Molecular Cancer Therapeutics最新文献

{"title":"Mutant-Selective T-cell Receptor Therapy for Solid Tumors.","authors":"Samuel Parry, Charley Q Jang, Alessandro Leal, Salman R Punekar","doi":"10.1158/1535-7163.MCT-23-0894","DOIUrl":"10.1158/1535-7163.MCT-23-0894","url":null,"abstract":"<p><p>Advanced solid tumors remain largely incurable, with most patients ultimately progressing despite modern therapies, including immune checkpoint blockade. The limited impact of these approaches reflects the biological complexity of solid tumors, including intratumoral heterogeneity, an immunosuppressive microenvironment, and the predominance of \"undruggable\" oncogenic drivers. Adoptive cellular therapy (ACT) offers a complementary strategy by delivering tumor-specific lymphocytes directly into patients. Among ACT modalities, T-cell receptor (TCR)-engineered T cells stand out for their ability to recognize intracellular neoantigens presented by major histocompatibility complex molecules, thus accessing a broader antigenic landscape. Early successes, such as the FDA approvals of lifileucel and afamitresgene autoleucel, highlight the promise of these approaches, whereas proof-of-concept clinical studies demonstrate the activity of personalized neoantigen-reactive TCRs in advanced solid tumors. Major challenges remain, including safety concerns from off-tumor toxicities and resistance mechanisms such as human leukocyte antigen loss of heterozygosity. Ongoing innovations in target discovery, TCR engineering, and combination strategies aim to overcome these barriers and establish mutant-selective TCR therapy as a viable therapeutic strategy in the treatment of solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1614-1632"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840514","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 Chromatin-Modifying Enzyme, KDM5C, Enhances AKT Inhibition Response in ER+ Breast Cancer.","authors":"Valentina Cutano, Shanade Dunn, Sungmi Park-Chouinard, Eleanor M Wigmore, Qing Wu, Lambert Montava Garriga, Lorna Hopcroft, David Esopi, Michele Chirichella, Siyu Liu, Cath Eberlein, Ming Tang, Hyung Joo Lee, Wenhao Zhang, Megan Callahan, Barrett R B Nuttall, Daniel Barrell, Toby Gurran, Jennifer Hillis, Adam Spruce, Ramy Elgendy, Jenna Bradley, Chang Kim, Sara Talbot, Lingling Dai, Laura H Rosenberg, Susana Ros, Huayang Liu, Neeraj Aryal, Jerome T Mettetal, Ho Man Chan, Ultan McDermott, Simon T Barry","doi":"10.1158/1535-7163.MCT-25-1006","DOIUrl":"10.1158/1535-7163.MCT-25-1006","url":null,"abstract":"<p><p>The AKT inhibitor capivasertib has demonstrated clinical benefit in combination with the selective estrogen receptor (ER) degrader fulvestrant in PIK3CA-altered, PTEN-altered, and AKT-1-altered ER+ breast cancer. A genomewide CRISPR screen was performed in phosphoinositide (3)-kinase-AKT pathway-altered ER+ breast cancer cells exploring modifiers of response to capivasertib which identified different resistance and sensitivity drivers. Loss of chromatin regulators including lysine demethylase 5C (KDM5C) and KAT6A increased sensitivity to capivasertib. Genetic knockout (KO) or pharmacologic inhibition of KDM5C strongly enhanced the antiproliferative effects of capivasertib monotherapy, as well as in combination with fulvestrant in treatment-naïve and endocrine therapy-resistant or capivasertib-resistant ER+ breast cancer cell lines. RNA sequencing and epigenetic profiling revealed that combining capivasertib with KDM5C KO had a modest effect on gene transcription, with some effect on cell cycle-related genes and ER signaling. In contrast, combining capivasertib with fulvestrant enhanced the effects of fulvestrant on transcriptional output and promoter occupancy. Rather than influencing gene expression, loss of KDM5C combined with capivasertib increased cell stress, DNA damage, cell-cycle arrest, and cell death. Collectively, the data suggest that chromatin regulators may have different functions following capivasertib treatment, with inhibition having potential to enhance sensitivity to capivasertib in PIK3CA-altered, PTEN-altered, and AKT-1-altered ER+ breast cancer cells.