Cancer research最新文献

{"title":"Comprehensive Characterization of Somatic Mutation Timing Reveals the Evolutionary Trajectory of Lung Adenocarcinoma in Chinese Patients","authors":"Na Qin, Zhoufeng Wang, Xianfeng Xu, Yuan Xie, Yingjia Chen, Wenxin Luo, Pan Tang, Xin Wang, Lingfeng Bi, Linnan Gong, Zhe Li, Congcong Chen, Kai Wang, Songwei Guo, Zihuan Zhao, Jun Xiang, Meng Zhu, Yue Jiang, Yuanlin He, Juncheng Dai, Rong Yin, Cheng Wang, Zhibin Hu, Hongxia Ma, Weimin Li, Hongbing Shen","doi":"10.1158/0008-5472.can-24-1799","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1799","url":null,"abstract":"Lung adenocarcinoma (LUAD) is a heterogeneous disease with substantial genomic differences between individuals of Chinese and European ancestry. Deciphering the timing of driver mutations may lead to insights into tumor evolution that can inform diagnostic and therapeutic approaches for LUAD. Here, we conducted whole-genome sequencing on LUAD samples from 251 patients with Chinese ancestry to reconstruct the evolutionary trajectories of somatic alterations, especially those across the non-coding regions. Tobacco-related mutations preferentially occurred early and plateaued at 28 packs of cigarettes per year. Well-known driver mutations (e.g., EGFR, TP53, and RB1) also occurred at the early stage, displaying ancestry heterogeneity among smokers. In contrast to exogenous mutagens, endogenous mutagen-related alterations (APOBEC) occurred late. The 3’UTR was the most frequently altered non-coding element in LUAD, with recurrent disrupting mutations in the 3’UTR of SFTPB and SFTPA1. Unlike other cancer types, TERT promoter mutations were observed specifically among female LUAD patients. Clustered mutations (e.g., doublet-base substitutions, multi-base substitutions, and kataegis) influenced LUAD evolution and were overrepresented in driver genes. These findings provide insights into the dynamic nature of genomic alterations during lung tumorigenesis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"43 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Anti-EGFR Antibody-Drug Radioconjugate Labeled with Actinium-225 Elicits Durable Antitumor Responses in KRAS- and BRAF-Mutant Colorectal Cancer.","authors":"Anjong Florence Tikum, Nikita W Henning, Jessica Pougoue Ketchemen, Alireza Doroudi, Hanan Babeker, Fabrice Ngoh Njotu, Emmanuel Nwangele, Alissar Monzer, Bridget Gray, Emina Torlakovic, Maruti Uppalapati, Humphrey Fonge","doi":"10.1158/0008-5472.CAN-24-2266","DOIUrl":"10.1158/0008-5472.CAN-24-2266","url":null,"abstract":"<p><p>EGFR is expressed in approximately 80% to 85% of colorectal cancers. Although anti-EGFR antibodies benefit some patients with colorectal cancer, tumors with Kirsten rat sarcoma viral oncogene (KRAS) or B-rapidly accelerated fibrosarcoma (BRAF), a proto-oncogene serine/threonine protein kinase, mutations are resistant. In this study, we developed a theranostic approach that uses an anti-EGFR antibody-drug conjugate labeled with either [225Ac]Ac or [89Zr]Zr and evaluated the strategy against KRAS- and BRAF-mutant EGFR-positive colorectal cancer models. The antibody-drug radioconjugate [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1 showed enhanced in vitro cytotoxicity compared with the unlabeled antibody-drug conjugate nimotuzumab-PEG6-DM1. [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1 extended the survival of mice bearing all tested xenografts compared with untreated and nimotuzumab-PEG6-DM1-treated controls. For the BRAFV600E-mutant xenograft, the median survival was not reached following treatment with [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1, whereas it was 24.5 and 39 days for the saline-treated and nimotuzumab-PEG6-DM1-treated groups, respectively. Micro-PET/CT imaging using the nonoverlapping anti-EGFR radioimmunoconjugate [89Zr]Zr-DFO-matuzumab before and after treatment of orthotopic colorectal cancer xenografts showed that 1/5 mice in the treatment group had complete remission, whereas metastatic spread was prevented in the other mice (4/5). These results show that treatment with [225Ac]Ac-macropa-nimotuzumab-PEG6-DM1 is a potential therapeutic approach for KRAS- and BRAFV600E-mutant metastatic colorectal cancer. Significance: Radiolabeling with [225Ac]Ac improves the efficacy of an anti-EGFR antibody-drug conjugate in KRAS- and BRAFV600E-mutant colorectal cancer, providing hope for patients with these mutations who do not qualify for EGFR-targeted therapies.