10%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. Clinical trial registration:ClinicalTrials.gov NCT02219711.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"547-558"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017445","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
Design optimization of Fucoidan-coating Cationic Liposomes for enhance Gemcitabine delivery. 优化褐藻糖胶包覆阳离子脂质体的设计,以增强吉西他滨的给药效果。
IF 3 3区 医学
Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-18 DOI: 10.1007/s10637-024-01455-x
Epiphane K Silli, Zhenjiang Zheng, Xintao Zhou, Mengfei Li, Jiali Tang, Ruizhe Guo, Chunlu Tan, Ying Wang
{"title":"Design optimization of Fucoidan-coating Cationic Liposomes for enhance Gemcitabine delivery.","authors":"Epiphane K Silli, Zhenjiang Zheng, Xintao Zhou, Mengfei Li, Jiali Tang, Ruizhe Guo, Chunlu Tan, Ying Wang","doi":"10.1007/s10637-024-01455-x","DOIUrl":"10.1007/s10637-024-01455-x","url":null,"abstract":"<p><p>Obstacles facing chemotherapeutic drugs for cancers led scientists to load Gemcitabine (GEM) into nanocarriers like liposomes, known for their nontoxicity profile and targeting capacity. The liposomal nanostructures containing GEM were coated with Fucoidan (FU) due to its anti-tumor properties by targeting cancer cells. Thus four different cationic liposomes formulations were prepared by thin-film hydration method in optimal conditions: DOTAP (formulation A); DPPC/DOTAP (4:1 molar ratio, formulation B), DPPC/DMPC/DOTAP (4:1:1 molar ratio, formulation C) and DPPC/DMPC/DOTAP/DSPE-mPEG2000 (4:1:1:0.1 molar ratio, formulation D). They were studied to identify lipid-compositions offering effective GEM-entrapment and successful coating of FU on the liposome surface. Additional qualitative characteristics, such as particle size, polydispersity index, zeta potential, stability and in vitro drug release were then evaluated. Formulation C gave the best GEM-entrapment efficiency (EE) but formed aggregates when coated with FU, giving non-homogenous large size particles then not suitable for effective delivery. It was the same situation with formulation A and B. Only the formulation D showed a good GEM-EE (> 80%) and affinity by successful coating FU from three different algae species. The PEGylated formulation D coated of FU, with regard to storage stability and drug release studies, revealed to be a promising approach on design of optimal drug delivery system.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"518-530"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995734","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
Advancements of prodrug technologies for enhanced drug selectivity in pharmacotherapies. 推进原药技术,提高药物治疗中的药物选择性。
IF 3 3区 医学
Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-13 DOI: 10.1007/s10637-024-01460-0
Helin Li, Wenjing Zhang, Qiu Meng, Qi Shuai
{"title":"Advancements of prodrug technologies for enhanced drug selectivity in pharmacotherapies.","authors":"Helin Li, Wenjing Zhang, Qiu Meng, Qi Shuai","doi":"10.1007/s10637-024-01460-0","DOIUrl":"10.1007/s10637-024-01460-0","url":null,"abstract":"<p><p>The therapeutic effects of many pharmacotherapies have been explored, but disadvantages such as low drug specificity, drug resistance and side effects makes their effective delivery to target sites a great challenge. Consequently, a distinctive prodrug-based technology have emerged as an effective treatments because of their distinctive advantages, such as high drug loading capacity, precise targeting, reduced side effects and spatial and temporal controllability. In particular, the use of gamma/X-ray-mediated strategies in radiotherapy is a new strategy that could enable the precise drug release from implanted devices. This review presents readers with the current state of prodrug therapy and reports the design protocols of rational and effective prodrugs for clinical use.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"590-600"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971105","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
Treatment response to durvalumab plus tremelimumab after progression with previous immune checkpoint inhibitor in unresectable hepatocellular carcinoma. 无法切除的肝细胞癌患者在使用前一种免疫检查点抑制剂治疗进展后,对durvalumab加tremelimumab的治疗反应。
IF 3 3区 医学
Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-30 DOI: 10.1007/s10637-024-01470-y
Nami Mori, Nobuharu Tamaki, Shintaro Takaki, Keiji Tsuji, Toshifumi Tada, Shinichiro Nakamura, Hironori Ochi, Toshie Mashiba, Masao Doisaki, Hiroyuki Marusawa, Haruhiko Kobashi, Hideki Fujii, Chikara Ogawa, Michiko Nonogi, Hirotaka Arai, Yasushi Uchida, Naohito Urawa, Ryoichi Narita, Takehiro Akahane, Masahiko Kondo, Yutaka Yasui, Kaoru Tsuchiya, Namiki Izumi, Masayuki Kurosaki
