Investigational New Drugs最新文献_第8页

Rucaparib induces mitochondrial fragmentation and apoptosis in prostate cancer cells by targeting Drp1. Rucaparib通过靶向Drp1诱导前列腺癌细胞线粒体断裂和凋亡。

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-09-21 DOI: 10.1007/s10637-025-01586-9

Xiaodong Lu, Yishu Lin, Hao Tang, Zhigang Chen, Kewei Tang

{"title":"Rucaparib induces mitochondrial fragmentation and apoptosis in prostate cancer cells by targeting Drp1.","authors":"Xiaodong Lu, Yishu Lin, Hao Tang, Zhigang Chen, Kewei Tang","doi":"10.1007/s10637-025-01586-9","DOIUrl":"10.1007/s10637-025-01586-9","url":null,"abstract":"Mitochondrial dynamics, particularly the balance between fission and fusion, are critical in regulating cellular metabolism, apoptosis, and cancer progression. Dysregulation of this balance contributes to tumor survival and therapeutic resistance in castration-resistant prostate cancer (CRPC). Rucaparib, a clinically approved poly (ADP-ribose) polymerase (PARP) inhibitor, is primarily known for its role in DNA damage repair; however, its impact on mitochondrial function remains largely unexplored. In this study, we demonstrate that Rucaparib induces significant cytotoxicity and apoptosis in PC-3 CRPC cells in a time- and concentration-dependent manner, characterized by increased Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 activation. Mechanistically, Rucaparib disrupts mitochondrial integrity by reducing mitochondrial membrane potential (MMP), inhibiting Complex IV activity, and depleting ATP levels. Confocal imaging and biochemical assays reveal that Rucaparib triggers mitochondrial fragmentation by promoting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and enhancing its translocation to mitochondria. This process is accompanied by elevated intracellular Ca2+ levels and activation of calcium/calmodulin-dependent protein kinase II (CaMKII), suggesting a Ca2⁺/CaMKII/Drp1 signaling axis. Importantly, pharmacological inhibition of CaMKII with KN-93 reverses Drp1 mitochondrial translocation, restores mitochondrial morphology, and partially rescues ATP production, confirming the functional role of CaMKII in Rucaparib-induced mitochondrial dysfunction. These findings uncover a previously unrecognized mechanism of Rucaparib action beyond DNA repair inhibition, highlighting its ability to target mitochondrial dynamics and bioenergetics through Ca2+/CaMKII/Drp1 signaling. Our results provide new insights into the multifaceted anticancer mechanisms of Rucaparib and suggest that modulation of mitochondrial fission may offer a promising therapeutic avenue for CRPC.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"968-980"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102962","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

Anti-CD47 tri-specific killer engager enhances NK cell cytotoxicity against lung cancer. 抗cd47三特异性杀手接合物增强NK细胞对肺癌的细胞毒性。

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-08-12 DOI: 10.1007/s10637-025-01568-x

Chutipa Chiawpanit, Yupanun Wutti-In, Somsakul Pop Wongpalee, Ratchaneewan Sumankan, Peeranut Winidmanokul, Prin Sungwan, Seiji Okada, Naravat Poungvarin, Pa-Thai Yenchitsomanus, Aussara Panya

