Cancer research最新文献

{"title":"Abstract ND03: ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate for the treatment of metastatic castrate-resistant prostate cancer","authors":"Regina M. Reilly","doi":"10.1158/1538-7445.am2025-nd03","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd03","url":null,"abstract":"Prostate cancer is the second leading cause of male cancer deaths in the US. There is currently no curative therapy available for advanced prostate cancer, indicating an urgent need for novel therapeutics. ABBV-969 is intended to address this critical need by delivering cytotoxin to tumor cells highly expressing prostate tumor antigens, STEAP1 (six transmembrane epithelial antigen of the prostate-1) and PSMA (prostate specific membrane antigen). STEAP1, minimally expressed on normal tissue, is highly enriched in over 85% of prostate tumors, where it promotes proliferation and invasion. As a prostate lineage marker PSMA expression is up to 100-fold higher on tumor versus healthy prostate tissue and correlates with tumor stage, aggressiveness, and recurrence. High expression and prevalence in prostate cancer identifies both antigens as attractive targets for antibody drug conjugates (ADCs). Since heterogeneous expression throughout and among tumors may limit effectiveness, a bispecific antibody that binds both STEAP1 and PSMA was designed using a dual variable domain immunoglobulin (DVD-Ig) format. This format enables bivalent engagement of both targets, potentially increasing tumor coverage and durability of therapy. ABBV-969 is a conjugate of the DVD-Ig with a proprietary topoisomerase-1 (Top1) inhibitor linker-drug identical to that used in two assets in clinical development, ABBV-400, targeting c-Met, and ABBV-706, targeting SEZ6. ABBV-969 binds to STEAP1 and PSMA with high affinity and is cytotoxic to cells expressing either or both antigens. ABBV-969 exhibits favorable drug-like properties, pharmacokinetics, and efficacy against patient-derived xenografts from castrate resistant prostate tumors and has broader activity than standard ADCs targeting either STEAP1 or PSMA. Furthermore, ABBV-969 is well tolerated in cynomolgus monkeys with bone marrow and gastrointestinal toxicities common to other Top1 inhibitor ADCs. ABBV-969 is currently in dose escalation in a Phase 1 clinical study (NCT06318273). Citation Format: Regina M. Reilly. ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate for the treatment of metastatic castrate-resistant 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 ND03.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"33 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122963","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 CT001: Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Phase 3 KEYNOTE-689 study","authors":"Ravindra Uppaluri, Robert I. Haddad, Yungan Tao, Christophe Le Tourneau, Nancy Y. Lee, William Westra, Rebecca Chernock, Makoto Tahara, Kevin Harrington, Arkadiy L. Klochikhin, Irene Braña, Gustavo Vasconcelos Alves, Brett G.M. Hughes, Marc Oliva, Iane Pinto Figueiredo Lima, Tsutomu Ueda, Tomasz Rutkowski, Ursula Schroeder, Paul-Stefan Mauz, Thorsten Fuereder, Simon Laban, Nobuhiko Oridate, Aron Popovtzer, Nicolas Mach, Yevhen Korobko, Diogo Alpuim Costa, Anupama Hooda-Nehra, Cristina P. Rodriguez, R. Bryan Bell, Cole Manschot, Kimberly Benjamin, Burak Gumuscu, Douglas Adkins","doi":"10.1158/1538-7445.am2025-ct001","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-ct001","url":null,"abstract":"Background: Neoadjuvant and adjuvant immune checkpoint inhibitors added to SOC (surgery + postoperative radiotherapy [PORT] ± concurrent chemotherapy) yielded promising efficacy results in participants (pts) with LA HNSCC in early phase studies. The randomized, open-label, phase 3 KEYNOTE-689 study (NCT03765918) evaluates neoadjuvant and adjuvant pembrolizumab + SOC vs SOC in this population. Methods: Adults with newly diagnosed resectable LA HNSCC (larynx/hypopharynx/oral cavity stage III/IVA; oropharyngeal stage III/IVA p16− or stage III T4 N0-2 p16+) were randomized 1:1 to 2 cycles neoadjuvant and 3 cycles concurrent (during PORT) and 12 cycles adjuvant pembrolizumab 200 mg IV Q3W + SOC vs SOC. SOC included surgery for all pts + PORT 60 Gy in 30 fractions for low-risk, PORT 66 Gy in 33 fractions + 3 cycles concurrent cisplatin 100 mg/m2 Q3W for high-risk, and PORT 70 Gy in 35 fractions + cisplatin for gross residual disease. The primary endpoint