Molecular Cancer Therapeutics最新文献

{"title":"Identification of Small-Molecule Inhibitors that Block the GTP-Binding Pocket of K-Ras and Other Members of the Ras Superfamily of Small GTPases.","authors":"Luca Carta, Rebecca Hutcheson, Carolina L Bigarella, Sufang Zhang, Simon A Davis, Michael J Rudolph, Charles H Reynolds, Matthias Quick, Theresa M Williams, Michael Schmertzler, Yaron R Hadari","doi":"10.1158/1535-7163.MCT-24-0618","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0618","url":null,"abstract":"<p><p>RAS genes encode small GTPases essential for mammalian cell proliferation, differentiation, and survival. RAS gene mutations are associated with 20% to 30% of all human cancers. Based on earlier reports of extremely high Ras binding affinities for GTP, Ras proteins were previously considered undruggable. Using three independent techniques, we report binding affinities of K-Ras and several K-Ras mutants for GTP in the 250 to 400 nmol/L range, orders of magnitude lower than previously reported (∼10 pmol/L). This discovery suggests that K-Ras and other small-GTPase proteins may indeed be druggable targets. We identified more than 400 small molecules that compete non-covalently with GTP binding to K-Ras. Focusing on two inhibitors, we demonstrate the inhibition of K-Ras in downstream signaling and cellular proliferation in human pancreatic and non-small cell lung cancer cells expressing wild-type or mutant K-Ras. These two compounds represent novel pan-Ras superfamily inhibitors as they also inhibited GTP binding to other members such as RAB5A and RAB35.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF10"},"PeriodicalIF":5.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040969","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":"Targeting the ERα DBD-LBD interface with mitoxantrone disrupts receptor function through proteasomal degradation.","authors":"Han Wang, Yuxuan Luo, Sandeep Artham, Qianqian Wang, Yi Peng, Zixi Yun, Xinyue Li, Chen Wu, Zhenghao Liu, Kristen L Weber-Bonk, Chun-Peng Pai, Yuan Cao, Jiangan Yue, Sunghee Park, Ruth A Keri, Lisheng Geng, Donald P McDonnell, Hung-Ying Kao, Sichun Yang","doi":"10.1158/1535-7163.MCT-25-0405","DOIUrl":"10.1158/1535-7163.MCT-25-0405","url":null,"abstract":"<p><p>The estrogen receptor (ER or ERα) remains the primary therapeutic target for luminal breast cancer, with current treatments centered on competitive antagonists, receptor down-regulators, and aromatase inhibitors. Despite these options, resistance frequently emerges, highlighting the need for alternative targeting strategies. We discovered a novel mechanism of ER inhibition that targets the previously unexplored interface between the DNA-binding domain (DBD) and ligand-binding domain (LBD) of the receptor. Through computational screening and functional assays, we identified mitoxantrone (MTO), an FDA-approved topoisomerase II inhibitor, as a specific ligand for this DBD-LBD interface. Comprehensive biophysical, biochemical, and cellular analyses demonstrate that MTO binding induces distinct conformational changes in ER, triggering rapid cytoplasmic redistribution and proteasomal degradation through mechanisms independent of its DNA damage activity. Critically, MTO effectively inhibits constitutively active ER mutants (Y537S and D538G) associated with endocrine therapy resistance, suppressing both wild-type and mutant ER-dependent gene expression and tumor growth more potently than fulvestrant in cellular and xenograft models. These findings establish the DBD-LBD interface as a druggable allosteric site that can overcome conventional resistance mechanisms, providing a new therapeutic paradigm for targeting nuclear receptor function through disruption of interdomain communication rather than hormone binding competition.