{"title":"Anti-CD47 tri-specific killer engager enhances NK cell cytotoxicity against lung cancer.","authors":"Chutipa Chiawpanit, Yupanun Wutti-In, Somsakul Pop Wongpalee, Ratchaneewan Sumankan, Peeranut Winidmanokul, Prin Sungwan, Seiji Okada, Naravat Poungvarin, Pa-Thai Yenchitsomanus, Aussara Panya","doi":"10.1007/s10637-025-01568-x","DOIUrl":"10.1007/s10637-025-01568-x","url":null,"abstract":"Lung cancer remains the leading cause of cancer-related deaths worldwide, with immune evasion posing a major therapeutic challenge. One key mechanism involves the 'don't eat me' signal mediated by the interaction between CD47 and signal regulatory protein alpha (SIRPα), which inhibits macrophage phagocytosis and natural killer (NK) cell cytotoxicity, facilitating tumor escape. To overcome this immune evasion, we developed a tri-specific killer engager (TriKE) targeting CD47, termed anti-CD47 TriKE, designed to enhance NK cell-mediated cytotoxicity against lung cancer cells. The activity of anti-CD47 TriKE was evaluated for its ability to induce NK cell proliferation and its binding affinity to NK cells and lung cancer cell lines (A549, NCI-H460, and NCI-H1975). At a concentration of 30 nM, anti-CD47 TriKE effectively promoted NK cell proliferation and exhibited strong binding to both NK cells and lung cancer cells. Functional assays in 2D and 3D co-culture models demonstrated that anti-CD47 TriKE significantly enhanced NK cell specificity and cytotoxicity. Notably, NK cell-mediated cytotoxicity correlated with the basal level of CD47 expression in target cells. In NCI-H1975 cells, which exhibit the highest CD47 expression, target cell viability was reduced by approximately 40%-a significantly greater reduction than in control groups. These findings highlight the potential of anti-CD47 TriKE as a promising immunotherapeutic strategy for lung cancer, particularly in targeting high-CD47-expressing tumor cells and overcoming immune evasion mechanisms.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"874-884"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821385","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

Assessing the risks and benefits of investigational new drugs in adult phase-I oncology trials in China, 2013-2021. 2013-2021年中国成人肿瘤i期临床试验新药的风险和获益评估

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-08-22 DOI: 10.1007/s10637-025-01560-5

Zhizhou Liang, Yu Yang, Yichen Zhang, Kexin Han, Huangqianyu Li, Luwen Shi, Xiaodong Guan

{"title":"Assessing the risks and benefits of investigational new drugs in adult phase-I oncology trials in China, 2013-2021.","authors":"Zhizhou Liang, Yu Yang, Yichen Zhang, Kexin Han, Huangqianyu Li, Luwen Shi, Xiaodong Guan","doi":"10.1007/s10637-025-01560-5","DOIUrl":"10.1007/s10637-025-01560-5","url":null,"abstract":"Previous research shows that the benefits of phase-I oncology trials increased from 5 to 18% between 2000 and 2019 globally. However, the risk-benefit profile of phase-I trials in China is unclear. This study aims to analyze the risk-benefit profile of phase-I oncology trials in China and explore their correlation. We included adult phase-I oncology trials registered on the Chinese Clinical Trial Registry and Information Disclosure Platform between September 2013 and December 2021. Data on response rates and grade-3/4 adverse events were retrieved from PubMed, Google Scholar, and CNKI to assess their correlation. A total of 189 trials with 9591 patients were analyzed. The median response rate was 25.4% (IQR, 9.4-41.4%), and the overall incidence of grade-3/4 adverse events was 29.3% (IQR, 15.0-43.8%). No significant trends were observed over time. Subgroup analysis showed higher response rates in lymphoma (45.8%), cell therapies (80.0%), and biomarker trials (38.0%). Higher adverse event rates were seen in breast cancer (55.0%), chemical drugs (33.3%), cytotoxic drugs (73.3%), and combination therapies (35.7%). A weak correlation was found between response rates and grade-3/4 adverse events (ρ = 0.217; p = 0.003), with a moderate correlation in immunotherapy (ρ = 0.417; p < 0.001). This is the first assessment of early efficacy and safety signals of phase-I oncology trials in China. No significant temporal trends were identified. However, the correlation in immunotherapy suggests that higher benefits may be accompanied by greater risks.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1062-1069"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954457","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

Addressing the drug development challenge for rare pediatric diseases in Japan: a case study of isotretinoin. 应对日本罕见儿科疾病的药物开发挑战：异维甲酸的案例研究。

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-07-22 DOI: 10.1007/s10637-025-01566-z

