Molecular Cancer Therapeutics最新文献

{"title":"Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Dabrafenib and Trametinib Clinical Trials.","authors":"Varun Jhanji, Jacob Duncan, Taylor Gardner, Griffin K Hughes, Ryan McIntire, Andriana M Peña, Chase Ladd, Brooke Gardner, Ty Moore, Elizabeth Garrett, Courtney Cook, Alyson Haslam, Vinayak K Prasad, Matt Vassar","doi":"10.1158/1535-7163.MCT-23-0805","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0805","url":null,"abstract":"<p><p>Dabrafenib and trametinib (D&T) received accelerated approval by the FDA in 2022 for the treatment of metastatic solid tumors harboring BRAF mutations. Our aim was to evaluate the risk/benefit profile of D&T in clinical trials. A comprehensive literature search was conducted to identify relevant clinical trial publications involving D&T in adult malignancies. Trials utilizing D&T measuring responses with RECIST or other criteria were included. Data screening and extraction were performed in a masked, duplicate fashion, focusing on adverse events (AE) and primary endpoints. D&T were evaluated in many BRAFV600-mutated cancers. The median progression-free survival across all trials was 4.5 months and the median overall survival was 11.5 months. However, 34% of trials did not report or reach their progression-free survival endpoint, and 54% did not report or obtain an overall survival value. The cumulative objective response rate remained consistent at around 30% throughout drug development, but the cumulative incidence of grade 3 to 5 AEs increased from 25% to 50% as off-label indications were studied. We found the studies that led to the accelerated approval of D&T's use in indications outside its original label to be deficient in reporting AEs and outcomes. The accelerated approval filled a space needed for the treatment of other BRAFV600 malignancies that did not have a standard method of treatment. However, it is still imperative that clinical trial data be empirically driven and transparent. This encourages quality research which lays the foundation for clinical decision making that affects patient quality of life and outcomes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF11"},"PeriodicalIF":5.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical pharmacokinetic, pharmacodynamic, and safety profile of OBI-992: a novel TROP2-targeted antibody-drug conjugate.","authors":"Chi-Sheng Shia, Shih-Ni Wen, Ren-Yu Hsu, Jyy-Shiuan Tu, Hui-Wen Chang, Hao-Cheng Weng, Jhih-Jie Yang, Ming-Feng Chiang, Yu-Hsuan Tsao, Chi-Huan Lu, Yu-Hung Chen, Yi-Chen Wu, Ya-Chi Chen, Wan-Fen Li, Teng-Yi Huang, Ming-Tain Lai","doi":"10.1158/1535-7163.MCT-24-1176","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1176","url":null,"abstract":"<p><p>OBI-992, a novel TROP2-targeted ADC, is composed of an anti-TROP2 antibody conjugated to exatecan, a topoisomerase 1 (TOP1) inhibitor, via an enzyme-cleavable hydrophilic linker. The stability, pharmacokinetics, pharmacodynamics, and off-target toxicity of OBI-992 were evaluated and compared with a benchmark ADC datopotamab deruxtecan (Dato-DXd). OBI-992 exhibited better stability in human and monkey serum than Dato-DXd, which was further supported by in-vivo PK study in rats. OBI-992 displayed a favorable PK profile compared to Dato-DXd in non-small cell lung cancer (NSCLC) cell line-derived xenograft (CDX) mouse models (NCI-H1975 and NCI-H1975/C797S), with lower clearance, longer half-lives of ADC in serum and higher exposure of payload in tumor. The higher level of breast cancer resistance protein (BCRP) expression was detected in NCI-H1975/C797S cells, which may contribute better antitumor activity of OBI-992 to compared with Dato-DXd as DXd is much better substrate to BCRP than exatecan. The levels of the payload of OBI-992 in non-target organs were lower or comparable to Dato-DXd. In addition, OBI-992 exhibited lower toxicity compared to Dato-DXd in the monocytic cell line THP-1 and differentiated neutrophils. Furthermore, in the Good Laboratory Practice (GLP) toxicity study with cynomolgus monkeys, the highest non-severely toxic dose (HNSTD) was determined to be ≥ 60 mg/kg. Major toxicities were target-related skin lesions and reduced reticulocytes, which were reversible during recovery period. These results support further clinical development of OBI-992 for the treatment of TROP2-expressing cancers, which it is currently in Phase 1 clinical trial (NCT06480240).