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12496009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033627","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":"Preclinical Anti-Tumor Efficacy of a Novel Anti-c-Kit Antibody Drug Conjugate, NN3201, in c-Kit Positive Tumors.","authors":"Chansik Kim, Jinwoo Park, Jin-Ock Kim, Han-Jik Ko, Jin Gu Cho, Yeonjy Lee, Jina Lee, TaeMin Wi, Jiwoo Moon, Sohyeon Park, Jaeyoung Song, Sun-Hwa Lee, Gong Sung, Sang Gyu Park","doi":"10.1158/1535-7163.MCT-25-0396","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0396","url":null,"abstract":"<p><p>Overexpression and gain-of-function mutations of c-Kit have been implicated in cancers including gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), acute myeloid leukemia, and systematic mastocytosis. In clinics, small molecule c-Kit inhibitors often result in secondary c-Kit mutations or are ineffective despite c-Kit overexpression. We developed NN3201, a novel c-Kit targeting antibody-drug conjugate (ADC), via rational design to evaluate its anticancer activity in c-Kit-positive tumors, and preclinical pharmacologic profiles. A fully human c-Kit antibody NN2101 was conjugated to monomethyl auristatin E (MMAE) as DAR of 4 utilizing ThioBridge linker to generate NN3201. Anti-tumor efficacies of NN3201 were evaluated in c-Kit-positive cancer cell lines, cell line derived xenografts and patient-derived xenografts. NN3201 selectively binds to c-Kit and is rapidly internalized. By its design, NN3201 exhibits no antibody-dependent cell mediated cytotoxicity and complement-dependent cytotoxicity and possessed decreased binding to FcγRs. Inhibition of SCF/c-Kit downstream signaling pathways, cell cycle arrest and bystander effect were demonstrated as mechanism of action for NN3201. In xenograft models, NN3201 showed superior efficacy regardless of c-Kit mutations. Repeated intravenous administration of NN3201 was well tolerated in cynomolgus monkeys, confirming No Observed Adverse Effect Level of NN3201 to be 2 mg/kg and Highest Non-Severely Toxic Dose over 2 mg/kg. NN3201 exhibited significant c-Kit-dependent anti-tumor efficacies in various tumor models, followed by favorable pharmacokinetic and toxicity profile in cynomolgus monkeys. These data suggest that NN3201 is a promising therapeutic in SCLC and GIST, and warrants evaluation in a phase 1 clinical study.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000939","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":"In Vivo Tumor Growth Control by General Control Nonderepressible 2-Targeting Agents Results from Kinase Activation.","authors":"Feven Tameire, Paulina Wojnarowicz, Crissy Dudgeon, Kathryn T Bieging-Rolett, Sho Fujisawa, Savi Ramurthy, Owen Reilly, Christopher G Thomson, Bradley S Sherborne, Simon J Taylor, Fang He, Pengwei Pan, Baozhong Li, Earl May, Alan C Rigby, Mark J Mulvihill, Nandita Bose, David Surguladze, Eric S Lightcap","doi":"10.1158/1535-7163.MCT-24-0960","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0960","url":null,"abstract":"<p><p>General control nonderepressible 2 (GCN2; EIF2AK4) is a serine-threonine kinase in the integrated stress response signaling pathway that initiates adaptive responses during nutrient stress conditions. Although pharmacologic inhibition of GCN2 under nutrient stress conditions induces apoptosis and inhibits tumor growth, GCN2 inhibition without nutrient stress has been reported to have no effect on tumor growth. By exploring an array of GCN2 inhibitors, we demonstrate that multiple agents in fact activate GCN2 in biochemical and cell-based assays at low concentrations and inhibit GCN2 at higher concentrations. Unexpectedly, it is this activation, and not inhibition, of the GCN2 pathway that is associated with decreased viability in vitro and tumor growth inhibition in vivo across multiple models. Knockdown and knockout experiments show that activation of the integrated stress response by GCN2-targeting agents is dependent on GCN2. ISRIB, a modulator of eIF2B, ablates the viability effect, demonstrating the dependence on translation initiation. Activating doses result in the induction of cleaved caspase 3 and cleaved PARP. In contrast, a nonactivating GCN2-targeting agent does not affect viability. These results provide a clearer understanding of the challenges and opportunities for the clinical development of compounds targeting GCN2.