Molecular Cancer Therapeutics最新文献

{"title":"Development of multivalent FAP-targeted Small Molecule-Drug Conjugates with tailored MMAE release kinetics.","authors":"Matilde Bocci, Lucrezia Principi, Dario Neri, Samuele Cazzamalli, Ettore Gilardoni, Andrea Galbiati","doi":"10.1158/1535-7163.MCT-25-0026","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0026","url":null,"abstract":"<p><p>Antibody-Drug Conjugates (ADCs) are one of the most diffused targeted therapeutic modalities for cancer treatment and consist of a tumor-targeted monoclonal antibody connected to a cytotoxic payload, which is released selectively at the tumor site. Small Molecule-Drug Conjugates (SMDCs) represent an alternative approach, where the antibody is replaced by a tumor-homing small organic ligand. Thanks to their small molecular size, SMDCs are characterized by rapid extravasation and enhanced penetration in solid tumors compared to ADCs. We recently developed SMDCs targeting Fibroblast Activation Protein (FAP), a cell surface endopeptidase abundant in the tumor microenvironment, using the highly specific FAP inhibitor OncoFAP as a targeting moiety. In this study, we compared the tumor-targeting properties and in vivo activity of SMDCs based on OncoFAP against products based on a stronger FAP inhibitor (i.e., trivalent OncoFAP), aiming to tune the release kinetic of the cytotoxic payload to the neoplastic site. We compared the kinetic profiles of the monovalent and trivalent derivatives of OncoFAP through in vivo and ex vivo biodistribution and therapy studies. The distinct in vivo MMAE release obtained for OncoFAP-GlyPro-MMAE and TriOncoFAP-GlyPro-MMAE did not lead to substantial differences in therapeutic efficacy in a preclinical FAP-positive cancer model.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528882","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":"Cancer Cell Permeability Induced by Tumor Treating Fields (TTFields) as a Physical Approach to Improve Chemotherapy Uptake and Overcome Multidrug Resistance.","authors":"Bella Koltun, Tali Voloshin, Cfir David, Tal Kan, Yiftah Barsheshet, Alexandra Volodin, Shay Cahal, Catherine Tempel-Brami, Mai Shai, Sara Jacobovitch, David Roash-Lancry, Boris Brant, Noa Kaynan, Lilach Koren, Anat Klein-Goldberg, Efrat Zemer Tov, Rom Paz, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti","doi":"10.1158/1535-7163.MCT-25-0019","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0019","url":null,"abstract":"<p><p>Multidrug resistance (MDR) is a major challenge in cancer treatment. One predominant MDR mechanism involves the overexpression of ATP-binding cassette (ABC) transporter proteins on the cell membrane, leading to increased chemotherapy efflux. Strategies to resolve MDR have not yet yielded substantial survival benefits. Tumor Treating Fields (TTFields) represent an innovative therapeutic modality for cancer treatment and have been shown to enhance membrane permeability in glioblastoma cells. The current study aimed to characterize this phenomenon and to evaluate its potential to increase chemotherapy accumulation, thus overcoming MDR. In vitro analyses using the exclusion dye 7-aminoactinomycin D (7-AAD) demonstrated that TTFields-induced enhancement of cancer cell permeability is pan-cancer, reversible, specific to cancer cells, and requires cell-cycle progression through the G2/M phase. Furthermore, TTFields significantly increased intracellular accumulation of doxorubicin (DOX), mitoxantrone (MTX), and cisplatin (CIS) in resistant cells, restoring uptake to levels observed in sensitive cells, without altering MDR transporter expression. Increased chemotherapy accumulation was confirmed in vivo, as demonstrated by elevated DOX accumulation in breast tumors and paclitaxel (PTX) accumulation in lung tumors. Importantly, TTFields sensitized both DOX-sensitive and DOX-resistant cells to DOX-induced cytotoxicity in vitro. In mouse models bearing breast tumors, co-administration of sub-therapeutic or therapeutic DOX doses with TTFields significantly reduced tumor growth compared to either treatment alone. In conclusion, the findings suggest that adding TTFields to chemotherapy regimens may enhance drug delivery and efficacy in tumors exhibiting MDR. Further clinical studies evaluating TTFields concomitant with chemotherapy in MDR cancer patients are warranted.