</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing the DNA Labeling Agent EdU for Therapy against Heterogeneous Patient Glioblastoma.","authors":"Humeyra Kaanoglu, Adebimpe Adefolaju, Casey Fraley, Mariah Shobande, Rajaneekar Dasari, Breanna Mann, Noah Bell, Stephen T Keir, Dominique Higgins, David E Kram, Shawn D Hingtgen, Aziz Sancar, Andrew B Satterlee","doi":"10.1158/1535-7163.MCT-24-1098","DOIUrl":"10.1158/1535-7163.MCT-24-1098","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common type of malignant central nervous system tumor, and more than 300,000 people are diagnosed with GBM worldwide annually. Based on its recognition as damage by nucleotide excision repair, we now repurpose the DNA labeling agent 5-ethynyl-2'-deoxyuridine (EdU) as a treatment for GBM. We tested the efficacy of EdU in several different model systems, including not only GBM cell lines in in vitro cell culture and in vivo orthotopic mouse models of GBM, but also against living, uncultured tumor tissues of patients with GBM grown within our organotypic brain slice culture (OBSC) ex vivo platform. When compared with the standard-of-care drug temozolomide (TMZ) in in vitro GBM cell survival assays, EdU displayed ED50 values orders of magnitude lower than those of TMZ in all five GBM tumor lines tested. Against two in vivo orthotopic brain tumor models, EdU significantly extended survival relative to controls. EdU efficacy against a panel of patient GBMs largely correlated with the clinical Ki-67 status of each tumor, save for one tumor that remained unresponsive to treatment with both EdU and TMZ. Overall, these data suggest that (i) EdU has potential to be repurposed as an anticancer therapeutic and is especially adept at killing rapidly proliferating cells with low off-target toxicity; (ii) the OBSC platform can measure nuanced differences in efficacy of experimental therapeutics on heterogeneous patient tumor tissues; and (iii) OBSCs can continue to help identify potential responders and nonresponders to EdU treatment via functional precision testing of patient tumors ex vivo.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1213-1225"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacologic Inhibition of SIRT1 Limits the Growth of Tumoral and Metastatic Granulosa Cells by Affecting mTOR, Myc, and E2F Pathways.","authors":"Victoria Cluzet, Eloïse Airaud, Arnaud Tete, Marie M Devillers, Florence Petit, Alexandra Leary, Alice Pierre, Haojian Li, Chi-Ping Day, Urbain Weyemi, Stéphanie Chauvin, Celine J Guigon","doi":"10.1158/1535-7163.MCT-24-0957","DOIUrl":"10.1158/1535-7163.MCT-24-0957","url":null,"abstract":"<p><p>Clinical management of patients with ovarian granulosa cell tumor (GCT) remains poor. Sirtuin-1 (SIRT1), a deacetylase enzyme involved in the regulation of tumor growth and metastasis, may represent a therapeutic target because of the availability of selective pharmacologic inhibitors with minimal toxicity. We assessed the possible overexpression of SIRT1 during tumorigenesis by Western blotting and IHC. We tested the effects of SIRT1 inhibition by EX-527 on growth, proliferation, death, migration, metabolism, and gene expression by RNA sequencing in vitro on three GCT cell lines (AT29, KGN, and COV434). Tumor growth in response to EX-527 treatment was examined in nude mice carrying subcutaneous GCT cell grafts using an electronic caliper and in GCT of AT83 mice by three-dimensional ultrasound imaging system. SIRT1 abundance increased during tumorigenesis. In vitro treatment with EX-527 efficiently reduced cell growth, either by inducing apoptosis or by inhibiting proliferation. EX-527 induced alterations in mTOR-, Myc-, and E2F-driven pathways, and in those controlling cell metabolism and oxidative stress. The administration of this treatment for 4 weeks efficiently reduced tumor progression in vivo. Inhibition of SIRT1 activity may have GCT growth suppressive effects, providing a rationale for evaluating the therapeutic potential of drugs targeting SIRT1 in patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1197-1212"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined