Cancer research最新文献

{"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":"Development of an Anti-CD99 Antibody Enables Targeting of Diffuse Midline Glioma","authors":"Ilango Balakrishnan, Krishna Madhavan, Angela Pierce, Joshua Michlin, Breauna Brunt, Senthilnath Lakshmanachetty, Dong Wang, John DeSisto, Zachary James. Nuss, Nathan Davidson, Faye Walker, Ammu Suresh, Andrew Donson, Bridget Sanford, Kenneth L. Jones, Etienne P. Danis, Siddhartha S. Mitra, Adam L. Green, Nathan Dahl, Rajeev Vibhakar, Sujatha Venkataraman","doi":"10.1158/0008-5472.can-24-5027","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-5027","url":null,"abstract":"Diffuse midline gliomas (DMGs) are devastating brain tumors that occur primarily in children. The salient feature of these tumors is the presence of a H3K27M mutation (K27M), associated with the worst prognosis. Development of effective strategies for treating K27M+ DMG is desperately needed to help improve patient outcomes. Here, we identified the cell surface antigen CD99 as notably expressed in DMGs, particularly in K27M+ DMGs. The increased expression of CD99 in K27M+ DMGs was a result of the onco-histone K27M mutation. In K27M+ DMG cells, CD99 inactivation impaired tumor growth by inducing cell differentiation. The development of a therapeutic anti-CD99 chimeric antibody, 10D1, with a membrane-proximal binding epitope enabled the evaluation of the antitumor efficacy of targeting CD99 in preclinical models of K27M+ DMG. 10D1 suppressed DMG growth in vitro and in vivo by inducing apoptosis. When combined with radiation treatment, 10D1 exhibited improved antitumor efficacy and prolonged xenograft survival. Together, these findings provide a strong justification for the clinical development of 10D1 as a therapy for targeting CD99 to treat DMGs.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"24 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153477","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":"Loss of SMARCA4 leads to Intron Retention and Generation of Tumor-Associated Antigens in Small Cell Carcinoma of the Ovary, Hypercalcemic Type.","authors":"Elizabeth A Raupach,Apurva M Hegde,Krystine Garcia-Mansfield,Marice Alcantara,David L Rose,Rebecca F Halperin,Krystal A Orlando,Jessica D Lang,Ritin Sharma,Victoria David-Dirgo,Salvatore J Facista,Rayvon Moore,Rochelle Kofman,Zoe N Jensen,Victoria L Zismann,Anthony N Karnezis,Yemin Wang,Lynda B Bennett,Timothy G Whitsett,Marcin Kortylewski,William P D Hendricks,David Huntsman,Lorna Rodriguez-Rodriguez,Bernard E Weissman,Jeffrey M Trent,Patrick Pirrotte","doi":"10.1158/0008-5472.can-24-0044","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0044","url":null,"abstract":"Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. Here, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary tumors harbored tumor-associated outlier splicing events compared to normal tissues. Many of the tumor events were retained introns encoding novel peptides predicted to bind to MHC-I complexes. Immune cells were observed in primary SCCOHT tumors, suggesting a potentially immune reactive tumor microenvironment. Mutations in several SWI/SNF subunits were associated with higher rates of outlier retained introns across tumor types in TCGA data. Interestingly, RNA sequencing of isogenic SCCOHT cell lines demonstrated a role for SMARCA4 in intron retention. Distinct protein-protein interactions between splicing factors identified in SCCOHT cell lines supported a role for SMARCA4 in splicing regulation. Further, SWI/SNF localized to genes which were differentially spliced. Mass spectrometry analyses confirmed expression of some of these novel peptides and a subset of these are predicted to bind to MHC-I complexes. A pool of these novel peptides derived from retained introns in SCCOHT triggered proliferation and expression of TNFa and INFb in primary human T cells. Together, these data suggest that SMARCA4 loss in SCCOHT leads to intron retention. Furthermore, T cell activation by novel peptides encoded by these tumor-specific splicing events suggests intron retention could be a source of tumor-associated antigens in SCCOHT.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122382","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 CT003: Non operative management of mismatch repair deficient tumors","authors":"Andrea Cercek, Michael B. Foote, Jinru Shia, Jenna Sinopoli, Benoit Rousseau, Jesse J. Smith, Jill Weiss, Lindsay Temple, Miteshkumar Patel, Callahan Wilde, Steven Maron, Yelena Janjigian, Daniela Molena, Gopa Iyer, Jonathan Coleman, Wassim Abida, Seth Cohen, Vivian Strong, Mithat Gonen, Marc Gollub, Vetri S. Jayaprakasham, Tae-Hyung Kim, Julio Garcia Aguilar, Martin Weiser, Luis A. Diaz","doi":"10.1158/1538-7445.am2025-ct003","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct003","url":null,"abstract":"Background: Neoadjuvant checkpoint blockade of locally advanced mismatch repair deficient (MMRd) rectal cancers results in a high rate of complete clinical responses that can eliminate the need for surgery. MMRd occurs broadly across solid tumors but is unknown if these findings could be extended in a tumor agnostic manner. Methods: Early stage MMRd solid tumors that were eligible for curative intent surgery were enrolled to a study of six months of neoadjuvant treatment with dostarlimab, a PD-1 blocking monoclonal antibody. The study was comprised of two cohorts. The first cohort enrolled MMRd locally advanced rectal cancers and the second cohort enrolled MMRd non rectal solid tumors. In both cohorts, patients who achieved a clinical complete response could elect non-operative management. The co-primary endpoints for cohort one included response rate and durability of complete response at 12 months, the primary endpoint for cohort