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1633-1649"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691068","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":"JNJ-79032421, a Novel Membrane-Restricted Mesothelin-Targeting T Cell-Engaging Bispecific Antibody for the Treatment of Mesothelin-Positive Cancers.","authors":"Karine Smans, Thomas Nesspor, Sabine De Breucker, Erika van Heerde, Annemie Valckx, Nele Van Slycken, Katrin Sproesser, Bethany Mattson Cypert, Kathryn Packman, Gerald Chu, Jamie Fisher, Nicholas Mazzanti, Ted Petley, Winnie Chan, Brian Del Rosario, Tun Liu, Stuart Ember, Paul L Shaffer, Jacalyn S Clawson, Joshua M Bauml, Sheri Moores, Sylvie Laquerre, Paul R Gavine","doi":"10.1158/1535-7163.MCT-25-0665","DOIUrl":"10.1158/1535-7163.MCT-25-0665","url":null,"abstract":"<p><p>Mesothelin (MSLN) is a cell membrane-anchored glycoprotein overexpressed in several cancers, including pancreatic cancer, ovarian cancer, and mesothelioma. MSLN is protease-cleaved at the membrane proximal region, releasing shed MSLN (sMSLN) into the tumor microenvironment, leaving behind a membrane-bound stub. sMSLN in the tumor microenvironment is hypothesized to create a \"sink\" that could limit tumor binding of MSLN-targeted anticancer therapies. We describe JNJ-79032421, a bispecific antibody (BsAb) targeting cluster of differentiation (CD) 3 on T cells and the membrane-restricted, non-shed region of full-length MSLN on cancer cells. Crystal structure analysis confirmed JNJ-79032421 binding to the membrane-restricted, non-shed C-terminal region of MSLN. Using Western blotting, enzyme-linked immunosorbent assay (ELISA), fluorescence-activated cell sorting (FACS), and immunohistochemistry (IHC), elevated levels of sMSLN were detected in blood, serosal fluids, and tumor tissue of patients and tended to increase with MSLN tumor expression. Binding and cytotoxicity of JNJ-79032421 against cancer cell lines were unaffected by the presence of sMSLN. In cancer cell lines and cell line-derived and patient-derived xenograft mouse models, increasing levels of MSLN expression led to increased JNJ-79032421 potency. In contrast, MSLNxCD3 BsAbs, binding of which is non-membrane-restricted, demonstrated a loss of cytotoxicity in the presence of sMSLN. This \"sink\" effect was most pronounced for high-affinity non-membrane-restricted BsAbs. Increases in CD45+ and CD8+ T-cell infiltration, as well as CD8+ T-cell activation, observed in xenograft tumor tissues were time-dependent and JNJ-79032421 dose-dependent. Overall, these data suggest that JNJ-79032421 may offer meaningful clinical activity by avoiding binding to sMSLN.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1585-1598"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147344703","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":"Balancing the Dual Mechanisms of Anti-VISTA mAbs for Antitumor Activity: CD8+ T-cell Responses and Fc-Dependent Depletion of VISTA-Expressing Immune Cells.","authors":"Miaomiao He, Tianqi Cao, Kailun Wang, Zhizhong Wei, Yuting Guo, Fang Yang, Yizhe Chen, Ximing Liu, Yajing Yang, Xinyan Hao, Xinxin Tian, Jianhua Sui","doi":"10.1158/1535-7163.MCT-24-1214","DOIUrl":"10.1158/1535-7163.MCT-24-1214","url":null,"abstract":"<p><p>V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune checkpoint and an emerging target for cancer immunotherapy, yet its broad expression on myeloid cells and T cells has complicated therapeutic antibody development. Here, we report two monoclonal antibodies (mAb), Vs22 and Mu61, which were engineered from a common parental antibody and are cross-reactive with both human VISTA (hVISTA) and mouse VISTA (mVISTA). Vs22 demonstrates antitumor efficacy in the CT26 syngeneic model, whereas Mu61 is ineffective despite having a slightly higher affinity for mVISTA than Vs22. Although both mAbs block VISTA-ligand interactions and deplete VISTA+ tumor-infiltrating immune cells via NK cytotoxicity, they differed in several aspects: they recognize similar but nonidentical epitopes; only Vs22 enhances cytokine production by CD8+ T cells; and Vs22 exhibits a better pharmacokinetic (PK) profile and greater VISTA endocytosis. This multifaceted profile likely underlies Vs22's antitumor efficacy, in contrast to the inactive Mu61. Mechanistic studies revealed that Vs22's antitumor activity requires coordinated fragment antigen-binding (Fab)-mediated VISTA blockade and fragment crystallizable (Fc) effector function and Vs22 treatment leads to durable, tumor-specific immune memory. Notably, combining Vs22 with TABBY106, an agonistic anti-4-1BB antibody, produced synergistic antitumor effects across CT26, MC38, and EMT6 models, substantially outperforming monotherapy. Collectively, we identify Vs22 as a cross-species anti-VISTA mAb that achieves effective tumor control by simultaneously blocking VISTA signaling and engaging strong Fc-mediated cytotoxicity. The synergy between Vs22 and 4-1BB stimulation highlights a promising combination strategy to enhance antitumor immunity and supports the clinical translation of VISTA-targeting therapeutics.