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF13"},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000960","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":"Advancing preclinical biology for Ewing Sarcoma: an international effort.","authors":"Filemon S Dela Cruz, Elizabeth A Stewart, Didier Surdez, Jessica D Daley, Alice Soragni, Eleni M Tomazou, Jaime Alvarez-Perez, Tamar Y Feinberg, James F Amatruda, Shireen S Ganapathi, Joyce E Ohm, Christine M Heske, Sarah Cohen-Gogo, Dusan Pesic, Joshua O Nash, Adam Shlien, Elizabeth A Roundhill, Susan A Burchill, Brian D Crompton, Elizabeth R Lawlor, David M Loeb, Olivier Delattre, Jaume Mora, Katia Scotlandi, Damon R Reed, Patrick J Grohar, Thomas G P Grünewald, Heinrich Kovar, Kelly M Bailey","doi":"10.1158/1535-7163.MCT-25-0428","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0428","url":null,"abstract":"<p><p>Ewing sarcoma (EwS) is an aggressive bone and soft tissue cancer affecting adolescents and young adults. In vitro and in vivo models of EwS have been instrumental in advancing our understanding of EwS biology and essential in evaluating potential therapies, particularly for metastatic or relapsed disease where effective treatment options remain limited. Through an international collaborative effort between the Children's Oncology Group (COG) Bone Tumor Committee and the Euro Ewing Consortium (EEC), we review the current landscape of preclinical modeling used in EwS research encompassing both in vitro (cell lines and tumor organoids) and in vivo (mouse and non-mammalian xenografts) model systems. We discuss factors that can influence experimental results, provide testing considerations for both in vitro and in vivo studies, and descriptions of existing preclinical data repositories. We highlight current needs in EwS modeling and the importance of enhanced international cooperative research and patient advocacy efforts which will be critical in expanding our resources of biologically-relevant EwS models to enable translation of preclinical findings into effective therapeutic strategies for EwS patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006328","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":"Co-Targeting BCL-xL with MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.","authors":"Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen, R Taylor Ripley","doi":"10.1158/1535-7163.MCT-24-0873","DOIUrl":"10.1158/1535-7163.MCT-24-0873","url":null,"abstract":"<p><p>Diffuse mesothelioma is a rare but highly aggressive and treatment-resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid cell leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are antiapoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance. We investigated whether B-cell homology domain3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells, and patient-derived xenografts (PDX) by B-cell homology domain-3 profiling; we observed striking consistency which enabled cross-model comparisons. Next, we co-targeted BCL-xl and MCL-1 and noted that the combination synergistically reduced cell viability and increased apoptosis. Mechanistically, BCL-xL inhibition affected the cells through both the canonical and the emerging noncanonical apoptotic pathways. BCL-xL induced mitochondrial depolarization which resulted in MCL-1 cellular dependency, rendering cells highly sensitive to MCL-1 inhibition. Next, we co-targeted BCL-xL and MCL-1 in vivo which induced synthetic lethality in PDX models within hours, implying that this approach is not a safe strategy for clinical development. However, targeting MCL-1, which exerts its antiapoptotic activity without non-apoptotic on-target effects, decreased the mitochondrial threshold for apoptosis and enhanced chemosensitivity without toxicity in PDX models. Our findings suggest that targeting the mitochondria via MCL-1 enhances the efficacy of chemotherapy but co-targeting two proteins in the Bcl-2 pathways results in synergistic lethality. These results will help define a safe clinical strategy to utilize Bcl-2-targeted therapy to undermine therapeutic resistance in patients with diffuse mesothelioma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF13"},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12475887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000926","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":"Anti-tumor activity of trastuzumab deruxtecan in pediatric solid tumors with variable HER2 expression.","authors":"Chelsey M Burke, Tamar Y Feinberg, Samantha Brosius, Umeshkumar K Bhanot, Mala Jain, Irina Linkov, Armaan Siddiquee, Kristina Guillan, Glorymar Ibanez, Andoyo A Ndengu, Paul Calder, Nestor Rosales, Diego F Coutinho, Matthew M Long, Raina Fishkin, Sheeno Thyparambil, Julia