{"title":"Treatment response to durvalumab plus tremelimumab after progression with previous immune checkpoint inhibitor in unresectable hepatocellular carcinoma.","authors":"Nami Mori, Nobuharu Tamaki, Shintaro Takaki, Keiji Tsuji, Toshifumi Tada, Shinichiro Nakamura, Hironori Ochi, Toshie Mashiba, Masao Doisaki, Hiroyuki Marusawa, Haruhiko Kobashi, Hideki Fujii, Chikara Ogawa, Michiko Nonogi, Hirotaka Arai, Yasushi Uchida, Naohito Urawa, Ryoichi Narita, Takehiro Akahane, Masahiko Kondo, Yutaka Yasui, Kaoru Tsuchiya, Namiki Izumi, Masayuki Kurosaki","doi":"10.1007/s10637-024-01470-y","DOIUrl":"10.1007/s10637-024-01470-y","url":null,"abstract":"<p><p>Although immune checkpoint inhibitors (ICI) are used for unresectable hepatocellular carcinoma (HCC), it is unclear whether sequential ICI treatment-durvalumab plus tremelimumab (DT) after progression on atezolizumab plus bevacizumab (AB)-is effective for HCC. In this nationwide multicenter study, we aimed to investigate the effect of DT treatment based on the timing of treatment. A total of 85 patients receiving DT treatment were enrolled. The primary endpoint is treatment response at week 8 among patients receiving first-line DT treatment, those receiving second-line or later treatment without prior AB therapy, and those receiving second-line or later treatment with prior AB therapy. Objective response rates (ORRs) in patients with first-line treatment, second-line treatment without AB, and second-line treatment with prior AB were 44%, 54%, and 5%, respectively (p < 0.001). Similarly, disease control rates (DCRs) were 69%, 91%, and 26%, respectively (p < 0.001). ORR and DCR were significantly lower in patients with prior AB treatment. Progression free survival (PFS) was significantly shortened in patients receiving second-line therapy following prior AB treatment and an adjusted hazard ratio (95% confidence interval) in those patients for PFS, using first-line therapy as a reference, was 2.35 (1.1-5.1, p = 0.03). In conclusion, the impact of DT sequencing following AB treatment was limited. However, even after second-line treatment, the treatment effect can be equivalent to that of first-line treatment in cases with no history of AB treatment. Thus, prior treatment history should be taken into account when initiating DT treatment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"559-565"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107521","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
Broad-spectrum anti-cancer activity of fused human arginase variants. 融合人精氨酸酶变体的广谱抗癌活性。
IF 3 3区 医学
Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-20 DOI: 10.1007/s10637-024-01466-8
Yenisetti Rajendra Prasad, J Anakha, Snehal Sainath Jawalekar, Abhay H Pande
{"title":"Broad-spectrum anti-cancer activity of fused human arginase variants.","authors":"Yenisetti Rajendra Prasad, J Anakha, Snehal Sainath Jawalekar, Abhay H Pande","doi":"10.1007/s10637-024-01466-8","DOIUrl":"10.1007/s10637-024-01466-8","url":null,"abstract":"<p><p>The rapid increase in cancer cases worldwide necessitates the development of novel therapeutic approaches. Therapies targeting cancer's altered metabolism, especially those that deplete critical amino acids, have emerged as promising ones, some of which are already being used in clinical practice and many others are under development. This study reports the anti-cancer activity of two novel fused human arginase I (FHA) variants, FHA-3 and FHA-12, assessed using the NCI-60 human tumor cell line panel. Both variants have demonstrated a range of potencies in a single-dose assay (10 µM), but FHA-3 was found to be more potent with significant growth inhibition in most tested cell lines. To calculate 50% growth inhibition (GI<sub>50</sub>), FHA-3 was further evaluated in a five-dose assay, where notable anti-cancer activity was observed across the nine cancer types of the NCI-60 panel. Our results demonstrated the broad-spectrum anti-cancer activity of novel FHA variants, with FHA-3 being the most potent. Further studies elucidating its efficacy in animal models will help explore its therapeutic potential.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"531-537"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004236","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
A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors ERK抑制剂MK-8353联合pembrolizumab治疗晚期实体瘤患者的1b期研究
IF 3.4 3区 医学