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1702-1715"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499415","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":"ABL209 (NEOK002): Designing an EGFR × MUC1 Bispecific TOP1i ADC with Promising Antitumor Activity and Enhanced Therapeutic Window.","authors":"Bora Lee, Hyeon Ji Park, Byeong Min Yoo, Hangil Kim, Arim Seo, Youngeun Hong, Yo-Seob Lee, Donghoon Yeom, Yong-Gyu Son, Jaehyun Eom, Daehae Song, Byungje Sung, Jinhyung Ahn, Junyoung Kim, Weon-Kyoo You, Sang Hoon Lee, Jinwon Jung","doi":"10.1158/1535-7163.MCT-26-0088","DOIUrl":"10.1158/1535-7163.MCT-26-0088","url":null,"abstract":"<p><p>ABL209 (NEOK002) is a bispecific antibody-drug conjugate (ADC) designed to enhance efficacy and therapeutic window through dual targeting of the epidermal growth factor receptor (EGFR) and mucin 1 (MUC1). EGFR is a key oncogenic driver in multiple tumor types; however, clinical targeting of EGFR is limited by dose-dependent skin toxicity. MUC1 is a tumor-associated antigen characterized by aberrant glycosylation and overexpression, but its expression can be heterogeneous, and the MUC1 extracellular domain is shed from the tumor, limiting monospecific targeting of MUC1. ABL209 is a heterodimeric 1 + 1 bispecific ADC with a drug-to-antibody ratio of 4, conjugated with tavatecan. ABL209 demonstrated enhanced cell binding and internalization compared with monospecific EGFR or MUC1 ADCs. ABL209 did not seem to inhibit the proliferation of human epidermal keratinocytes in vitro, unlike cetuximab-based ADCs. In vivo, ABL209 resulted in complete regression of tumors with single doses as low as 1.5 mg/kg in a CFPAC-1 pancreatic cell line-derived xenograft model. ABL209 demonstrated tumor growth inhibition across all 36 tested patient-derived xenograft models, inducing tumor regressions in 78% of models and showing efficacy in 6 of 10 KRAS-mutant tumors. Cotreatment with sotorasib prolonged tumor regression in a KRAS-mutated NCI-H1373 model for 58 days following treatment. ABL209 showed a favorable pharmacokinetic profile with a half-life of 5.2 days at 10 mg/kg in monkeys. ABL209 was well tolerated in monkeys up to 40 mg/kg. Our data suggest that a bispecific ADC leverages the benefits of cotargeting two antigens, resulting in enhanced antitumor activity while reducing liabilities through attenuated target-related toxicities.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1599-1613"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729497","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":"Identification of CD74-Positive Antigen-Presenting Glioma Cells in Primary Human Tumors and Murine Models of NF1 High-Grade Glioma.","authors":"Stephanie N Brosius, Jonathan H Sussman, Isabella A DiStefano, Grant P Grothusen, Keanu N Natan, Isabelle Seka, Steven Foltz, Katherine Labella, Kristopher R Bosse, Kai Tan, Thomas De Raedt","doi":"10.1158/1535-7163.MCT-25-1215","DOIUrl":"10.1158/1535-7163.MCT-25-1215","url":null,"abstract":"<p><p>Compared with the general population, individuals with neurofibromatosis type 1 have a 50-fold higher risk of developing a high-grade glioma (HGG) in their lifetime. Despite improved understanding of the molecular and cellular drivers of these neoplasms, we have yet to translate this knowledge into therapies that improve overall survival. One limitation has been the paucity of in vivo models for drug testing within this population. We generated three distinct glioma stem cell lines from HGGs arising in mice with Nf1 and Trp53 mutations in cis (NPcis) and characterized the allografts resulting from one Nf1-glioma stem cell line (Nf1-HGG17) by single-cell and single-nucleus RNA sequencing. Because our cell lines are grown in stem cell media, there is an inherent reduction of the differentiation states present in primary HGG, with only oligodendrocyte precursor-like and neural-like cells identified. However, orthotopic allografts of Nf1-HGG17 regained the other differentiation states typically observed in HGG and glioblastoma (neuronal progenitor cell-like and astrocyte-like). About half of the neoplastic cells cluster separately from these classical groups and highly express genes of the antigen presentation machinery, including Cd74, which we also observed in patient samples. Notably, heterozygosity of Nf1 within the tumor microenvironment does not cause marked changes in the immune tumor microenvironment, gene expression, or differentiation states of neoplastic cells. These data indicate that allografted HGG lines from NPcis mice are an effective model of NF1-HGG, mimicking the complexity observed in human HGG that can be used for larger-scale in vivo drug screening and evaluation.