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"2067-2080"},"PeriodicalIF":12.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editor's Note: Normoxic Stabilization of Hypoxia-Inducible Factor-1α by Modulation of the Labile Iron Pool in Differentiating U937 Macrophages: Effect of Natural Resistance-Associated Macrophage Protein 1.","authors":"Helen J Knowles, David R Mole, Peter J Ratcliffe, Adrian L Harris","doi":"10.1158/0008-5472.CAN-25-0515","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-0515","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 11","pages":"2134"},"PeriodicalIF":12.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Degradation of Mutant p53 Reverses the Pro-oncogenic Dominant-Negative Effect","authors":"Jovanka Gencel-Augusto, Guillermina Lozano","doi":"10.1158/0008-5472.can-25-1054","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1054","url":null,"abstract":"p53 is a transcription factor that functions as a tumor suppressor and the active unit of which is a tetramer. Nearly all cancers inactivate the p53 pathway, primarily through missense mutations in TP53. Most mutant p53 proteins lose their function and often exhibit increased protein stability. In addition to this loss of function, mutant p53 can drive oncogenicity through a dominant-negative effect by forming mixed tetramers with wild-type (WT) p53 to inhibit its activity. The study in this issue of Cancer Research by Klemm and colleagues provides definitive evidence for the mechanism by which mutant p53 inactivates WT p53 function. The p53R248Q mutant has a longer half-life than WT p53, resulting in an approximate ratio of 3 or 4 mutant molecules to every WT molecule. This imbalance facilitates the dominant-negative effect, which can be overcome either by exogenously increasing WT p53 levels or by selectively degrading mutant p53. In experiments whereby mutant p53 was degraded using a degron-tagged construct combined with iberdomide as a molecular glue, remarkable therapeutic efficacy was observed when this approach was used in combination with an MDM2 inhibitor. This work paves the way for therapeutic strategies that aim to degrade mutant p53 proteins in cases in which a WT TP53 allele is retained. See related article by Klemm et al., p. 1978","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMAD4 Deficiency Promotes Pancreatic Cancer Progression and Confers Susceptibility to TGFβ Inhibition.","authors":"Gilbert Z Murimwa, Natalie E Williams, Dina Alzhanova, Amir Mohammadi, Jill M Westcott, Francisca Beato, Ruifan Dai, Luis Nivelo, Francesca Rossi, Henry K Fleming, Alexandra F Tassielli, Zeynep Yazgan, Jason E Toombs, Jason B Fleming, Aatur D Singhi, Cecilia G Ethun, Huocong Huang, Rolf A Brekken","doi":"10.1158/0008-5472.CAN-24-1970","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-1970","url":null,"abstract":"<p><p>The 5-year overall survival rate for pancreatic cancer remains ~13%, underscoring the urgent need for improved treatment strategies. TGFβ is a promising target due to its significant involvement in the desmoplasia, immune suppression, and chemoresistance characteristic of pancreatic cancer. Over 300 clinical trials targeting TGFβ have been conducted in unselected patient cohorts; however, none of the therapies have gained FDA approval. Nevertheless, TGFβ blockade may hold promise for a subset of cancers with non-functional TGFβ signaling. Greater than 25% of pancreatic cancers carry mutations in