is event-free survival (EFS) per RECIST 1.1 by blinded independent central review. Key secondary endpoints are major pathological response (mPR; ≤10% invasive SCC) by blinded independent pathologist review and overall survival (OS). Efficacy endpoints are sequentially assessed in 3 populations: pts with tumors with PD-L1 combined positive score (CPS) ≥10, CPS ≥1, and all pts. Treatment-related adverse events (TRAEs) are graded per CTCAE v4.03. Results: From December 2018 to October 2023, 363 pts were randomized to pembrolizumab + SOC and 351 to SOC. As of 25 July 2024 (first interim analysis), median follow-up was 38.3 months (range, 9.0-66.5). Baseline demographics were balanced between arms. The CPS ≥10 population included 234 pts in the pembrolizumab + SOC arm and 231 in the SOC arm; the CPS ≥1 population included 347 and 335 pts, respectively. EFS (CPS ≥10: median 59.7 vs 26.9 months, HR 0.66, 95% CI 0.49-0.88, P=.00217; CPS ≥1: 59.7 vs 29.6 months, HR 0.70, 95% CI 0.55-0.89, P=.00140; all pts: 51.8 vs 30.4 months, HR 0.73, 95% CI 0.58-0.92, P=.00411) and mPR rate difference (CPS ≥10: 13.7%, 95% CI 9.7-18.7, P<.00001; CPS ≥1: 9.8%, 95% CI 7.0-13.3, P<.00001; all pts: 9.3%, 95% CI 6.7-12.8, P<.00001) analyses were statistically significant with pembrolizumab + SOC vs SOC in all prespecified populations. Additional follow-up for OS is ongoing. Grade ≥3 TRAE frequency was similar (44.6% with pembrolizumab + SOC vs 42.9% with SOC); 4 and 1 deaths occurred due to TRAE, respectively. Immune-mediated AEs occurred in 43.2% of pts with pembrolizumab + SOC, most commonly hypothyroidism (24.7%). Conclusions: Adding neoadjuvant and adjuvant pembrolizumab to SOC significantly improved EFS and mPR rate difference in pts with resectable LA HNSCC independent of CPS. The safety profile of pembrolizumab was consistent with expectations. Citation Format: Ravindra Uppaluri, Robert I. Haddad, Yungan Tao, Christophe Le Tourneau, Nancy Y. Lee, William Westra, Rebecca Chernock, Makoto Tahara, Kevin Ha","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122989","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 ND09: BAY 3547926: Novel targeted radionuclide therapy for hepatocellular carcinoma","authors":"Jenny Karlsson, Franziska Siegel, Ingrid Moen, Arne Scholz, Anne Mobergslien, Frans Suurs, Ana Oteiza, Vasiliki Pelekanou, Charles Glaus, Stefan Zimmermann","doi":"10.1158/1538-7445.am2025-nd09","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd09","url":null,"abstract":"Hepatocellular carcinoma (HCC) is the most common form of liver cancer ranking sixth among all cancers and the third leading cause of cancer death worldwide in 2020. Despite the advent of systemic therapies with tyrosine kinase and later immune checkpoint inhibitors, the prognosis of patients with HCC is still dismal and therefore new more effective therapies are needed. Glypican-3 (GPC3) is an oncofetal protein overexpressed in ∼75% of HCC lesions and with limited membrane expression in healthy adult tissues which makes it an attractive target for targeted radionuclide therapy. Targeted alpha therapy (TAT) induces difficult-to-repair clustered DNA double strand breaks by delivering an alpha-particle payload specifically to the lesion using tumor antigen targeting moieties. Patients suitable for TAT can be selected from the larger population by adopting an approach employing paired molecular imaging. We present herein the development of a GPC3 actinium-225 (225Ac), 225Ac-GPC3 therapeutic agent, and a zirconium-89 (89Zr), 89Zr-GPC3 imaging agent, suitable for targeting GPC3-expressing tumors. 225Ac-GPC3 is a novel GPC3 targeting high affinity antibody, conjugated with a macropa chelator for efficient and stable radiolabeling with 225Ac. In vitro, 225Ac-GPC3 induced DNA double-strand breaks and selectively reduced cell viability in a panel of HCC cancer cell lines in GPC3-expression dependent manner. In vivo, 225Ac-GPC3 highly accumulated in tumors while a low uptake and fast clearance were observed in normal organs using human HCC xenograft models. 