inactivation of MEK and mTOR can lead to synergistic cell death in glioblastoma models and associates with NF1-deficiency and a mesenchymal subtype.","authors":"Fleur M G Cornelissen, Yoran Broersma, Ravi S Narayan, Rogier Dik, Sander R Piersma, Richard de Goeij-de Haas, Thang V Pham, David Noske, William P Vandertop, Connie R Jimenez, Bart A Westerman","doi":"10.1158/1535-7163.MCT-23-0864","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0864","url":null,"abstract":"<p><p>Glioblastoma (GB) is the most common and aggressive brain derived tumor. It often shows genetic alterations in kinase signaling pathways, such as the Pi3K/mTOR and RAS/MAPK pathways, that frequently converge onto oncogenic processes. However, it is unknown to what extend co-vulnerabilities exist within this network and which kinase drug targets are promising for GB treatment. We investigated the drug sensitivity of GB cell line models to monotherapy and synergy effects in dual combination therapy to targeting components of Pi3K/mTOR and RAS/MAPK pathways. In addition, we examined cell line drug sensitivities in relation to their individual genetic tumor driving lesions (i.e. NF1 alterations as well as transcriptomic defined GB subtypes). Synergy levels were correlated to in-lab generated phospoproteomic data. Lastly, serial or simultaneous addition of MEK and mTOR inhibitors were investigated in longitudinal experiments. Dual inhibition of MEK and mTOR resulted in synergistic effects, which associated with NF1-deficiency. Strong synergy effects was also associated with the mesenchymal subtype. Dual inhibition of MEK and mTOR led to prolonged growth inhibition in GB spheroids. In addition, sequential drug treatment resulted in similar growth inhibitory effects compared to simultaneous combination therapies. Our findings highlight the potential of dual inhibition strategies targeting multiple kinases for the treatment of GB, particularly in NF1-deficient and mesenchymal tumors, the most lethal subtype of GB.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HER1 (EGFR) and/or HER2 Inclusion Potentiates the Antitumor Effect Elicited by a HER3-Specific Monovalent Vaccine.","authors":"Ernesto Bermudez-Abreut, Gretchen Bergado-Báez, Talia Fundora-Barrios, Jessica Arencibia-Perezleo, Armando Lopez Medinilla, Lisset Chao, Belinda Sanchez Ramirez","doi":"10.1158/1535-7163.MCT-24-0973","DOIUrl":"10.1158/1535-7163.MCT-24-0973","url":null,"abstract":"<p><p>The development of active specific immunotherapies for cancer treatment has mainly focused on the design of CTL vaccines. However, the inactivation of signaling induced by membrane oncogenes highlights the value of vaccines that generate a polyclonal antibody response against these oncogenes. In this sense, the EGFR family oncogenes play a critical role in tumor biology and could, therefore, be targeted by antibodies generated through vaccination to block receptor-mediated signaling and induce an antitumor effect in cancer cells. In this study, we focus on demonstrating the antitumor properties triggered by the specific polyclonal response of vaccine candidates based on three members of the EGFR family (HER1, HER2, and HER3). We are presenting two novel HER3-based multivalent vaccine candidates: a bivalent candidate that combines the extracellular domains of HER3 and HER2 in its formulation and a trivalent candidate that includes the extracellular domains of HER3, HER2, and HER1. Both candidates are adjuvanted with a combination of VSSP and Montanide ISA 51. As part of our study, we compared the antitumor properties of both HER3-based multivalent candidates with the monovalent HER3-based vaccine candidate previously reported. Our results confirm that the polyclonal response generated by HER3-based vaccine candidates has in vitro and in vivo antitumor effects through the induction of apoptosis, especially in resistance scenarios, and indicate that these effects can be enhanced with the inclusion of HER1 and HER2 in the formulation. Our results suggest the potential use of HER3-based multivalent vaccines as a first-line treatment or after resistance to first-generation anti-HER1 tyrosine kinase inhibitor therapies appears.