Investigational New Drugs Pub Date : 2024-09-14 DOI: 10.1007/s10637-024-01461-z
Nehal J. Lakhani, Howard Burris, Wilson H. Miller, Mo Huang, Lin-Chi Chen, Lillian L. Siu
{"title":"A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors","authors":"Nehal J. Lakhani, Howard Burris, Wilson H. Miller, Mo Huang, Lin-Chi Chen, Lillian L. Siu","doi":"10.1007/s10637-024-01461-z","DOIUrl":"https://doi.org/10.1007/s10637-024-01461-z","url":null,"abstract":"<p>Combining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255690","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 characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia 尼伐单抗诱发免疫性血小板减少症的临床特征、治疗和预后
IF 3.4 3区 医学
Investigational New Drugs Pub Date : 2024-09-12 DOI: 10.1007/s10637-024-01472-w
Liping Peng, Zhaoquan Wu, Wei Sun, Chunjiang Wang
{"title":"Clinical characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia","authors":"Liping Peng, Zhaoquan Wu, Wei Sun, Chunjiang Wang","doi":"10.1007/s10637-024-01472-w","DOIUrl":"https://doi.org/10.1007/s10637-024-01472-w","url":null,"abstract":"<p>Immune thrombocytopenia (ITP) represents an uncommon hematological side effect associated with nivolumab, and its distinct clinical attributes remain poorly defined. This research aimed to explore the clinical manifestations and outcomes of ITP induced by nivolumab. Reports on nivolumab induced ITP up to April 30, 2024, were collected for retrospective analysis. The study involved 34 patients with a median age of 67 years (range 32, 82). The onset of ITP varied from 10 to 100 days post initial dosage, with a median onset at 70 days. The majority of patients exhibited no symptoms, with only 23.5% experiencing clinically significant bleeding and 11.8% facing non-clinically significant bleeding. The median platelet count was 12 × 10<sup>9</sup>/L (range 0, 115), with 67.6% of patients having platelet levels below 25 × 10<sup>9</sup>/L. Bone marrow biopsy revealed mainly elevated megakaryocytes. Platelet-associated IgG levels were elevated with a median of 210 ng/10<sup>7</sup> cells (range 73, 1130). Subsequent interventions, which included cessation of nivolumab, administration of systemic corticosteroids, intravenous immunoglobulin therapy, a thrombopoietin receptor agonist, platelet transfusion, and rituximab treatment, resulted in 82.4% of subjects achieving normalized platelet counts, whereas 5.9% passed away due to ITP. ITP is a rare life-threatening immune-related adverse event and necessitates close monitoring. Systemic steroids are the primary treatment for ITP, while intravenous immunoglobulin, thrombopoietin receptor agonist and rituximab are other options.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"280 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142213298","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
A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors 在晚期实体瘤患者中开展的普卢巴林和吉西他滨安全性和有效性 I 期临床试验
IF 3.4 3区 医学
Investigational New Drugs Pub Date : 2024-08-03 DOI: 10.1007/s10637-024-01458-8
Mohammad H. Ghalib, Mariano Provencio Pulla, Maria J. De Miguel Luken, Virginia Calvo de Juan, Imran Chaudhary, M Bakri Hammami, Sindhu Vikash, Radhashree Maitra, Sara Martinez, Carmen Kahatt, Sonia Extremera, Salvador Fudio, Sanjay Goel
{"title":"A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors","authors":"Mohammad H. Ghalib, Mariano Provencio Pulla, Maria J. De Miguel Luken, Virginia Calvo de Juan, Imran Chaudhary, M Bakri Hammami, Sindhu Vikash, Radhashree Maitra, Sara Martinez, Carmen Kahatt, Sonia Extremera, Salvador Fudio, Sanjay Goel","doi":"10.1007/s10637-024-01458-8","DOIUrl":"https://doi.org/10.1007/s10637-024-01458-8","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Summary</h3><p>Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies. This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors. Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62 years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5 mg/m<sup>2</sup>/Gem 1000 mg/m<sup>2</sup>) was the MTD. Accrual into DL7 (Plo 10.0 mg/m<sup>2</sup>/Gem 1000 mg/m<sup>2</sup>) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4 months occurred among 13 pts with ovarian cancer. The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5 mg/m<sup>2</sup>/Gem 1000 mg/m<sup>2</sup>. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"98 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141886836","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
Effect of PAWI-2 on pancreatic cancer stem cell tumors. PAWI-2 对胰腺癌干细胞肿瘤的影响
IF 3 3区 医学
