Investigational New Drugs最新文献

{"title":"A phase I study of liposomal Irinotecan (ONIVYDE®) in combination with TAS-102 (LONSURF®) in refractory solid tumors.","authors":"Nai-Jung Chiang, Li-Yuan Bai, I-Wei Ho, Chih-Hung Hsu, Yi-Hsin Liang, Chang-Fang Chiu, Ching-Chan Lin, Kwang-Yu Chang, Shang-Hung Chen, Hui-Jen Tsai, Yu-Ping Lin, Li-Tzong Chen, Chia-Chi Lin","doi":"10.1007/s10637-025-01547-2","DOIUrl":"10.1007/s10637-025-01547-2","url":null,"abstract":"<p><p>Onivyde, a liposome-encapsulated irinotecan, is used for advanced pancreatic, while TAS-102 (trifluridine/tipiracil) is indicated for metastatic colorectal and gastric cancers. This study aims to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety profiles of liposomal irinotecan combined with TAS-102. This multicenter, phase I study utilized a 3 + 3 dose-escalation design. Patients with treatment-refractory solid malignancies received free base liposomal irinotecan at 50-70 mg/m² on Day 1 and TAS-102 at 25-35 mg/m² twice daily on Days 1-5 of a 14-day cycle. Patients homozygous for UGT1A1*28 (TA7/TA7), UGT1A1*6 (A/A), or double heterozygous (TA6/TA7 and G/A) alleles were excluded. Prophylactic G-CSF was allowed. Twenty-six evaluable patients were enrolled across seven dose levels of liposomal irinotecan (free-base)/TAS-102 combination: 3 patients each at level 1 (50/25 mg/m²), level 2A (60/25 mg/m²), level 2B (50/30 mg/m²), and level 3 (60/30 mg/m²); 6 at level 4A (70/30 mg/m²); 3 at level 4B (60/35 mg/m²); and 5 at level 5 (70/35 mg/m²). An additional 15 patients were enrolled in the expansion cohort at the MTD of 70/30 mg/m² (level 4A), designated as the RP2D. Overall grade 3-4 treatment-related adverse events occurred in 44.2% of 43 all treated patients, with neutropenia (16.3%), diarrhea (14%), and fatigue (11.6%). Partial responses were observed in 18.4% of patients, predominantly in neuroendocrine tumor, gastric and esophageal carcinomas. The combination of liposomal irinotecan and TAS-102 at the RP2D of 70/30 mg/m² demonstrated acceptable safety and promising efficacy in refractory solid tumors, warranting further investigation.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"709-718"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225454","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}

{"title":"Evaluation of anti-leukemic activity and underlying mechanisms of the novel GSPT1 degrader AB138 in acute myeloid leukemia.","authors":"Liqiang Wang, Xin Cai, Yang Kong, Qingchun Wu, Wei Hu, Yongsheng Wang","doi":"10.1007/s10637-025-01541-8","DOIUrl":"10.1007/s10637-025-01541-8","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a relapsing and drug-resistant hematologic malignancy. We report AB138, a novel molecular glue degrader that recruits G1-to-S phase transition protein 1 (GSPT1) to cereblon (CRBN). In AML cell lines, AB138 induces rapid, sustained GSPT1 degradation. qPCR and immunoblotting revealed activation of the integrated stress response, as evidenced by eIF2α phosphorylation and the upregulation of ATF3 and CHOP. The subsequent depletion of the oncoproteins MCL1 and c-Myc coincides with the accumulation of cleaved caspase-3 and cleaved PARP and marked apoptosis. Flow cytometric analysis confirmed pronounced S-phase arrest together with an increase in the number of Annexin V-positive cells. Oral administration of AB138 significantly reduces the tumor burden in an MV-4-11-Luc xenograft model without overt toxicity. These findings demonstrate that efficient GSPT1 degradation by AB138 promtoes integrated stress signaling and downregulates the survival-promoting BCL-2 family member MCL1 and the oncogenic driver c-Myc, leading to potent antileukemic activity in vitro and in vivo and supporting further development of AB138 for AML therapy.