SMAD4, a key component of canonical TGFβ signaling. In this study, we investigated the potential for stratifying patients based on SMAD4 mutational status to identify tumors susceptible to TGFβ inhibition. Analysis of SMAD4 expression in human pancreatic tumors revealed that SMAD4 mutation or loss is associated with worse disease-free survival. Intriguingly, intratumoral SMAD4 expression displayed heterogeneity among human pancreatic cancer samples. SMAD4 deficient genetically engineered mouse models and orthotopic SMAD4 knockout tumor models exhibited reduced survival, increased metastasis, and alterations in the tumor microenvironment compared to SMAD4 wildtype controls, consistent with gene and protein expression changes in the absence of functional SMAD4. Importantly, treating mice bearing SMAD4 deficient tumors with a blocking TGFβ antibody reduced tumor weight and improved survival. These findings suggest that genomic stratification by TGFβ axis alterations, such as SMAD4 mutations, may be a promising approach to identifying patients likely to benefit from a TGFβ inhibitor.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mathematical Modeling and Association Analysis Deciphers the Impact of the Gut Microbiome on Cancer Immunotherapy.","authors":"Andreas G Hadjigeorgiou, Constantinos Harkos, Aditya K Mishra, Golnaz Morad, Sarah B Johnson, Nadim J Ajami, Jennifer A Wargo, Lance L Munn, Triantafyllos Stylianopoulos, Rakesh K Jain","doi":"10.1158/0008-5472.CAN-24-2232","DOIUrl":"10.1158/0008-5472.CAN-24-2232","url":null,"abstract":"<p><p>The gut microbiome has emerged as a key regulator of response to cancer immunotherapy. However, a better understanding of the underlying mechanisms by which the microbiome influences immunotherapy is needed to identify strategies to optimize outcomes. To this end, we developed a mathematical model to obtain insights into the effect of the microbiome on the immune system and immunotherapy response. This model was based on i) gut microbiome data derived from preclinical studies, ii) mathematical modeling of the antitumor immune response, iii) association analysis of microbiome profiles with model-predicted immune profiles, and iv) statistical models that correlate model parameters with the microbiome. The model was used to investigate the complexity of murine and human studies on microbiome modulation. Comparison of model predictions with experimental observation of tumor response in the training and test datasets supported the hypothesis that two model parameters, the activation and killing rate constants of immune cells, are the most influential in tumor progression and are potentially affected by microbiome composition. Evaluation of the associations between the gut microbiome and immune profile indicated that the components and structure of the gut microbiome affect the activation and killing rate of adaptive and innate immune cells. Overall, this study contributes to a deeper understanding of microbiome-cancer interactions and offers a framework for understanding how microbiome interactions influence cancer treatment outcomes.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract CT019: Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer (NSCLC) from a phase 1 study in advanced solid tumors","authors":"Kathryn C. Arbour, Tanvetyanon Tawee, Rona Yaeger, Aparna R. Parikh, Paul Oberstein, Kyriakos P. Papadopoulos, John Strickler, Alexander Spira, John Powderly, Minal Barve, Judy Wang, Jia Luo, Nilofer Saba Hazad, Alexander Starodub, Patricia LoRusso, Avantika Elgin, Michelle Yang, Walter Yu, Mark McCleland, Satwant Lally, Sophia Sohoni, David S. Hong","doi":"10.1158/1538-7445.am2025-ct019","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct019","url":null,"abstract":"Background: Patients with previously treated NSCLC have a high unmet medical need, with a median reported overall survival (OS) of &amp;lt;1 year. In NSCLC, KRAS G12D oncogenic mutations occur in approximately 