Shota Inoue, Akihiko Ozaki, Hayase Hakariya, Jungang Zhao, Ivan D Florez, Yoshihiko Morikawa, Tetsuya Tanimoto

{"title":"Addressing the drug development challenge for rare pediatric diseases in Japan: a case study of isotretinoin.","authors":"Shota Inoue, Akihiko Ozaki, Hayase Hakariya, Jungang Zhao, Ivan D Florez, Yoshihiko Morikawa, Tetsuya Tanimoto","doi":"10.1007/s10637-025-01566-z","DOIUrl":"10.1007/s10637-025-01566-z","url":null,"abstract":"Drug lag in rare pediatric diseases remains a significant challenge in Japan despite its sophisticated healthcare system. We examined this issue through a case study of isotretinoin, an established standard drug for high-risk neuroblastoma (affecting 45-60 new patients annually in Japan) since the 2000s that has not been granted regulatory approval in Japan as of 2025. Analysis of regulatory documents and clinical practices revealed that while isotretinoin has demonstrated improved event-free survival rates in international trials when used as maintenance therapy for high-risk neuroblastoma, multiple barriers have hindered its domestic approval. These include the challenges of conducting clinical trials in limited pediatric populations, substantial development costs, diminishing market attractiveness due to Japan's demographic shift, and restrictions on \"mixed billing system\" which means combining covered insurance treatments with uncovered treatments under the universal health insurance system in Japan. Currently, patients must rely on costly private imports or clinical trial participation to access the drug, leading to financial burdens and treatment discontinuation risks. Recent regulatory reforms, including the establishment of the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs in 2009 and amendments enabling investigator-led trials, have facilitated progress. An investigator-led Phase II clinical trial evaluating isotretinoin's safety and efficacy is ongoing since 2023, with expected completion in 2026. However, the lengthy timeline of approximately 25 years from global adoption to potential approval highlights persistent challenges in pediatric drug development and Japan's isolation from global drug development networks. This case demonstrates the need for innovative policy approaches to ensure sustainable drug development for rare pediatric diseases in an aging society.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"757-763"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690221","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

The multifaceted role of KIF15 in cancer progression and therapy. KIF15在癌症进展和治疗中的多方面作用。

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-08-16 DOI: 10.1007/s10637-025-01572-1

Sarah Qutayba Badraldin, Karar H Alfarttoosi, Hayder Naji Sameer, Ashok Kumar Bishoyi, Subbulakshmi Ganesan, Aman Shankhyan, Subhashree Ray, Ahmed Yaseen, Zainab H Athab, Mohaned Adil

{"title":"The multifaceted role of KIF15 in cancer progression and therapy.","authors":"Sarah Qutayba Badraldin, Karar H Alfarttoosi, Hayder Naji Sameer, Ashok Kumar Bishoyi, Subbulakshmi Ganesan, Aman Shankhyan, Subhashree Ray, Ahmed Yaseen, Zainab H Athab, Mohaned Adil","doi":"10.1007/s10637-025-01572-1","DOIUrl":"10.1007/s10637-025-01572-1","url":null,"abstract":"Kinesin family member 15 (KIF15), a kinesin superfamily motor protein, is known to be involved in mitotic spindle formation and chromosome movement during cell division. Recent research has determined KIF15 to be a crucial regulator in several oncogenic pathways and proposed that its role may extend beyond mere cell mechanics. Aberrant KIF15 expression has also been found to be involved in the onset of numerous cancers by promoting the proliferation, migration, and invasive abilities of cancer cells, thereby leading to increased metastatic capability. This review summarizes knowledge of the complex roles of KIF15 in cancer biology, highlighting its regulatory functions and interactions with key signaling pathways that control cell cycle kinetics and mechanisms for tumorigenesis. Moreover, the elevated levels of KIF15 in certain types of cancer make it an amenable target for therapy. New directions toward inhibiting activity or reducing the levels of KIF15 promise to restrict tumor growth, offering new hope for cancer treatment. This combined understanding of KIF15 functions stresses its importance not only in the fundamental processes of cell division but also in the developing field of cancer treatment, highlighting the ongoing necessity for extensive research into creating effective treatments targeted against KIF15 in oncology.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1022-1042"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859137","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