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"646-655"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995521","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 orelabrutinib combined with rituximab and high dose methotrexate in primary or secondary central nervous system diffuse large B-cell lymphoma: a retrospective analysis.","authors":"Jiahao Zhou, Lingxiao Xing, Yi Miao, Shuchao Qin, Run Zhang, Hanning Tang, Wei Xu, Yi Xia, Huayuan Zhu, Jianyong Li","doi":"10.1007/s10637-025-01542-7","DOIUrl":"10.1007/s10637-025-01542-7","url":null,"abstract":"<p><p>Central nervous system lymphoma (CNSL) are mainly diffuse large B-cell lymphomas (DLBCLs). Orelabrutinib is a second-generation Bruton's tyrosine kinase (BTK) inhibitor and has shown single-agent activity in CNSL. This study aims to evaluate the efficacy and safety of orelabrutinib combined with rituximab and high dose methotrexate (ORM) regimen in the treatment of patients with CNSL. We retrospectively analyzed data from CNSL patients treated with ORM regimen at Jiangsu Province Hospital, the First Affiliated Hospital of Nanjing Medical University from April 2021 to October 2023. Patients receiving rituximab plus high-dose methotrexate (RM regimen) from June 2017 to January 2024 were identified as the control group. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A total of 32 patients were identified: 14 patients in the ORM group and 18 in the RM group. CR rates were 84.6% in the ORM group and 44.4% in the RM group (P = 0.032). Median PFS was 18.6 months in the RM group and 26.3 months in the ORM group (P = 0.133). Median OS was 34.1 months in the RM group and has not yet been reached in the ORM group (P = 0.041). Patients in the ORM group showed a higher 2-year OS rate than those in the RM group (82.1% vs. 57.5%). No grade 5 AE was reported in both groups. The incidence of grade 3-4 AE was comparable between the two treatment groups. ORM regimen was effective and well-tolerated in patients with CNSL. This combination therapy provides a new potential therapeutic strategy for patients with CNSL.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"451-459"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191827","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":"An investigation of extended-interval dosing of atezolizumab in Japanese patients with advanced solid tumors: safety and pharmacokinetics of a dose of 1680 mg every 4 weeks.","authors":"Shunsuke Kondo, Shigehisa Kitano, Jun Sato, Yuki Katsuya, Takahiro Kogawa, Hidenori Mizugaki, Ippei Miyamoto, Shunichiro Iwasawa, Tatsuki Imaizumi, Hiroaki Tomita, Chika Murakami, Takeshi Miyake, Noboru Yamamoto","doi":"10.1007/s10637-024-01498-0","DOIUrl":"10.1007/s10637-024-01498-0","url":null,"abstract":"<p><p>In Japan, atezolizumab is indicated for several cancers at a dose of 1200 mg every 3 weeks or 840 mg every 2 weeks. This open-label study (jRCT2031220151) aimed to assess an atezolizumab monotherapy dose of 1680 mg every 4 weeks (Q4W) in Japanese patients ≥ 18 years of age with advanced or recurrent solid tumors that were not responsive to standard treatment. The primary endpoints were tolerability, safety, and pharmacokinetics (PK). Secondary endpoints included overall response rate and progression-free survival. Overall, 21 patients were enrolled in the study. The median age for males (42.9%) and females (57.1%) was 61 years, and the median (range) treatment duration was 29.0 (1-224) days. During the dose-limiting toxicity (DLT) evaluation period, 3 out of 6 (50.0%) patients experienced at least 1 adverse event, although no DLTs or deaths were experienced. The PK profile of atezolizumab 1680 mg Q4W monotherapy in cycle 1 after 30 min of administration had an arithmetic mean maximum concentration (standard deviation [SD]) of 699 (146) µl/mL and a mean minimum concentration (SD) 133 (46.0) µl/mL, The mean (SD) area under the curve was 7180 (1340) days‧µg/mL. These data show that atezolizumab 1680 mg Q4W monotherapy was well tolerated in Japanese patients with no new safety concerns, suggesting that this less frequent dosing regimen could have the potential to offer greater flexibility and convenience for patients and caregivers.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"602-608"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015574","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}