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1226-1239"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RGN6024 Is a Brain-Penetrant, Small-Molecule Tubulin Destabilizer for the Treatment of Glioblastoma.","authors":"Lilian A Patrón, Helen Yeoman, Joseph Ramos, April L Risinger, Vijay Gokhale, Teri C Suzuki","doi":"10.1158/1535-7163.MCT-24-1208","DOIUrl":"10.1158/1535-7163.MCT-24-1208","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults, with a median survival of ∼15 months. Given the poor survival with the currently approved treatments, new therapies are urgently needed. Microtubule-targeting agents (MTA) represent one of the most successful first-line therapies for cancers; however, the inability of approved MTAs to cross the blood-brain barrier (BBB) limits their use for central nervous system cancers. The development of novel MTAs with good BBB penetrance, decreased toxicity, and an ability to overcome drug-induced resistance is an attractive prospect. In this study, we describe the characterization of RGN6024, a brain-penetrant small-molecule tubulin destabilizer that binds the colchicine-binding site of tubulin. RGN6024 has excellent in vitro potency against GBM cell lines in viability assays with IC50 values in the low to mid nanomolar range. RGN6024 is less susceptible to common drug resistance mechanisms; its activity is unaffected by βIII-tubulin overexpression and it demonstrates good blood-brain penetration in in vivo mouse and rat models. With oral dosing, RGN6024 shows excellent BBB penetration in both mice (Cmax = 3,530 ng/g) and rats (Cmax = 1,667 ng/g). Drug efficacy was confirmed in two xenograft models. In a temozolomide-resistant LN-18 GBM xenograft model, RGN6024 showed a reduction in tumor growth when dosed orally at 7.5 or 15 mg/kg. Additionally, RGN6024 suppressed the growth of BT142 GBM cells in an orthotopic murine model and significantly prolonged survival. Taken together, these data provide support for the development of RGN6024 for the treatment of GBM.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1129-1144"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Azenosertib Is a Potent and Selective WEE1 Kinase Inhibitor with Broad Antitumor Activity Across a Range of Solid Tumors.","authors":"Jianhui Ma, Wen Liu, Jiali Li, Daehwan Kim, Sangyub Kim, Alexandra Levy, Zhen Cai, Kevin D Bunker, Alejandro Recio-Boiles, Jennifer M Segar, Shiraj Sen, Deborah B Doroshow, Danielle Jandial, Michael Rutgard, Olivier Harismendy, Stephan K Grant, Ahmed A Samatar, Kimberlee M Fischer, Mark R Lackner","doi":"10.1158/1535-7163.MCT-24-1194","DOIUrl":"10.1158/1535-7163.MCT-24-1194","url":null,"abstract":"<p><p>Genomic instability and accumulation of DNA damage are hallmarks of tumor development and progression. To ensure the maintenance of genomic integrity, cells rely on a coordinated DNA damage response network that regulates cell-cycle progression, including activation of WEE1-dependent cell cycle checkpoints. If DNA damage occurs during replication, the WEE1 checkpoint is activated, thereby preventing the progression of the cell cycle. This allows damaged DNA to be repaired before cells enter mitosis, or if the damage is too extensive, induction of apoptosis. These observations have made WEE1 a promising anticancer therapeutic target. Azenosertib (ZN-c3) is a novel, selective, and orally bioavailable WEE1 inhibitor. The antiproliferative activity of azenosertib on cancer cell lines is consistent with a WEE1-dependent mechanism of action exemplified by reduction of pY15-CDK1 levels and increases in DNA damage markers. Azenosertib further exacerbates the effect of replicative stress and DNA damage by allowing cancer cells to prematurely enter mitosis, leading to mitotic catastrophe and apoptosis. Azenosertib has optimized pharmacokinetic and pharmacodynamic properties, yielding robust tumor growth inhibition in a broad range of tumor models, and is highly effective at delaying the duration of tumor regrowth after cessation of treatment. We have explored various dosing schedules in preclinical efficacy models for azenosertib that preserve antitumor activity with minimal toxicity. Phase I studies with azenosertib as monotherapy have shown preliminary clinical activity in patients with advanced solid tumors. The data presented herein support further studies of azenosertib monotherapy across multiple solid tumor indications.