4% of patients, but there are currently no RAS-targeted therapies approved for this population. Zoldonrasib (RMC-9805) is a potent, oral, RAS(ON) G12D-selective, covalent, tri-complex inhibitor targeting the active, GTP-bound state of oncogenic RAS G12D isoforms. Methods: In this Phase 1 study (NCT06040541), patients with previously treated, advanced KRAS G12D solid tumors received escalating zoldonrasib doses (150-1200 mg once daily [QD] or 300-600 mg twice daily [BID]). Antitumor activity was assessed every 6 weeks for the first 24 weeks then every 9 weeks. Additional patients were enrolled at doses that cleared the dose-limiting toxicity (DLT) evaluation to further characterize pharmacokinetics, safety, and antitumor activity of zoldonrasib. Results: As of a December 2, 2024 data cutoff, 211 patients with KRAS G12D solid tumors received 5 escalating dose levels of zoldonrasib monotherapy (150-1200 mg daily). No DLTs or Grade 4 or 5 treatment-related adverse events (TRAEs) were reported, and the maximum tolerated dose was not reached. Among patients who received a candidate recommended Phase 2 dose (RP2D) of 1200 mg QD (n=90), the most common (≥10% of patients) TRAEs were nausea (39%), diarrhea (24%), vomiting (18%), and rash (12%). TRAEs were primarily Grade 1 or 2 in severity with the exception of 1 patient with Grade 3 diarrhea and 1 patient with Grade 3 ALT elevation. Both Grade 3 TRAEs resolved following dose interruption. Among patients who received 1200 mg QD, 1 patient (1%) discontinued treatment, 4 patients (4%) had dose reductions, and 8 patients (9%) had dose interruptions due to a TRAE. At daily doses ≥600 mg, exposures to zoldonrasib were within the range of preclinical exposures that induced tumor regressions in mice. In patients with NSCLC (n=18) receiving 1200 mg QD zoldonrasib who enrolled at least 8 weeks prior to the data cutoff, the objective response rate (confirmed response or pending confirmation) was 61% (95% CI: 36, 83). Median time to onset of initial response was 1.4 months (range, 1.2-2.8) and the disease control rate was 89% (95% CI: 65, 99). Conclusions: Zoldonrasib showed encouraging initial antitumor activity in patients with KRAS G12D NSCLC. Tolerability was manageable across all dose levels in the Phase 1 study, which enrolled various tumor types. This overall safety profile and antitumor activity support continued evaluation as monotherapy in patients with KRAS G12D NSCLC, and in combination with immunotherapy, chemotherapy, and targeted therapies (NCT06162221). Citation Format: Kathryn C. Arbour, Tanvetyanon Tawee, Rona Yaeger, Aparna R. Parikh, Paul Oberstein, Kyriakos P. Papadopoulos, John Strickler, Alexander Spira, John Powderly, Minal Barve, Judy Wang, Jia Luo, Nilofer Saba Hazad, Alexander Starodu","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ND02: GDC-2992: A heterobifunctional Androgen Receptor (AR) antagonist and degrader for the treatment of AR wild-type and mutant prostate cancer","authors":"Ciara Metcalfe, Wei Zhou, Darlene Dela Cruz, Thomas Hunsaker, Pablo Saenz-Lopez Larrocha, Elizabeth Levy, Bu-Er Wang, Tonia Hafner, Nayan Chaudhary, Marc Hafner, Kalpit Shah, Elisia Villemure, Yuxiang Zheng, Jodie Pang, Udi Segal","doi":"10.1158/1538-7445.am2025-nd02","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd02","url":null,"abstract":"Prostate cancer is the second most commonly diagnosed cancer in men, with 1 in 8 men being diagnosed with prostate cancer in his lifetime. AR is a hormone-activated transcription factor that promotes cell growth and survival in the normal prostate, and AR signaling is a key driver of cell proliferation in prostate cancer. Inhibition of AR signaling is a mainstay of current prostate cancer treatment, however, patients often develop resistance to these therapies through mechanisms that retain dependency on AR signaling. GDC-2992 (also known as RO7656594) is a potent, orally bioavailable, heterobifunctional molecule that inhibits AR