{"title":"A novel CDK4 inhibitor for myeloid protection in chemotherapy-treated triple-negative breast Cancer.","authors":"Ava Safaroghli-Azar, Laychiluh B Mekonnen, Ramin Hassankhani, Jimma Lenjisa, Sunita Kc Basnet, Hajer Batayneh, Muhammed H Rahaman, Shudong Wang","doi":"10.1007/s10637-025-01550-7","DOIUrl":"10.1007/s10637-025-01550-7","url":null,"abstract":"<p><strong>Background: </strong>Despite advances in cancer treatment, chemotherapy remains a cornerstone of clinical practice. However, its efficacy is often compromised by dose-limiting haematologic toxicities. Recent strategies aim to enhance chemotherapy tolerability while preserving its effectiveness. One emerging approach involves selective CDK4 inhibitors to serve as myeloid-protective agents in retinoblastoma (RB)-negative tumours, such as triple-negative breast cancer (TNBC). Because bone marrow (BM) cells rely on RB for proliferation, CDK4 inhibitors may protect these cells while sparing RB-deficient tumour cells. The present study investigated the potential of AU2-94, a first-in-class CDK4 inhibitor, to protect BM cells during myelosuppressive chemotherapy in TNBC, beyond its established application in RB-positive cancers.</p><p><strong>Methods: </strong>This study employed in vitro, ex vivo, and in vivo experiments to evaluate the myeloid-protective effects of AU2-94 against chemotherapy-induced damage.</p><p><strong>Results: </strong>AU2-94 induced a transient G1 arrest that protects BM cells from chemotherapy-induced apoptosis by preventing DNA double-strand breaks. Pre-treatment with AU2-94 prior to 5-fluorouracil (5-FU) administration reduced BM cells apoptosis, preserved Ki67-positive cells, and mitigated declines in red blood cells and neutrophils. Similarly, AU2-94 pre-treatment before cisplatin administration reduced cisplatin-induced haematologic toxicity in RB-deficient TNBC bearing mice without compromising the efficacy of chemotherapy.</p><p><strong>Conclusion: </strong>These findings support the repurposing of AU2-94 as a myeloprotective agent, highlighting its therapeutic potential in RB-deficient tumours. With AU2-94 advancing to clinical trials, these results underscore its broader therapeutic promise, extending to both RB-positive and RB-negative cancer treatment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"728-741"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234081","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}

{"title":"Medulloblastoma associated with Lynch syndrome: a case report of germline MLH1 variant and tumor molecular characterization.","authors":"Han Zheng, Gang Zhang, Bin Jiang, Luyi Zhang, Qianqian Duan, Hangyu Shi","doi":"10.1007/s10637-025-01527-6","DOIUrl":"10.1007/s10637-025-01527-6","url":null,"abstract":"<p><p>Lynch syndrome (LS) is an autosomal autosomal dominant inherited disease characterized by impaired DNA mismatch repair (dMMR), resulting in an elevated susceptibility to various types of cancer. The incidence of brain cancers in individuals with LS ranges from 2 to 8%, with the highest risk observed for glioblastoma, astrocytoma, and oligodendroglioma. Medulloblastoma (MB) with Lynch syndrome, a common malignant brain tumor in children, is exceedingly rare. In this case, we present a case of a pediatric patient diagnosed with MB based on clinical and pathological findings, which was further characterized as an TP53-mutant, SHH-activated MB through next-generation sequencing (NGS), and methylation profiling. His tumor was found to harbor a somatic MSH2 mutation and a suspected pathogenic germline MLH1 heterozygous variant. Simultaneously, the tumor exhibited microsatellite instability-high (MSI-H) and an exceptionally elevated tumor mutation burden (TMB = 297.17 Mut/Mb). The presence of the MLH1 germline variant in the patient's mother and maternal grandmother was confirmed by sequencing, and the patient's maternal grandmother had a history of colorectal cancer. Ultimately, the patient was diagnosed with MB associated with LS. This case is the third case of LS with medulloblastoma, which contributes additional evidence to the cancer spectrum associated with LS and presents a novel avenue for patient treatment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"460-465"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093583","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":"Safety, tolerability, and preliminary efficacy of nadunolimab, an anti-IL- 1 receptor accessory protein monoclonal antibody, in combination with pembrolizumab in patients with solid