L Glade Bender, Damon R Reed, Daoqi You, Michael V Ortiz, Emily K Slotkin, Andrew L Kung, Filemon S Dela Cruz","doi":"10.1158/1535-7163.MCT-25-0437","DOIUrl":"10.1158/1535-7163.MCT-25-0437","url":null,"abstract":"<p><p>Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate (ADC) with efficacy across adult cancers exhibiting variable HER2 expression. Prior studies demonstrating HER2 expression in osteosarcoma (OS) motivated a clinical trial of T-DXd in pediatric and adolescent/young adults with OS but was terminated early for inactivity. We evaluated the activity of T-DXd using OS patient-derived xenograft (PDX) models and found a 22% objective response rate despite no detectable HER2 expression across PDXs tested. To further assess non-HER2 mediated activity, we evaluated the activity of T-DXd across 31 pediatric cancer cell lines and found OS to be amongst the most resistant to T-DXd, as well as unconjugated deruxtecan, providing a potential explanation for the negative results observed in the clinical trial of T-DXd in OS. T-DXd evaluation in PDX models representing pediatric histologies with greater intrinsic sensitivity to deruxtecan, including pediatric renal tumors and desmoplastic small round cell tumor (DSRCT), revealed both HER2-enhanced activity, as well as substantial non-HER2 mediated activity as evidenced by equipotent activity using an isotype-matched control ADC. Together, these results underscore translational opportunities for ADC therapeutics in tumor histologies with high sensitivity to the payload, and where enhanced tumor delivery may be mediated by antibody-targeted mechanisms as well as macromolecular characteristics of ADCs (e.g., enhanced permeability and retention effect) and tumor microenvironmental factors (e.g., proteolytic payload release). Our findings challenge the role of HER2 as a biomarker predictive of T-DXd response in pediatric cancers and support further biomarker-agnostic clinical development of T-DXd in DSRCT and pediatric renal tumors. .</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006385","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":"CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer.","authors":"Ujas A Patel, Mary Y Shi, Jalal M Kazan, Kevin C J Nixon, Xiaozhuo Ran, Sree N Nair, Olivia Huang, Lifang Song, Mansi K Aparnathi, Michael Y He, Mehran Bakthiari, Rehna Krishnan, Razan K Hessenow, Vivek Philip, Troy Ketela, Verena Jendrossek, Razqallah Hakem, Housheng H He, Robert Kridel, Benjamin H Lok","doi":"10.1158/1535-7163.MCT-24-0861","DOIUrl":"10.1158/1535-7163.MCT-24-0861","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is an aggressive malignancy, with most patients presenting with prognostically poor extensive-stage disease. Limited progress in standard care stresses the urgent need for novel therapies. Radiotherapy offers some survival benefit for selected patients with SCLC but could be enhanced with radiosensitizers. In this study, we identify HDAC3 as a novel radiosensitizing target in SCLC using a CRISPR knockout screen and demonstrate its efficacy and mechanism. SBC5 cells were transduced with a custom EpiDrug single-guide RNA library and treated with ionizing radiation (IR) to identify radiosensitizing genes. HDAC3 emerged as a candidate and was validated through genetic knockdown and pharmacologic inhibition (RGFP966) in multiple SCLC cell lines. Both approaches enhanced radiosensitivity, as shown by cell viability (dose modification factor10 = 1.14-1.69) and clonogenic assays (dose modification factor10 = 1.16-1.41). We assessed changes in chromatin accessibility by assay for transposase-accessible chromatin using sequencing and IR-induced DNA damage and repair using γH2AX foci detection, double-strand break (DSB) repair assays, and immunoblotting of repair proteins. HDAC3-deficient cells exhibited increased chromatin accessibility, greater IR-induced DSBs, and impaired repair capacity, resulting in persistent DNA damage. This repair defect sensitized cells to PARP inhibitors, for which combining RGFP966 with olaparib or talazoparib produced additive to synergistic effects. In SCLC xenograft models, HDAC3 knockdown or RGFP966, combined with IR, achieved significant tumor growth inhibition. Collectively, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increased the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF13"},"PeriodicalIF":5.