Investigational New Drugs Pub Date : 2024-08-01 Epub Date: 2024-05-25 DOI: 10.1007/s10637-024-01447-x
John R Cashman, Emily A Cashman
{"title":"Effect of PAWI-2 on pancreatic cancer stem cell tumors.","authors":"John R Cashman, Emily A Cashman","doi":"10.1007/s10637-024-01447-x","DOIUrl":"10.1007/s10637-024-01447-x","url":null,"abstract":"<p><p>Worldwide, pancreatic cancer (PC) is a major health problem and almost 0.5 million people were diagnosed with PC in 2020. In the United States, more than 64,000 adults will be diagnosed with PC in 2023. PC is highly resistant to currently available treatments and standard of care chemotherapies cause serious side effects. Most PC patients are resistant to clinical therapies. Combination therapy has showed superior efficacy over single-agent treatment. However, most therapy has failed to show a significant improvement in overall survival due to treatment-related toxicity. Developing efficacious clinically useful PC therapies remains a challenge. Herein, we show the efficacy of an innovative pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) against tumors arising from human pancreatic cancer stem cells (i.e., hPCSCs, FGβ<sub>3</sub> cells). PAWI-2 is a potent inhibitor of tumor growth. In the present study, we showed PAWI-2 potently inhibited growth of tumors from hPCSCs in orthopic xenograft models of both male and female mice. PAWI-2 worked in a non-toxic manner to inhibit tumors. Compared to vehicle-treated animals, PAWI-2 modulated molecular regulators of tumors. Anti-cancer results showed PAWI-2 in vivo efficacy could be correlated to in vitro potency to inhibit FGβ<sub>3</sub> cells. PAWI-2 represents a safe, new approach to combat PC.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"353-360"},"PeriodicalIF":3.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093628","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
Radiosensitization effect of quinoline-indole-schiff base derivative 10E on non-small cell lung cancer cells in vitro and in tumor xenografts. 喹啉-吲哚-席夫碱衍生物 10E 对体外和肿瘤异种移植非小细胞肺癌细胞的放射增敏效应
IF 3 3区 医学
Investigational New Drugs Pub Date : 2024-08-01 Epub Date: 2024-06-17 DOI: 10.1007/s10637-024-01451-1
Hongwei Liu, Qianqian Wang, Wanying Lan, Duanya Liu, Jiangang Huang, Jie Yao
{"title":"Radiosensitization effect of quinoline-indole-schiff base derivative 10E on non-small cell lung cancer cells in vitro and in tumor xenografts.","authors":"Hongwei Liu, Qianqian Wang, Wanying Lan, Duanya Liu, Jiangang Huang, Jie Yao","doi":"10.1007/s10637-024-01451-1","DOIUrl":"10.1007/s10637-024-01451-1","url":null,"abstract":"<p><p>Radioresistance is an inevitable obstacle in the clinical treatment of inoperable patients with non-small cell lung cancer (NSCLC). Combining treatment with radiosensitizers may improve the efficacy of radiotherapy. Previously, the quinoline derivative 10E as new exporter of Nur77 has shown superior antitumor activity in hepatocellular carcinoma. Here, we aimed to investigate the radiosensitizing activity and acting mechanisms of 10E. In vitro, A549 and H460 cells were treated with control, ionizing radiation (IR), 10E, and 10E + IR. Cell viability, apoptosis, and cycle were examined using CCK-8 and flow cytometry assays. Protein expression and localization were examined using western blotting and immunofluorescence. Tumor xenograft models were established to evaluate the radiosensitizing effect of 10E in vivo. 10E significantly inhibited cell proliferation and increased their radiosensitivity while reducing level of p-BCRA1, p-DNA-PKs, and 53BP1 involved in the DNA damage repair pathway, indicating that its radiosensitizing activity is closely associated with repressing DNA damage repair. A549 cells showed low level of Nur77 and a low response to IR but 10E-treated A549 cells showed high level of Nur77 indicating that Nur77 is a core radiosensitivity factor and 10E restores the expression of Nur77. Nur77 and Ku80 extranuclear co-localization in the 10E-treated A549 cells suggested that 10E-modulated Nur77 nuclear exportation inhibits DNA damage repair pathways and increases IR-triggered apoptosis. The combination of 10E and IR significantly inhibits tumor growth in a tumor xenograft model. Our findings suggest that 10E acts as a radiosensitizer and that combining 10E with radiotherapy may be a potential strategy for NSCLC treatment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"405-417"},"PeriodicalIF":3.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330953","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}
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