signaling by binding to both AR and the E3 ubiquitin ligase cereblon (CRBN), resulting in ubiquitination and subsequent degradation of AR. GDC-2992 inhibits AR signaling in the context of wild-type AR and AR proteins with mutations associated with resistance to standard-of-care AR signaling inhibitors (ARSIs). Unlike ARSIs, GDC-2992 does not display evidence of agonism against any AR variants evaluated. Co-treatment of GDC-2992 with the CRBN ligand pomalidomide prevents AR degradation mediated by GDC-2992 in vitro, supporting the role of CRBN in GDC-2992-mediated AR degradation. Importantly however, anti-proliferative potential of GDC-2992 is maintained even when degradation is attenuated, suggesting that the mechanism of GDC-2992 includes competitive AR antagonism in addition to degradation. In vivo, GDC-2992 decreases circulating PSA and inhibits prostate tumor growth in a dose responsive manner. The totality of in vitro and in vivo preclinical data supports that GDC-2992 represents a compelling advance over standard-of-care ARSIs. An ongoing Phase I dose-escalation and expansion study will assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of GDC-2992 in patients with advanced or metastatic prostate cancer who have previously received AR-targeted therapy [NCT05800665]. By providing more complete and sustained AR inhibition, GDC-2992 has the potential to reduce the occurrence of treatment-resistance and disease relapse in prostate cancer. Citation Format: Ciara Metcalfe, Wei Zhou, Darlene Dela Cruz, Thomas Hunsaker, Pablo Saenz-Lopez Larrocha, Elizabeth Levy, Bu-Er Wang, Tonia Hafner, Nayan Chaudhary, Marc Hafner, Kalpit Shah, Elisia Villemure, Yuxiang Zheng, Jodie Pang, Udi Segal. GDC-2992: A heterobifunctional Androgen Receptor (AR) antagonist and degrader for the treatment of AR wild-type and mutant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr ND02.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"31 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ND06: Discovery of RMC-5127, an oral, RAS (ON) G12V-selective, noncovalent, tri-complex inhibitor","authors":"Anne Edwards","doi":"10.1158/1538-7445.am2025-nd06","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd06","url":null,"abstract":"The RAS G12V mutation is among the most common oncogenic drivers in pancreatic, colorectal, and non-small cell lung cancers. Within a tumor cell, RAS G12V exists predominantly in the active, GTP-bound (“RAS(ON)”) state leading to excessive downstream oncogenic signaling. The intrinsic GTP hydrolysis rate of RAS G12V is about 12-fold lower than that of KRAS G12C, biasing the cellular RAS G12V pool to the ON state and emphasizing the importance of targeting RAS G12V(ON) for maximal suppression of this oncogenic driver. Additionally, achieving selectivity for RAS G12V over wild-type RAS has, to date, been extremely challenging using conventional small molecules because the Val-12 residue is neither amenable to covalent inhibition nor to formation of polar, noncovalent interactions.The investigational agent RMC-5127 is a potent, orally bioavailable, RAS (ON) G12V-selective, noncovalent tri-complex inhibitor. In KRAS G12V mutant cancer cells, RMC-5127 forms a tri-complex between KRAS G12V(ON) and cyclophilin A (CypA), driving near-immediate disruption of RAS effector binding through steric occlusion and extinction of KRAS G12V(ON) signaling.RMC-5127 suppressed ERK phosphorylation and cell growth in multiple human KRAS G12V-addicted cancer cell lines in vitro, and a single dose induced dose-dependent, deep, and durable suppression of RAS pathway activation in vivo in subcutaneous xenograft models of KRAS G12V mutant cancers in mice. Across a panel of preclinical PDAC and NSCLC models harboring KRAS G12V, RMC-5127 monotherapy induced tumor regressions in the majority of models and was well-tolerated. In addition, dose-dependent exposure of RMC-5127 was observed in the whole brain of naïve mice, indicating the compound is brain penetrant, and RMC-5127 exhibited profound antitumor activity in relevant intracranial KRAS G12V mutant tumor xenograft models, with regressions observed at well-tolerated doses. Citation Format: Anne Edwards. Discovery of RMC-5127, an oral, RAS (ON) G12V-selective, noncovalent, tri-complex inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr ND06.