225Ac-GPC3 significantly inhibited tumor growth in a dose and GPC3-expression dependent manner. Increased level of γH2AX, indicating DNA double strand breaks, was demonstrated for 225Ac-GPC3 in a subcutaneous xenograft HCC tumor model. In an orthotopic HCC model, 225Ac-GPC3 led to a marked reduction of serum alpha-fetoprotein levels and induced complete tumor regression. Furthermore, it was demonstrated that the α-emissions co-localized with GPC3-positive malignant tissue in liver sections. The imaging surrogate agent 89Zr-GPC3, GPC3 targeted antibody conjugated to an efficient chelator (DFO*) for 89Zr, demonstrated comparable ex vivo biodistribution and clearance to 225Ac-GPC3 in an HCC mouse model. These data and additional non-clinical data enabled the initiation of the phase I clinical study of the 89Zr-GPC3 imaging agent (NCT06345001) in patients with HCC or other selected solid tumors. PET imaging was used to measure the whole-body biodistribution at multiple total mass doses. Adequate biodistribution was observed, and no unexpected uptake was detected. PET imaging data was also used to estimate 225Ac dosimetry to key normal organs. The preclinical and clinical imaging results supported the initiation of the first-in-human trial to evaluate 225Ac-GPC3. BANTAM-01 (NCT06764316) is a multicenter, open label, non-randomized study to evaluate the safety and tolerability, PK, and anti-tumor activity of ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"63 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123003","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 ND07: FXX489, a FAP targeting ligand with best-in-class potential for radioligand therapy","authors":"Markus Reschke, Danielle Park, Sarah Choi, Takeru Ehara, Andrei Golosov, Philipp Grosche, Dominik Hainzl, Philipp Holzer, Patrick Klein, Lukas Leder, Shiva Malek, Eloisa Jimenez Nunez, Patrick Reid, Holger Sellner, Quincey Simmons, Therese Stachyra, Hayato Yanagida, Alexei Karpov","doi":"10.1158/1538-7445.am2025-nd07","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd07","url":null,"abstract":"FAP (Fibroblast Activation Protein) is expressed on cancer-associated fibroblasts (CAFs) and is a highly attractive target in Radioligand Therapy (RLT) due to its pan cancer potential. The penetrating nature of β radiation is hypothesized to drive a ‘cross-fire effect’ from CAFs to tumor cells resulting in DNA damage and tumor cell death. Known FAP targeting ligands show excellent and selective tumor uptake in the clinic but suffer from short tumor retention which limits their application as a therapeutic modality. Herein we describe FXX489 (FAP targeting ligand) which improves tumor retention and is currently undergoing clinical evaluation in Phase 1 (NCT06562192) in patients with PDAC, NSCLC, Breast Cancer, and CRC. Importantly, FXX489 demonstrates BiC potential for anti-tumor efficacy in translationally relevant models (e.g., PDAC, NSCLC) where FAP is expressed on CAFs, thus relying on the cross-fire mechanism. Multiple starting points were identified using mRNA display platform, co-crystallized with FAP and assessed for biodistribution in vivo. The series with the best tumor/kidney ratio was selected for further optimization. Optimization was enabled by the co-crystal structure and was focusing on maximizing compound affinity and proteolytic stability. FXX489 binds to both human and mouse FAP with the affinity < 10 pM; shows exquisite selectivity over other proteases (such as DPP4); is stable in blood and plasma. Citation Format: Markus Reschke, Danielle Park, Sarah Choi, Takeru Ehara, Andrei Golosov, Philipp Grosche, Dominik Hainzl, Philipp Holzer, Patrick Klein, Lukas Leder, Shiva Malek, Eloisa Jimenez Nunez, Patrick Reid, Holger Sellner, Quincey Simmons, Therese Stachyra, Hayato Yanagida, Alexei Karpov. FXX489, a FAP targeting ligand with best-in-class potential for radioligand therapy [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 ND07.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"56 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123029","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 ND10: An innovative and reversible WRN helicase inhibitor, GSK4418959 (IDE275), emerges as a promising clinical candidate for MSI-H cancers","authors":"Yanhua Rao, Brian T. Jones, Edward J. Brnardic, Joshua E. Cottom, Yang Lee, Diana M. Munoz, Claire Neilan, Sunjay Sethi, Robert A. Reid, Lisa M. Shewchuk, Ethan D. McSpadden, Daniel L. Severance, Kira Campbell, Philip Landis, Jay Prakash Jain, Richard Zang, Leng Nickels, Dennis J. Murphy, H. Christian Eberl, Muzaffar Alam, Melissa Fleury, Lara K. Leister, Tessa Lynch-Colameta, James P. Phelan, Michael D. VanHeyst, Amberly B. Sanford, Ann M. Rowley, Hongyi Yu, Anna Rutkowska-Klute, Thilo Werner, Xin Linghu, Ian S. Young, An D. Nguyen, Sabrina Bédard, Eldridge N. Nartey, Nanhua Deng, Yang