Synergistic effects of the curcumin analog HO-3867 and olaparib in transforming fallopian tube epithelial cells. 姜黄素类似物HO-3867和奥拉帕尼在输卵管上皮细胞转化中的协同作用。

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-08-04 DOI: 10.1007/s10637-025-01571-2

Cai-Chieh Tseng, Min-Hsi Ku, Wei-Min Wu, Ava Mendez, Tessa Christner, Yun-Chieh Wu, Wei-Lun Huang, Yu-Hsiang Chen, Ching-Wen Huang, Johnathan Barefoot, Chi-Wei Chen

{"title":"Synergistic effects of the curcumin analog HO-3867 and olaparib in transforming fallopian tube epithelial cells.","authors":"Cai-Chieh Tseng, Min-Hsi Ku, Wei-Min Wu, Ava Mendez, Tessa Christner, Yun-Chieh Wu, Wei-Lun Huang, Yu-Hsiang Chen, Ching-Wen Huang, Johnathan Barefoot, Chi-Wei Chen","doi":"10.1007/s10637-025-01571-2","DOIUrl":"10.1007/s10637-025-01571-2","url":null,"abstract":"Ovarian cancer remains one of the most lethal gynecologic malignancies, largely due to high recurrence rates and treatment-related toxicities. Although PARP inhibitors like Olaparib have shown efficacy in BRCA-mutated cancers, their benefit is limited in broader patient populations. TP53 mutations, highly prevalent in ovarian cancer, promote tumor progression and resistance, making p53 a key therapeutic target. This study evaluated the anticancer potential of HO-3867, a curcumin analog known to restore mutant p53 function, alone and in combination with Olaparib. We used fallopian tube-derived ovarian cancer models harboring mutant or null TP53 and analyzed TP53 expression and mutation profiles using TCGA datasets. Molecular docking simulations and cellular thermal shift assays (CETSA) confirmed HO-3867 binding to the p53Y220C mutant core domain. Cytotoxicity was assessed via SRB assays; flow cytometry and Western blotting were used to examine cell cycle progression, apoptosis, and DNA damage. HO-3867 treatment increased phospho-p53 (Ser15) and p21 expression, induced G1 phase arrest, and suppressed cell viability. Notably, co-treatment with Olaparib synergistically enhanced apoptosis, as indicated by increased caspase-3 and PARP1 cleavage and elevated γH2AX levels. These findings suggest that HO-3867 reactivates mutant p53 and potentiates Olaparib efficacy by promoting apoptosis and amplifying DNA damage, offering a promising therapeutic strategy for TP53-mutant ovarian cancer.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"857-873"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784325","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

Targeting neuroblastoma with hydroxamic acid based HDAC1 and HDAC2 inhibitors: Insights from in vitro and in vivo studies. 基于羟肟酸的HDAC1和HDAC2抑制剂靶向神经母细胞瘤：来自体外和体内研究的见解

IF 2.7 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-07-10 DOI: 10.1007/s10637-025-01559-y

Padmini Pai, Yashaswini Reddy, Ipshita Das, Babu Santhi Venkidesh, Poonam Bhandari, Pallavi Rao, Srinivas Oruganti, Keshava Prasad, Manasa Gangadhar Shetty, Kapaettu Satyamoorthy, Babitha Kampa Sundara