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1731-1741"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13204374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147609491","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":"An Integrin β6-Targeted Antibody-Drug Conjugate Optimized for Intravesical Delivery to Treat Non-Muscle-Invasive Bladder Cancer.","authors":"Christopher M Carosino, Devra J Olson, Rebecca C Mazahreh, David J Ortiz, Steve Duniho, Eliana Moskovitz, Marlena Gray, Renee F Hein, Nicolas H Garcia, Hamidreza Ardalani, Lauren Farr, Tianyang Yan, Maddy Burcher, Iliyana Mikell, Matthew R Levengood, Sharsti Sandall, Joseph D Dekker","doi":"10.1158/1535-7163.MCT-26-0077","DOIUrl":"10.1158/1535-7163.MCT-26-0077","url":null,"abstract":"<p><p>Non-muscle-invasive bladder cancer (NMIBC) accounts for 75% of all new bladder cancer diagnoses. Despite new therapeutic treatment options aiming to replace Bacillus Calmette-Guérin (BCG), the standard of care for 40+ years, high rates of failure and recurrence of disease remain in patients with NMIBC. Integrins are a large family of cell surface receptors involved in key biological processes such as cellular adhesion, motility, and cytokinesis, and integrin β-6 (IB6) has emerged as a clinically relevant target due to its restricted expression in normal adult epithelial tissues and elevated levels in solid tumors. IB6 is being actively tested in lung cancer with the antibody-drug conjugate (ADC) sigvotatug vedotin. In this study, we introduce PF-08052667, an IB6-directed ADC that has been optimized for local delivery via intravesical dosing in patients with NMIBC. PF-08052667 leverages the high and consistent expression of IB6 in NMIBC tumors for efficient ADC internalization. In PF-08052667, an average of 8 monomethyl auristatin E molecules are attached to an IB6-specific humanized IgG1 antibody via a glucuronide linker shown to increase potency in vitro. PF-08052667 efficacy was further optimized when administered after a bladder prewash, which improved ADC delivery to the bladder tissue. The combination of highly potent PF-08052667 with bladder prewash demonstrated enhanced in vivo efficacy while maintaining minimal systemic exposure and no systemic toxicity. Together, the results position PF-08052667 as a potential first-in-class ADC optimized for intravesical delivery and support further clinical examination in an ongoing phase I trial testing safety and efficacy in BCG-unresponsive and BCG-exposed NMIBC (NCT07206225).</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1716-1730"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729504","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":"Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance.","authors":"Chengxi Li, Yu-Hsuan Chang, Minori Maki, Ikuko Omori, Naru Sato, Susumu Goyama, Toshio Kitamura, Yutaka Enomoto","doi":"10.1158/1535-7163.MCT-25-0986","DOIUrl":"10.1158/1535-7163.MCT-25-0986","url":null,"abstract":"<p><p>Venetoclax (VEN), a selective BCL-2 inhibitor, effectively induces apoptosis in a wide range of malignancies. VEN-based regimens, which combine VEN with either hypomethylating agents or low-dose cytarabine, have markedly improved treatment outcomes in elderly patients with acute myeloid leukemia (AML). However, approximately one third of patients exhibit intrinsic resistance to these regimens, and the majority of initial responders eventually develop acquired resistance. Therefore, intrinsic and acquired resistance to VEN-based regimens remains a major barrier to achieving durable clinical responses in patients with AML. In this study, we aimed to identify effective treatment strategies to overcome VEN resistance. Among the drugs tested in this study, we found that bortezomib (BTZ), a proteasome inhibitor, showed potent synergy with VEN in inducing apoptosis in a wide range of AML cell lines, irrespective of RAS or TP53 mutation status. Mechanistically, BTZ upregulates proapoptotic proteins such as NOXA, BIM, and PUMA, which neutralize MCL1 and promote apoptosis. Notably, NOXA upregulation plays a critical role in the efficacy of the combination of VEN and BTZ. Moreover, BTZ resensitized AML cell lines with acquired resistance to VEN, further supporting its role in overcoming therapeutic resistance. Importantly, the combination of BTZ and VEN significantly prolongs the survival of mice inoculated with a VEN-resistant AML cell line harboring BAX mutations, which are commonly observed in relapsed AML following VEN-based regimens and confer resistance to VEN by inhibiting the BAX-dependent apoptotic pathway. Collectively, this study provides a rationale for the VEN-BTZ combination as a potential strategy to overcome VEN resistance in certain AML subsets.