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961727","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":"IL15/IL15Ra complex induces an anti-tumor immune response following radiation therapy only in the absence of Tregs and fails to expand progenitor TCF1+ CD8 T cells.","authors":"Miles Piper, Chloe A Hodgson, Jacob Gadwa, Maureen Hoen, Michael W Knitz, Justin Yu, Sophia Corbo, Nicholas A Olimpo, Elliott J Yee, Yuwen Zhu, Keira Y Larson, Christian Klein, Maria Amann, Anthony J Saviola, Sana D Karam","doi":"10.1158/1535-7163.MCT-24-0900","DOIUrl":"10.1158/1535-7163.MCT-24-0900","url":null,"abstract":"<p><p>In this work, we show that the combination of radiation therapy (RT) and an IL15/IL15Rα fusion complex (denoted IL15c) fails to confer anti-tumor efficacy; however, a CD8-driven anti-tumor immune response can be elicited with the concurrent administration of an aCD25 Treg-depleting antibody. Using IL15-/- and Rag1-/- knockout mouse models, we show that the response to RT + IL15c + aCD25 is dependent on both IL15 and CTLs. Furthermore, despite an equivalent survival benefit following treatment with RT + IL15c + aCD25 and combination RT and PD1-IL2v, a novel immunocytokine with PD-1 and IL2Rbg binding domains, CTL immunophenotyping and phospho-proteomic analysis of intracellular metabolites showed a significant upregulation of activation and functionality in CD8 T cells in the RT + PD1-IL2v regimen. Finally, we show that in the absence of functional IL15 signaling, the immunostimulatory response to RT + PD1-IL2v is significantly diminished with a concurrent lack of TCF+ CD8 T cell generation, suggesting a necessity of IL15 for CD8 stem cells in mediating a durable response to treatment. Together, our results are illustrative of a mechanism wherein unimpeded effector T cell activation through IL2Rb signaling and Treg inhibition are necessary in mediating an anti-tumor immune response.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961723","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":"Anti-HER2, High-DAR Antibody Fragment-Drug Conjugates with a Glucuronide-Based MMAE Linker-Payload Demonstrate Superior Efficacy over IgG-Based ADCs.","authors":"Ioanna Stamati, Gokhan Yahioglu, Soraya Diez-Posada, Anja Pomowski, Isabel Perez-Castro, Ashleigh Stewart, Laura Bouché, Antony Constantinou, Benjamin J Stenton, Savvas Saouros, Bryan Edwards, Sam Ness, Mahendra P Deonarain","doi":"10.1158/1535-7163.MCT-24-1182","DOIUrl":"10.1158/1535-7163.MCT-24-1182","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADC) are poised to embed themselves as pillars of cancer therapy after decades of development and fine-tuning. The vast majority of those in preclinical and clinical development are based on full-length immunoglobulins employing a variety of linker-payloads and conjugation strategies. Other, smaller formats are being considered to overcome some of the current limitations of ADCs, notably poor solid tumor penetration and prolonged systemic toxin exposure. By combining stable, high-lysine-containing single-chain variable antibody fragments, compact hydrophilic linkers, and a validated payload monomethyl auristatin E (MMAE), high-drug:antibody ratio (DAR) antibody fragment-drug conjugates (FDC) were made, which retained significant binding and developability properties. Against the established target HER2, an average DAR six FDC was reproducibly obtained (equivalent to a DAR 30 ADC by mass) with picomolar binding affinity, low aggregation, and translatable pharmacokinetics. Despite the faster elimination kinetics, rapid and intense tumor payload delivery was seen leading to tumor cure efficacy in multiple HER2 tumor xenografts at dosages as low as 0.6 mg/kg given weekly four times. Internalization and tumor uptake quantification data illustrate the benefits of the higher-penetrating format. Experience with more than a dozen linker-payload structures has provided an insight into the critical design features that could make FDCs a viable alternative to ADCs in the most challenging solid tumor indications.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1295-1307"},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266740","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}