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528881","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 DDR2 for Treating Pancreatic Cancer.","authors":"Chris Tp Do, Prabhakar Pitta Venkata, Jack Y Prochnau, Deepika Singh, Santosh Timilsina, Panneerdoss Subbarayalu, Daisy Medina, Shahad Abdulsahib, Saif Nirzhor, Sajid Khan, Guiming Li, Srikanth R Polusani, Daohong Zhou, Pei Wang, Yidong Chen, Ratna K Vadlamudi, Matthew J Hart, Radhika Amaradhi, Stanton F McHardy, Manjeet K Rao","doi":"10.1158/1535-7163.MCT-24-1226","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1226","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited effective treatments, partly due to its complex tumor microenvironment. Herein, we report Discoidin Domain Receptor 2 (DDR2), a receptor tyrosine kinase, as a critical protein that promotes PDAC growth and survival. Our results reveal that DDR2 is highly expressed, and its expression correlates with the worst survival outcome of PDAC patients. Using an unbiased high throughput screen of small molecule inhibitor libraries, we identified CIDD-8633, a novel inhibitor targeting DDR2. Our study suggests that CIDD-8633 interacts with DDR2 and inhibits DDR2-associated signaling. Importantly, in vivo studies demonstrate that CIDD-8633 effectively blocks PDAC tumor growth in preclinical mouse models. Additionally, combining CIDD-8633 with gemcitabine enhanced its efficacy synergistically. Mechanistically, CIDD-8633 treatment induces pro-apoptotic genes in PDAC cells. These findings position DDR2 as a promising therapeutic target and CIDD-8633 as a potential DDR2 inhibitor, offering new avenues for treatment of PDAC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497509","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":"Ubiquitin-specific protease 6 (USP6) mRNA lipid nanoparticles ignite anti-tumor immunity and suppress tumorigenesis in Ewing sarcoma.","authors":"Ian C Henrich, Margaret M Billingsley, Kanika Jain, Shreya Mondal, Laura N Quick, Robert Young, Ngan Nguyen, Andre M Oliveira, Gerd A Blobel, Michael J Mitchell, Margaret M Chou","doi":"10.1158/1535-7163.MCT-24-0173","DOIUrl":"10.1158/1535-7163.MCT-24-0173","url":null,"abstract":"<p><p>Ewing sarcoma (ES) is an aggressive pediatric cancer that has remained refractory to current therapeutics. Immunotherapy has been unsuccessful in ES, largely due to poor understanding of how its immune tumor microenvironment (TME) is regulated. We recently demonstrated that ubiquitin-specific protease 6 (USP6) can remodel the ES immune landscape to engender an anti-tumorigenic TME. USP6 expression in ES cells enhances surface expression of immunostimulatory ligands and receptors, and induces production of multiple chemokines, driving recruitment and activation of tumor-suppressive immune lineages, including natural killer (NK) cells. We sought to harness this multi-faceted immunostimulatory function into a novel therapeutic by delivering in vitro transcribed USP6 mRNA via ionizable lipid nanoparticles (LNPs). Treatment of ES cells with USP6 mRNA in vitro is capable of inducing the aforementioned anti-tumorigenic and immunostimulatory responses. In addition, USP6 mRNA-treated ES cells elicit cytolytic activation of primary human CD8+ and CD4+ T lymphocytes and NK cells in vitro. Intratumoral (IT) delivery of USP6 mRNA LNPs suppresses growth of ES xenografts, coincident with increased immune infiltration and activation. We further demonstrate that USP6 mRNA is capable of igniting an immunostimulatory program in other cancer types (including acute myeloid leukemia (AML), melanoma, prostate cancer, head and neck cancer, and osteosarcoma) in vitro, and suppressing AML xenograft growth in vivo. Treatment with USP6 mRNA LNPs was well-tolerated, with no observed gross toxicity. Together, these pre-clinical studies provide proof-of-concept for the immunogenic and anti-tumorigenic efficacy of USP6 mRNA LNPs, and support its promise as a novel immunotherapeutic in diverse cancer types.