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1171-1185"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting CAFs-Mediated Stromal Signaling in a Patient-Derived Organotypic Colorectal Tumor Model.","authors":"Astha Lamichhane, Prasiddha Guragain, Jacob Heiss, Pouria Rafsanjani Nejad, Anju Rana Magar, Nicholas Ciavattone, Seema Agrawal, Gary D Luker, Hossein Tavana","doi":"10.1158/1535-7163.MCT-24-0756","DOIUrl":"10.1158/1535-7163.MCT-24-0756","url":null,"abstract":"<p><p>Colorectal cancer, a significant cause of cancer-related mortality, often exhibits drug resistance, highlighting the need for improved tumor models to advance personalized drug testing and precision therapy. We generated organoids from primary colorectal cancer cells cultured through the conditional reprogramming technique, establishing a framework to perform short-term drug testing studies on patient-derived cells. To model interactions with stromal cells in the tumor microenvironment, we combined cancer cell organoids with carcinoma-associated fibroblasts, a cell type implicated in disease progression and drug resistance. Our organotypic models revealed that carcinoma-associated fibroblasts promote cancer cell proliferation and stemness primarily through hepatocyte growth factor-MET paracrine signaling and activation of cyclin-dependent kinases. Disrupting these tumor-stromal interactions reduced organoid size while limiting oncogenic signals and cancer stemness. Leveraging this tumor model, we identified effective drug combinations targeting colorectal cancer cells and their tumorigenic activities. Our study highlights a path to incorporate patient-derived cells and tumor-stromal interactions into a drug testing workflow that could identify effective therapies for individual patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1265-1276"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navitoclax, a Bcl-2/xL Inhibitor, and YM155, a Survivin Inhibitor, in Combination with Carboplatin, Effectively Inhibit Ovarian Cancer Tumor Growth.","authors":"Hilary A Kenny, Carman Ka Man Ip, Lucy Kelliher, Tejas Samantaray, Kasjusz Kordylewicz, Rachael Hoffmann, Sarah Rauch, Beatrice Malacrida, Sophie L P Skingsley, Frances R Balkwill, Chiara Battistini, Ugo Cavallaro, Wolf R Wiedemeyer, Ernst Lengyel","doi":"10.1158/1535-7163.MCT-23-0863","DOIUrl":"10.1158/1535-7163.MCT-23-0863","url":null,"abstract":"<p><p>High-grade serous ovarian cancer is generally treated with upfront chemotherapy, including carboplatin. The persistence of platinum-resistant cells drives recurrent disease. A high-throughput screen using a 3D organotypic culture assembled with extracellular matrix, primary human fibroblasts, and mesothelial cells was established and validated. Using a library of FDA-approved drugs, the 3D high-throughput screen was performed with the goal of identifying a combination of drugs that synergistically target two populations of ovarian cancer: aldehyde dehydrogenase (ALDH) high (ALDHhi) and ALDH low (ALDHlo) enzyme activity cells, which are less sensitive to carboplatin treatment than the bulk ovarian cancer cells. Initial results showed that omipalisib, verteporfin, CA3, mitoxantrone, navitoclax, venetoclax, and YM155 had significant single-drug activity in either the ALDHlo or both the ALDHlo/ALDHhi cell populations. Synergistic drug activity was identified with three drug combinations: navitoclax/omipalisib, navitoclax/YM155, and YM155/omipalisib. In vitro, the combination of navitoclax/YM155 was most efficient at blocking primary human ovarian cancer sphere formation and the proliferation of four different ovarian cancer cell lines in the 3D organotypic culture. In vivo, the combination of navitoclax/YM155/carboplatin decreased ovarian cancer metastasis, decreased the percentage of ALDHhi ovarian cancer cells in tumors, and increased survival when compared with carboplatin treatment alone in xenograft models. Our results suggest that the combination of navitoclax/YM155/carboplatin has promise as a therapy for treating ovarian cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1252-1264"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}