tumors.","authors":"Roger B Cohen, Antonio Jimeno, Jennifer Hreno, Lova Sun, Marie Wallén-Öhman, Camilla Rydberg Millrud, Annika Sanfridson, Ignacio Garcia-Ribas","doi":"10.1007/s10637-025-01538-3","DOIUrl":"10.1007/s10637-025-01538-3","url":null,"abstract":"<p><p>Interleukin (IL)-1 signaling has an essential role in tumor progression and immunosuppression and is linked to acquired resistance to anti-PD-1/PD-L1 treatment. Nadunolimab is an IL1RAP (IL-1 receptor accessory protein)-targeting antibody that blocks IL-1α/IL-1β signaling and has enhanced antibody-dependent cellular cytotoxicity. We investigated the safety and preliminary efficacy of nadunolimab with pembrolizumab in patients with metastatic solid tumors who had progressed on previous checkpoint inhibitor treatment, suggesting acquired checkpoint inhibitor resistance (NCT04452214). This phase 1b trial enrolled patients with metastatic disease who had exhausted or declined standard-of-care alternatives. Patients received nadunolimab (5 mg/kg) and standard-dose pembrolizumab. The primary objective was to assess safety. Secondary objectives were anti-tumor response as per iRECIST, pharmacokinetics, and changes in immune mediators. Fifteen patients with stage IV cancer (head and neck squamous cell carcinoma, non-small cell lung cancer, melanoma) entered the trial. Grade ≥ 3 adverse events were reported for 7 patients (47%). There was one dose-limiting toxicity of febrile neutropenia. The most frequent grade ≥ 3 adverse event was dysphagia (two patients). Seven patients (47%) had reductions in target lesion size. Median iPFS was 3.4 months (95% CI 1.4-8.6). Median OS was 19.7 months (95% CI 4.3-28.7) with 67% 1-year survival. Survival was significantly longer in patients with higher baseline tumor infiltration of CD163 + macrophages and natural killer cells and in patients with reduced on-treatment circulating IL-6 levels or neutrophil-to-lymphocyte ratio. Nadunolimab with pembrolizumab had an acceptable safety profile, and prolonged disease control was observed in a subset of patients. The results support further development of nadunolimab in combination with checkpoint inhibitors.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"609-620"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012326","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}

{"title":"Novel GPC3 N-terminal bispecific antibody exhibits dual anti-tumor effect against tumor cells.","authors":"Xinsheng Zhou, Yixin Liu, Xuan Liu, Xu Song, Sijie Li, Peng Chen, Xiaotao Jiang, Yongyin Li","doi":"10.1007/s10637-025-01530-x","DOIUrl":"10.1007/s10637-025-01530-x","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with poor prognosis and limited treatment options, particularly in advanced stages. Glypican-3 (GPC3) has emerged as a promising therapeutic target, but existing antibodies primarily bind its C-terminal region, where glycosylation can mask epitopes and compromise efficacy. To address this limitation, we focused on the GPC3 N-terminal region, which offers better accessibility and potential for tumor signaling regulation. We developed Pro-12, a high-affinity humanized IgG1 antibody targeting the 25-45 peptide of the GPC3 N-terminus, avoiding glycosylation interference while modulating tumor pathways. Building on Pro-12, we engineered a GPC3/CD3 bispecific antibody (BsAb) using CrossMab and Knob-into-Hole technologies. This BsAb demonstrated dual anti-tumor effects by activating immune cells and inhibiting both the Wnt/β-catenin and PI3K/AKT pathways, achieving outcomes typically requiring tri-specific antibodies. Our findings highlight the GPC3 N-terminal region as a novel therapeutic target and introduce a promising bispecific antibody approach for the treatment of GPC3-positive HCC.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"588-601"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012452","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":"Orelabrutinib combined with rituximab and high-dose methotrexate as induction therapy in newly diagnosed primary central nervous system lymphoma.","authors":"Xi-Bin Xiao, Yi-Qin Weng, Hua-Wei Jiang, Xian Li, Jing Xie, Chang-Qian Bao, Wen-Bin Qian","doi":"10.1007/s10637-025-01548-1","DOIUrl":"10.1007/s10637-025-01548-1","url":null,"abstract":"<p><strong>Objective: </strong>Limited treatment options for primary central nervous system lymphoma (PCNSL) highlight the need for alternative therapies. This study evaluated orelabrutinib (O) and rituximab (R), plus high-dose methotrexate (M) (ORM), as a potential induction therapy for newly diagnosed PCNSL.