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485134","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":"PV-10 triggers immunogenic cell death in head and neck squamous cell carcinoma via endoplasmic reticulum stress and apoptosis.","authors":"Sowjanya Thatikonda, Ritu Chaudhary, Yeva Meshkovska, Maria Biernacki, Robbert J C Slebos, Xiaofei Song, MacLean S Hall, Kenneth Lilley, Shari Pilon-Thomas, Jose A Guevara-Patino, Philippe E Spiess, Jad Chahoud, Antonio L Amelio, Eric A Wachter, Dominic Rodrigues, Christine H Chung","doi":"10.1158/1535-7163.MCT-24-0218","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0218","url":null,"abstract":"<p><p>Primary risk factors of head and neck squamous cell carcinoma (HNSCC) include human papillomavirus (HPV) infection and exposure to tobacco and excessive alcohol. Despite currently available treatments, patients with recurrent HNSCC still have poor survival, highlighting the need for innovative therapies. PV-10, also known as rose bengal sodium (RBS, 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein disodium), is a small molecule being developed as an intralesional (IL) therapeutic agent, exhibiting substantial anti-tumor activity across diverse cancer types, but current knowledge regarding the molecular mechanisms involved in response to PV-10 remains limited. We evaluated the cytotoxic effects of PV-10 in HNSCC and explored its molecular mechanisms. In vitro, we found that PV-10 induced cytotoxicity in mEER and MTE-RAS cell lines, primarily by increasing the production of reactive oxygen species and leading to apoptosis through a caspase-dependent mechanism. Additionally, we observed that PV-10 treatment increased the release of damage-associated molecular pattern molecules such as HMGB1 and ATP and enhanced expression of calreticulin, HSP-70, and HSP-90 indicating potent immunogenic cell death (ICD). In vivo, IL PV-10 injections led to significant tumor regression in both mEER and MTE-Ras models. Complete responses (CR) were observed in 7 of 21 (33%) mice in mEER although no CR was observed in MTE-Ras. Our data suggests that one of the possible mechanisms by which PV-10 triggers ICD is by inducing endoplasmic reticulum stress, autophagy, and apoptosis. Our findings contribute to further understanding of the underlying mechanisms of PV-10 induced cytotoxicity and to develop future clinical trials in locally recurrent HNSCC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476058","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":"Antitumor Effect of Farletuzumab ecteribulin in Molecular Subtypes of Endometrial Cancer Patient-Derived Xenograft Models.","authors":"Shigehiro Yagishita, Sho Sato, Daisuke Shintani, Tadaaki Nishikawa, Aiko Ogasawara, Masanori Yasuda, Hironori Ishii, Keiji Furuuchi, Toshimitsu Uenaka, Hiroshi Yoshida, Kosei Hasegawa, Akinobu Hamada","doi":"10.1158/1535-7163.MCT-25-0035","DOIUrl":"10.1158/1535-7163.MCT-25-0035","url":null,"abstract":"<p><p>Endometrial cancer (EC) represents a significant health burden globally, particularly in postmenopausal women. Current treatment options for advanced-stage EC remain limited, emphasizing the need for novel therapeutic strategies. This study aimed to investigate farletuzumab ecteribulin (FZEC), an antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα), as a potential new therapeutic agent for EC. We utilized a panel of 22 patient-derived xenograft (PDX) models, representing various histological and molecular subtypes of EC with different levels of FRα expression, to evaluate the antitumor effect of FZEC. FZEC was administered intravenously at doses of 5 mg/kg and 12.5 mg/kg on day 0. Intratumoral accumulation of eribulin, the payload of FZEC, was visualized using phosphor-integrated dot imaging. FZEC demonstrated dose-dependent antitumor effects across the EC-PDX panel. At 5 mg/kg, the FZEC efficacy was associated with FRα expression, with 100% of FRα 3+ models exhibiting tumor shrinkage compared to 33.3% of FRα-negative models. FZEC also demonstrated broad activity across both histological and molecular subtypes. Intratumoral eribulin accumulation was highly correlated with antitumor effects, even in models with low FRα expression. Follow-up studies confirmed FRα-dependent antitumor effects, while also indicating potential FRα-independent mechanisms of action. FZEC demonstrated robust antitumor effect against the FRα high EC-PDX modelswith significant antitumor effects also observed, even in FRα-low or negative models. Notably, intratumoral eribulin accumulation exhibited a stronger correlation with efficacy than with FRα expression alone. These findings support further clinical development of FZEC for EC treatment and highlight the complexity of the mechanisms of action of ADCs.