two was response and exploratory endpoints included genomic and circulating tumor DNA analyses for both cohorts. Results: 110 patients were enrolled. In cohort one (MMRd rectal cancers), to date, 48 patients completed 6-months of treatment and 100% achieved a clinical complete response and did not undergo surgical resection of their primary tumor. Twenty nine of these 48 have attained 12 or more months of recurrence-free survival median 24.8 (range 15.6,48.6). In the second cohort of locally advanced MMRd non-rectal solid tumors, which included esophagogastric, hepatobiliary, genitourinary, and gynecologic tumors, at time data submission, 49 patients completed treatment and 31 patients (63%) achieved a clinical complete response and did not undergo resection surgical resection of their primary tumor. Across both cohorts, 81% of patients (79 of 97) who completed 6-months of treatment achieved a clinical complete response and 79% (77 of 97) were managed non-operatively. Baseline tumor mutational burden and MSI sensor scores in cohort one was 55.2 mutations per megabase (range 22.8, 106) and 19 (range 2.2, 37.6),and for cohort two 51.1 mutations per megabase (range 4.9, 145) and 18.6 (range 0.23, 39.4), respectively. Tumor-informed circulating tumor DNA levels were detectable at baseline in 87% of patients and on-therapy levels correlated with complete and incomplete responses especially at the completion of treatment. Conclusion: In the curative setting, neoadjuvant PD-1 blockade offers the option of organ preservation for most patients with early stage MMRd malignancies regardless of tumor type. Citation Format: Andrea Cercek, Michael B. Foote, Jinru Shia, Jenna Sinopoli, Benoit Rousseau, Jesse J. Smith, Jill Weiss, Lindsay Temple, Miteshkumar Patel, Callahan Wilde, Steven Maron, Yelena Janjigian, Daniela Molena, Gopa Iyer, Jonathan Coleman, Wassim Abida, Seth Cohen, Vivian Strong, Mithat Gonen, Marc Gollub, Vetri S. Jayaprakasham, Tae-Hyung Kim, Julio Garcia Aguilar, Martin Weiser, Luis A. Diaz. Non operative managemen","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"140 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123001","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 2423: Automated classification of pediatric sarcoma using digital histopathology","authors":"Adam Thiesen, Sergii Domanskyi, Ali Foroughi pour, Jingyan Zhang, Todd B. Sheridan, Steven B. Neuhauser, Alyssa Stetson, Katelyn Dannheim, Danielle B. Cameron, Shawn Ahn, Hao Wu, Emily R. Christison-Lagay, Carol J. Bult, Jeffrey H. Chuang, Jill C. Rubinstein","doi":"10.1158/1538-7445.am2025-2423","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-2423","url":null,"abstract":"Introduction: Pediatric sarcomas are challenging to accurately classify due to their rarity and the wide diversity of subtypes. The process requires highly specialized pathologists as well as molecular and genetic testing that is expensive, takes time, and is not universally available. Deep neural network models (DNNs) trained on histopathology slides can reduce the time and cost to diagnosis and attenuate disparities in care based on geographical location and socioeconomic status. Here, we demonstrate the efficacy of automated image analysis for assigning sarcoma diagnoses across centers by identifying Ewing Sarcoma (ES), distinguishing rhabdomyosarcoma (RMS) vs non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), as well as classifying alveolar, embryonal, and spindle cell RMS subtypes. Methods: Images were collected from Massachusetts General Hospital, Yale School of Medicine, St Jude Children’s, and the Children’s Oncology Group. A total of 691 images were collected across all centers, including 9 different sarcoma subtypes. Images were harmonized using our published STQ pipeline including focus checking, resolution standardization, and stain normalization. Image tiling and feature extraction was performed comparing multiple deep learning backbones (CTransPath, UNI, CONCH). Tile-level features were transposed to whole slide-level representations using our published SAMPLER method in which each feature is represented as the vector of decile values of its distribution across all tiles. Resulting feature sets were fed into logistic regression models for sarcoma classification tasks. We benchmark this approach against transformer based multi-head self-attention models trained on a V100 GPU. Results: We are able to distinguish ES from all other sarcoma types with an AUROC of 0.966. In the task of NRSTS v. alveolar RMS v. embryonal RMS we achieve an AUROC of 0.939. Restricting to RMS subtypes, we distinguish alveolar from embryonal with an AUROC of 0.95. Also, despite uneven sample representation, we obtain an AUROC of 0.88 for alveolar v. embryonal v. spindle type RMS. Finally, we have developed spatially-resolved attention maps, which provide interpretability for the regions of a slide that contain malignant cells. Conclusion: To our knowledge, we have amassed the largest multicenter pediatric sarcoma imaging dataset with broad representation across subtypes, anatomical locations, race, and sex. Our pipeline allows for further integration of images from any center, which may be co-analyzed to attenuate center-specific batch effects. Our classification accuracies are state of the art for multiple tasks fundamental to clinical sarcoma pathology, including novel multiclass distinction among three different RMS subtypes. Importantly, our pipeline and SAMPLER model can be run with minimal computational requirements, allowing for broad accessibility. Citation Format: Adam Thiesen, Sergii Domanskyi, Ali Foroughi pour, Jingyan Zhang, Todd B. Sheridan, Stev","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123128","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}