{"title":"Targeting neuroblastoma with hydroxamic acid based HDAC1 and HDAC2 inhibitors: Insights from in vitro and in vivo studies.","authors":"Padmini Pai, Yashaswini Reddy, Ipshita Das, Babu Santhi Venkidesh, Poonam Bhandari, Pallavi Rao, Srinivas Oruganti, Keshava Prasad, Manasa Gangadhar Shetty, Kapaettu Satyamoorthy, Babitha Kampa Sundara","doi":"10.1007/s10637-025-01559-y","DOIUrl":"10.1007/s10637-025-01559-y","url":null,"abstract":"Histone deacetylases (HDACs) serve a crucial function in transcription regulation, and their dysregulation is linked to numerous diseases, including cancer. Among them, HDAC1 and HDAC2 are particularly significant in neural progenitors and are frequently overexpressed in neural-derived cancers. HDAC inhibitors (HDACis) have shown promise in overcoming chemoresistance by restoring tumor suppressor function in neuroblastoma cells. However, the lack of selectivity in existing HDACis presents challenges, highlighting the need for isoform-selective inhibitors to reduce side effects. This research investigated the anticancer properties of a newly synthesized hydroxamic acid derivative, emphasizing its selective HDAC1 and HDAC2 inhibition and strong antitumor activity. Our findings demonstrated that the newly developed hydroxamic acid analogues, 3A and 3B, effectively inhibited neuroblastoma cells (SH-SY5Y) proliferation, with IC50 values of 8.49 µM and 4.44 µM, respectively, comparable to suberoylanilide hydroxamic acid (SAHA) with IC50 of 0.91 µM. Additionally, compounds 3A and 3B exhibited potent HDAC inhibition. Compound 3A selectively inhibited HDAC2 with an IC50 value of 0.89 μM, while compound 3B showed dual inhibition of HDAC1 and HDAC2, with IC50 values of 0.44 μM and 1.94 μM, respectively. Compound 3B triggered cell cycle arrest in the G2/M phase, reduced colony formation efficiency, and altered cellular architecture upon treatment, further highlighting its anticancer potential. In an in vivo xenograft model, compound 3B significantly decreased tumor growth and tumor weight, highlighting its potential as an effective anticancer agent for neuroblastoma, offering both isoform-selective HDAC inhibition and potent anticancer effects.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"780-791"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608370","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

Direct functional HOXA9/DNA-binding competitors versus epigenetic inhibitors of HOXA9 expression on cell proliferation, death and differentiation processes in the model of MLL-rearranged acute myeloid leukemia. 直接功能性HOXA9/ dna结合竞争者与HOXA9表达的表观遗传抑制剂对mll重排急性髓系白血病模型中细胞增殖、死亡和分化过程的影响

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-08-04 DOI: 10.1007/s10637-025-01561-4

Julie Vrevin, Mélanie Lambert, Marine Andrique, Nathalie Jouy, Marie-Hélène David-Cordonnier

{"title":"Direct functional HOXA9/DNA-binding competitors versus epigenetic inhibitors of HOXA9 expression on cell proliferation, death and differentiation processes in the model of MLL-rearranged acute myeloid leukemia.","authors":"Julie Vrevin, Mélanie Lambert, Marine Andrique, Nathalie Jouy, Marie-Hélène David-Cordonnier","doi":"10.1007/s10637-025-01561-4","DOIUrl":"10.1007/s10637-025-01561-4","url":null,"abstract":"Recent progress in cancer treatment has led to the development of advanced therapies targeting specific oncogenic drivers, with, for instance, new small molecule-targeted agents, antibody-drug conjugates, peptide drugs, cell-based, or gene therapies. The key target may be either the mutated/fused protein itself or a protein whose expression is directly dysregulated and involved in proliferation, resistance to cell death, or other cellular processes associated with the oncogenic process. Identifying the best therapeutic strategy requires evaluating both inhibitors of the altered protein and the dysregulated oncogene linked to the pathology. Within this context, the MLL-rearranged subtype (MLL-r) of acute myeloid leukemia (AML) poses significant challenges due to unfavorable prognosis, frequent relapses, and treatment resistance. MLL-r AMLs are known to be addicted to the oncogene transcription factor HOXA9, with a differentiation blockade that relies on its ability to bind DNA. Recently, several MLL-r epigenetic complex inhibitors have been developed, some entering clinical trials. We identified and optimized two HOXA9 functional inhibitors, DB818 and DB1055, operating at the DNA-binding level. The present study compares the cellular effects of both indirect (epigenetic MLL inhibitors) and direct (DNA binding) HOXA9 inhibitors in two distinct pediatric MLL-r cell models, THP-1 and MV4-11. Our findings indicate that direct DNA-binding inhibition of HOXA9 by DB818 and DB1055 resulted in more favorable outcomes in facilitating leukemic cell differentiation, impairing uncontrolled proliferation, and promoting cell death. Thus, a direct DNA-binding inhibition of the addiction oncogene HOXA9 could represent an interesting opportunity for MLL-r therapy.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"844-856"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775378","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