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1650-1663"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513526","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":"YB-1 Inhibition Suppresses Osteosarcoma Growth and Reverses Tumor Immunosuppression.","authors":"Kirsten Stefan, Jee Min Lee, Dhanir Tailor, Arpit Dheeraj, Annah S Rolig, Sokchea Khou, Benedikt W Grau, Fernando J Garcia-Marques, Abel Bermudez, Lara E Davis, Sharon J Pitteri, Sanjay V Malhotra","doi":"10.1158/1535-7163.MCT-25-1240","DOIUrl":"10.1158/1535-7163.MCT-25-1240","url":null,"abstract":"<p><p>Osteosarcoma, the most common primary bone malignancy in adolescents and young adults, is still marked by poor long-term survival and high mortality. Although immune checkpoint blockade (ICB) has transformed treatment for several cancers, its benefit in osteosarcoma has been minimal, largely due to osteosarcoma's \"immune-cold\" phenotype characterized by scarce tumor-infiltrating lymphocytes. Novel strategies are urgently needed to overcome this resistance. Y-box binding protein 1 (YB-1), a pro-oncogenic member of the cold-shock protein superfamily, represents a promising target to sensitize osteosarcoma to ICB. In this study, we evaluate SU056, a small-molecule YB-1 inhibitor, which both suppressed intrinsic osteosarcoma tumor growth and remodeled the tumor microenvironment. SU056 treatment markedly reduced immunosuppressive populations, including regulatory T cells and M2-polarized tumor-associated macrophages, while enhancing the infiltration of granzyme B-positive cytotoxic CD8+ T and NK cells. Combination therapy with SU056 and anti-PD-1 blockade produced superior tumor growth inhibition and significantly prolonged survival compared with either monotherapy. These findings highlight SU056 as a potent immunomodulatory agent and support its coadministration with ICB as a promising therapeutic approach for osteosarcoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1678-1690"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776564","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 NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.","authors":"Zachary A Schaaf, Shu Ning, Amy R Leslie, Masuda Sharifi, Richard Y Gao, James P Maine, Kristina D Leslie, Yuqiu Shen, Alan P Lombard, Wei Lou, Pui-Kai Li, Chengfei Liu, Marc Dall'Era, Allen C Gao","doi":"10.1158/1535-7163.MCT-25-1157","DOIUrl":"10.1158/1535-7163.MCT-25-1157","url":null,"abstract":"<p><p>Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) remains a major challenge in the treatment of advanced prostate cancer. Although metabolic rewiring has been implicated in this process, the molecular drivers and therapeutic vulnerabilities underlying this adaptation remain poorly defined. We integrated transcriptomic, functional, and clinical analyses to identify mitochondrial regulators of PARPi resistance. RNA sequencing and gene set enrichment analysis revealed robust enrichment of oxidative phosphorylation (OxPhos) pathways in PARPi-resistant prostate cancer cells, with consistent upregulation of NDUFS4, a nuclear-encoded subunit of electron transport chain complex I. Elevated NDUFS4 expression correlated with poor survival in patient cohorts from The Cancer Genome Atlas and SU2C/PCF. Functional analyses demonstrated that genetic knockdown of NDUFS4 impaired complex I activity, reduced mitochondrial mass, and resensitized resistant cells to olaparib. Pharmacologic targeting of NDUFS4 using the niclosamide analog ARVib-7 phenocopied genetic depletion, suppressing mitochondrial respiration and enhancing olaparib efficacy to inhibit the growth of resistant spheroids. Both NDUFS4 silencing and ARVib-7 treatment induced ferroptotic stress, as evidenced by intracellular iron accumulation and altered expression of ferroptosis-associated markers, including COX2, CHAC1, NRF2, and GPX4. These findings identify NDUFS4 as a key mediator of PARPi resistance and a therapeutic vulnerability in advanced prostate cancer. Targeting NDUFS4 disrupts OxPhos and induces ferroptosis, providing a strong rationale for combination strategies with PARPis to overcome drug resistance.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1742-1754"},"PeriodicalIF":6.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13159469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840529","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}