</p><p><strong>Methods: </strong>Patients received six cycles of 150 mg/day orelabrutinib, 375 mg/m² rituximab, plus 3.5 g/m² methotrexate every 3 weeks, followed by autologous hematopoietic stem cell transplantation and orelabrutinib maintenance. The primary endpoint was the overall response rate (ORR) at the end of induction therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.</p><p><strong>Results: </strong>From October 21, 2020, to October 22, 2024, 28 patients were treated and evaluated for efficacy and safety analyses. At the end of induction therapy, the ORR was 71.4% (95% CI, 51.3-86.8), including 16 (57.1%) complete and 4 (14.3%) partial responses. At a median follow-up of 21.6 months, the median PFS was 35.3 months (95% CI, 8.4-not evaluable), and the median OS was not reached, with PFS and OS rates of 64.3% and 96.3% at 1 year, 64.3% and 90.9% at 2 years, and 45.9% and 82.7% at 3 years, respectively. All 28 (100%) patients experienced treatment-related adverse events (TRAEs) of any grade. Grade 3 TRAEs occurred in seven (25.0%) patients, including five (17.9%) leukopenia, one (3.6%) thrombocytopenia, and one (3.6%) diarrhea. No other Bruton's tyrosine kinase inhibitor-related off-target toxicities (e.g., atrial fibrillation/flutter) or TRAE-related deaths were observed.</p><p><strong>Conclusion: </strong>The ORM induction regimen showed anti-tumor activity with a favorable safety profile, offering a potential therapeutic strategy for newly diagnosed PCNSL.</p><p><strong>Clinical trial registration: </strong> ClinicalTrials.gov: NCT05600660.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"679-686"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144158185","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}

{"title":"Targeting Myc through BET-PROTAC elicits potent anti-lymphoma activity in diffuse large B cell lymphoma.","authors":"Hui Wang, Ximei Wu, Jingjing Gao, Suchang Chen, ZiTao Zhou, Luyong Zhang, Bing Liu, Min Wei","doi":"10.1007/s10637-025-01535-6","DOIUrl":"10.1007/s10637-025-01535-6","url":null,"abstract":"<p><p>Diffuse large B cell lymphoma (DLBCL) presents a great challenge in the clinic due to its poor prognosis. Prior research has identified c-Myc as a promising therapeutic target in DLBCL; however, direct targeting of c-Myc protein has proven challenging. The bromodomain and extraterminal (BET) protein family, which acts as transcriptional and epigenetic regulators, plays a crucial role in super-enhancer organization and transcriptional regulation of oncogenic drivers like c-Myc, offering an alternative approach. Recently developed BET proteolysis targeting chimera (PROTAC) compounds can rapidly and effectively degrade BET proteins and potentially offer a more durable effect than traditional BET inhibitors. In this work, we compared the anti-tumor activity of a BET PROTAC, ARV-825, with a BET inhibitor, JQ1, in DLBCL. Cell proliferation was assessed by CCK-8 assay, apoptosis was evaluated by Annexin V/PI staining, and the cell cycle was analyzed by staining DNA with propidium iodide (PI). Western blotting was used to determine the expression levels of BET family proteins and its downstream regulatory gene c-Myc, and the in vivo SCID mouse model implanted with SU-DHL-4 cells was used to analyze the in vivo drug efficacy. Our results showed that ARV-825 was superior to JQ1 in inhibiting DLBCL cell proliferation, inducing apoptosis, promoting cell cycle arrest, and prolonging survival. Notably, ARV-825 was more effective at downregulating c-Myc and BET protein levels than JQ1 in both in vitro and in vivo experiments. These evidences suggest that BET-PROTACs may offer a promising novel strategy for the clinical treatment of DLBCL.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"621-633"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966340","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}