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"31 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract ND12: M0324, a novel MUC-1 conditional CD40 agonist for selective immune activation in MUC-1 overexpressing tumors","authors":"Weixiao Sha, Yilang Tang, Jing Ni, Anika Bergmann, Nathalie Duncan, Bo Marelli, Feng Jiang, Julia Marie Mueller, Sina Junkers, Edith Doering, Christina Hubl, Ivana Durutovic, Sonia Jaramillo, Laura Helming, Paul Lyne","doi":"10.1158/1538-7445.am2025-nd12","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd12","url":null,"abstract":"Background: Anti-CD40 agonistic antibodies have been explored in clinical trials over the last few decades; however, to date none have been approved. Systemic activation of CD40 by anti-CD40 antibodies can lead to adverse effects such as liver toxicity, infusion-related reactions, thrombocytopenia, and cytokine release syndrome, limiting the therapeutic window of these agents. Targeting CD40 activation specifically to the tumor microenvironment could enhance antitumor activity while minimizing systemic toxicity. MUC-1 is a glycoprotein commonly overexpressed in various cancers, playing a pivotal role in tumor progression and immune evasion. M0324 is a novel MUC-1-conditional CD40 agonist composed of an anti-MUC-1 IgG and two identical camelid heavy-chain variable domains (VHH) binding CD40, designed to conditionally activate immune cells in the presence of MUC-1-overexpressing tumor cells. Methods: The effect of M0324 on the activation of CD40 expressed on human dendritic cells (DCs) was assessed in vitro, using MUC-1 expressing HCC827 tumor cell line co-cultured with primary human monocyte-derived DCs. In vivo efficacy was evaluated using MUC-1 overexpressing tumor models and M0324m, a mouse surrogate for M0324. Results: Preclinical in vitro studies demonstrated that M0324 significantly enhanced the activation of DCs when interacting with MUC-1-positive tumor cells, with no activity observed in the absence of MUC-1 expressing cells. Compared with anti-CD40 agnostic antibodies currently under clinical evaluation, M0324 showed superior ability to activate IL-12p40 expression in DC tumor cell co-cultures. The ability of M0324 to activate CD40 on immune cells was reliant on MUC-1 expression of tumor cells. Single dose, single agent M0324m treatment demonstrated robust tumor eradication in two different immune competent mouse tumor models (93% tumor-free mice in orthotopic Panc02-MUC-1 model and 100% tumor-free mice in MC38-MUC-1 model). The conditional activation of CD40 occurred solely in the presence of MUC-1, minimizing off-tumor effects and enhancing the therapeutic index. In contrast to M0324m, anti-mouse CD40 benchmark antibody induced body weight loss of mice and a marginally tolerable dose of anti-mouse CD40 failed to control tumor growth. Conclusions: M0324 is the first MUC-1 conditional CD40 agonist, engineered to selectively activate immune cells in the presence of MUC-1 overexpressing tumor cells. The conditional mode of action of M0324 leverages the high expression of MUC-1 in carcinomas to induce targeted antitumor immunity, potentially overcoming the safety limitations of traditional CD40 agonists. Our encouraging preclinical data support the clinical investigation of M0324 in patients with MUC-1 overexpressing tumors. Citation Format: Weixiao Sha, Yilang Tang, Jing Ni, Anika Bergmann, Nathalie Duncan, Bo Marelli, Feng Jiang, Julia Marie Mueller, Sina Junkers, Edith Doering, Christina Hubl, Ivana Durutovic, Sonia Jaramillo, Laura Helm","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}