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369079","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":"Antineoplastic activity of a novel tri-specific single chain antibody targeting the hERG1/β1 integrin complex and TRAIL receptors.","authors":"Claudia Duranti, Jessica Iorio, Chiara Capitani, Tiziano Lottini, Michele Martinelli, Julia Roosz, Nicole Anderle, Tengku Ibrahim Maulana, Peter M Loskill, Rossella Colasurdo, Cesare Sala, Lara Magni, Annarosa Arcangeli","doi":"10.1158/1535-7163.MCT-24-0646","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0646","url":null,"abstract":"<p><p>Targeted therapies and immunotherapies have largely improved cancer treatment in the last years. One of the most promising approaches is the induction of tumor apoptosis by the Tumor Necrosis Factor (TNF) Related Apoptosis Inducing Ligand (TRAIL) through its binding to apoptosis-inducing receptors DR4 and DR5 on the plasma membrane of target cells. However, some constraints (e.g. the short in vivo half-life, the poor activity on DR5 receptors) hinder the use of naked, soluble forms of TRAIL. Previous studies have shown that fusing TRAIL sequences with antibody-based moieties may represent a novel and efficacious strategy to overcome such hindrances. On these bases, novel TRAIL-related anticancer therapeutic strategies are being developed. In the present paper we describe a novel antibody represented by a single chain diabody directed against a cancer-specific target, i.e. the hERG1/β1 integrin complex-scDb-hERG1-β1- fused with three TRAIL sequences. The scDb-hERG1-b1-TRAIL antibody combines the specific targeting and the down regulation of cancer-specific signaling pathways by the scDb-hERG1-b1 with the pro-apoptotic activity triggered by TRAIL. We provide substantial evidence of the efficacy of the scDb-hERG1-b1-TRAIL antibody to decrease tumor growth triggering apoptotic cell death in vitro in Breast Cancer (BCa) cells as well as in vivo in a mouse model of Triple Negative BCa (TNBCa). Being characterized by a favorable pharmacokinetic and toxicity profile, the scDb-hERG1-b1-TRAIL antibody can be proposed for the treatment of difficult to treat cancers, such as TNBCa, which express the hERG1/β1 complex and TRAIL receptors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326229","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":"Acrolein induces exosomal miR-30a-5p/NCAM1 axis promoting glioma progression.","authors":"Hong-Chieh Tsai, Pei-Yu Liu, Zhen-Jie Tong, Chian-You Wu, Ya-Rou Lin, Kuo-Chen Wei, Chiung-Yin Huang, Ko-Ting Chen, Ya-Jui Lin, Pin-Yuan Chen, Hsiang-Tsui Wang","doi":"10.1158/1535-7163.MCT-25-0117","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-0117","url":null,"abstract":"<p><p>Glioblastoma (GBM), a highly aggressive brain tumor, thrives in hypoxic environments. Tumor-derived exosomes are key drivers of glioma progression, facilitating tumor growth, immune evasion, angiogenesis, and therapy resistance. Acrolein, a toxic byproduct produced under hypoxic conditions, causes DNA damage, inflammation, mitochondrial dysfunction, and potentiates oxidative stress. Elevated acrolein levels and associated DNA damage are linked to poor GBM prognosis. This study aims to uncover the role of acrolein in GBM progression through exosome-mediated pathways and the associated molecular mechanisms. We found that acrolein production under hypoxia promotes GBM cell malignant behavior, such as migration and spheroid formation, by downregulating neural cell adhesion molecule 1 (NCAM1) via autocrine and paracrine signaling of miR-30a-5p. Inhibiting the miR-30a-5p/NCAM1 axis reverses the tumor-promoting effects of acrolein treatment. Analysis of tumor samples from GL261 tumor-bearing mice and glioma patients showed that decreased NCAM1 levels in glioma tissues correlate with elevated acrolein expression. In patient GBM samples, lower NCAM1 levels are associated with a worse prognosis. This study suggests that targeting the miR-30a-5p/NCAM1 axis could be a potential therapeutic strategy for GBM.