Comparative analysis of the effects of PSPH and PHGDH inhibitors on tumor cell proliferation. PSPH与PHGDH抑制剂对肿瘤细胞增殖影响的比较分析。

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-09-12 DOI: 10.1007/s10637-025-01581-0

Yanbing Wang, Longze Sha

引用次数: 0

Comparative analysis of engineered-exosome delivered si-HER2 and trastuzumab in the treatment of HER2-positive gastric cancer. 工程外泌体递送si-HER2和曲妥珠单抗治疗her2阳性胃癌的比较分析。

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2025-08-01 Epub Date: 2025-07-24 DOI: 10.1007/s10637-025-01558-z

Yuehong Zhu, Yaoyang Guo, Ziyi Dong, Mingqing Zhang, Hui Liu, Xinyi Wen, Wenwen Pang, Xipeng Zhang, Zhansheng Jiang, Chong Chen, Jie Hao, Ming Gao, Haiyang Zhang

{"title":"Comparative analysis of engineered-exosome delivered si-HER2 and trastuzumab in the treatment of HER2-positive gastric cancer.","authors":"Yuehong Zhu, Yaoyang Guo, Ziyi Dong, Mingqing Zhang, Hui Liu, Xinyi Wen, Wenwen Pang, Xipeng Zhang, Zhansheng Jiang, Chong Chen, Jie Hao, Ming Gao, Haiyang Zhang","doi":"10.1007/s10637-025-01558-z","DOIUrl":"10.1007/s10637-025-01558-z","url":null,"abstract":"Trastuzumab is currently a key targeted drug for HER2-positive gastric cancer (GC), but there are common problems of drug resistance and cardiotoxicity in clinical treatment, resulting in poor therapeutic effects. Exosomes are natural nanocarriers for drug delivery and engineered exosomes have been widely used in translational medicine research. This study is designed to compare the anti-tumor effects and adverse effects between engineered exosomes carrying HER2 siRNA and trastuzumab. The stable cell line of iRGD-293T was constructed by using lentiviruses, and iRGD-293T and 293T cells were transfected with si-HER2 and exosomes were isolated by ultra-centrifugation. Functional experiments were performed to examine the inhibitory effects of iRGD-exo-si-HER2 and trastuzumab on both HER2-positive GC cells and mouse xenograft models. Blood biochemical indexes were used to test the adverse effects, especially cardiotoxicity. The engineered exosomes modified by iRGD peptide showed higher tumor affinity compared to control exosomes in vitro and in vivo. si-HER2 delivered by iRGD-exosomes significantly inhibited the proliferation and promoted apoptosis of HER2-positive GC cells, and iRGD-exo-si-HER2 significantly reduced the expression of HER2 in GC cells in vitro and in vivo, showing similar efficacy as trastuzumab but with lower cardiac side effects. Our data indicated that iRGD-exo-si-HER2 shows good anti-tumor effect both in vivo and in vitro, and has fewer side effects compared with trastuzumab. And this study suggested that engineering exosomes with si-HER2 can serve as novel strategy for the treatment of HER2-positive GC.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"820-835"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698539","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