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289413","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":"The antibody-drug conjugate sacituzumab govitecan (IMMU-132) represents a potential novel therapeutic strategy in cholangiocarcinoma.","authors":"Racha Hosni, Niklas Klümper, Christine Sanders, Sana Hosni, Vittorio Branchi, Alexander Semaan, Abdullah Alajati, Natalie Pelusi, Susanna S Ng, Damian J Ralser, Saif-Eldin Abedellatif, Hanno Matthaei, Jörg Kalff, Jasmitha Boovadira Poonacha, Veronika Lukacs-Kornek, Glen Kristiansen, Maria A Gonzalez-Carmona, Michael Hölzel, Marieta I Toma","doi":"10.1158/1535-7163.MCT-24-0972","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0972","url":null,"abstract":"<p><p>Cholangiocarcinoma is a rare and aggressive cancer type with limited therapeutic options. Several novel antibody-drug conjugates (ADCs) have demonstrated promising anti-tumor activity in solid tumors. This study aimed to investigate the expression and the potential prognostic role of the protein targets of the recently-developed ADCs, in cholangiocarcinoma. Moreover, the study aimed to establish patient-derived tumor organoids (PDOs) and to employ them for in vitro ADC testing. We evaluated the expression of TROP2, NECTIN4, folate receptor 1, HER2, and HER3 via immunohistochemistry (IHC) in a cholangiocarcinoma tissue microarray (TMA) (n=113) and analyzed the expression level with respect to clinico-pathological parameters. Furthermore, we generated cholangiocarcinoma PDO culture lines and used them to test the anti-tumor activity of ADCs in vitro. IHC analyses revealed that TROP2 was the most frequently expressed (91% of cases), followed by folate receptor 1 (51%), NECTIN4 (49%), HER3 (20%), and HER2 (7%). TROP2 showed moderate to high expression (H-score ≥100) in 74% of cases. No significant correlations with overall or disease-free survival, tumor grade, or tumor stage were observed. Six cholangiocarcinoma PDO lines were successfully established (55% success rate). All PDO lines expressed TROP2 concordantly with their parental tumors and showed growth-inhibition (IC50= 0.1 to 0.4 µg/mL) in response to sacituzumab govitecan (TROP2-targeting ADC). This study reveals that TROP2 is widely expressed in cholangiocarcinoma. Moreover, it provides preclinical evidence for the potential of use of sacituzumab govitecan as a novel therapeutic strategy in treating cholangiocarcinoma patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285510","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 (FDC) with a Glucuronide-based MMAE linker-payload demonstrates 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":"https://doi.org/10.1158/1535-7163.MCT-24-1182","url":null,"abstract":"<p><p>Antibody-Drug Conjugates (ADCs) 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 tumour penetration and prolonged systemic toxin exposure. By combining stable, high-lysine containing single-chain Fv antibody fragments, compact hydrophilic linkers and a validated MMAE (monomethyl auristatin-E) payload, high-DAR (Drug:Antibody Ratio) FDCs (Antibody-Fragment Drug Conjugates) were made which retained significant binding and developability properties. Against the established target HER2, an average DAR 6 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 tumour payload delivery was seen leading to tumour cure efficacy in multiple HER2 tumour xenografts at doses as low as 0.6mg/kg given 4-times, weekly. Internalization and tumour uptake quantification data illustrate the benefits of the higher-penetrating format. Experience with over 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 tumour indications.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-10","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}