Peng, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Gabriele Picco, Mathew J. Garnett, Jessica L. Schneck, Geeta Sharma, Joshua P. Taygerly, Michael P. DeMartino, Yujiro S. Hata, Paul A. Barsanti, Michael A. White, Benjamin Schwartz","doi":"10.1158/1538-7445.am2025-nd10","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd10","url":null,"abstract":"Large scale genome wide CRISPR screens identified WRN helicase as a promising synthetic lethal target for MSI-H cancers, independent of tumor type. Here we describe the discovery of the novel clinical WRN helicase inhibitor GSK4418959 (IDE275), which recapitulates the MSI-H synthetic lethality of WRN genetic inhibition in vitro and in vivo. GSK4418959 (IDE275) engages a unique allosteric site in the WRN helicase domain, competing with ATP binding and inducing an inhibitory conformation distinct from previously reported WRN inhibitors. It selectively inhibits the ATPase and DNA unwinding activities of WRN, but not other RecQ helicase family members, including BLM helicase. GSK4418959 (IDE275) binds directly to WRN in cells, inducing DNA damage selectively in MSI-H cancer cells in a concentration-dependent manner. GSK4418959 (IDE275) shows strong anti-proliferative effects in MSI-H cell lines and patient-derived organoids across multiple tumor types with no measurable effects in MSS models. In vivo, GSK4418959 (IDE275) causes tumor regressions and induces DDR markers in several MSI-H CDX and PDX models harboring different oncogenic drivers and tumor suppressor mutations, without affecting MSS models. One of these models was an MSI-H CRC PDX from a patient that had failed 3 previous lines of therapy, including the immune checkpoint inhibitor Nivolumab. Due to its unique binding mode, GSK4418959 (IDE275) also induced regressions in an MSI-H CDX CRC tumor model that had developed resistance to treatment with other reported WRN inhibitors. These findings demonstrate GSK4418959 (IDE275)'s potent and selective preclinical activity against MSI-H cancer models, indicating its potential as a promising clinical treatment for MSI-H cancer patients, including those that have failed existing therapies. All studies were conducted according to GSK's Policy on the Care, Welfare and Treatment of Animals and reviewed by the Institutional Animal Care and Use Committee at GSK or by the ethical review process at the institution where the work was performed. Citation Format: Yanhua Rao, Brian T. Jones, Edward J. Brnardic, Joshua E. Cottom, Yang Lee, Diana M. Munoz, Claire Neilan, Sunjay Sethi, Robert A. Reid, Lisa M. Shewchuk, Ethan D. McSpadden, Daniel L. Severance, Kira Campbell, Philip Landis, Jay Prakash Jain, Richard Zang, Leng Nickels, Dennis J. Murphy, H. Christian Eberl, Muzaffar Alam, Melissa Fleury, Lara K. Leister, Tessa Lynch-Colameta, James P. Phelan, Michael D. VanHeyst, Amberly B. Sanford, Ann M. Rowley, Hongyi Yu, Anna Rutkowska-Klute, Thilo Werner, Xin Linghu, Ian S. Young, An D. Nguyen, Sabrina Bédard, Eldridge N. Nartey, Nanhua Deng, Yang Peng, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Gabriele Picco, Mathew J. Garnett, Jessica L. Schneck, Geeta Sharma, Joshua P. Taygerly, Michael P. DeMartino, Yujiro S. Hata, Paul A. Barsanti, Michael A. White, Benjamin Schwartz. An innovative and reversible WRN helicase inhibitor, GSK4418959 (IDE275), eme","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"155 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123121","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 ND08: FAP-LTBR (RO7567132): a first-in-class bi-specific stromal immunomodulatory agonist designed to enable and enhance efficacy of cancer immunotherapies","authors":"Roberta Bianchi, Leo Kunz, Michelle Brydon, Dario Speziale, Ralf Hosse, Juliana Bessa, Christophe Boetsch, Ana De Oliviera Rodrigues Amorim, Petra Schwalie, Alberto Valdeolivas Urbelz, Nadine Kumpesa, Christine Trumpfheller, Ashley Lakner, Pablo Umana, Meher Majety","doi":"10.1158/1538-7445.am2025-nd08","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd08","url":null,"abstract":"RO7567132 is a novel bispecific antibody that binds bivalently to the lymphotoxin beta receptor (LTBR) and monovalently to the fibroblast activation protein (FAP). LTBR is a member of the tumor necrosis factor receptor superfamily, expressed by various cells including stromal cells. Activation of LTBR upon engagement with its ligands leads to the upregulation of genes involved in the attraction of immune cells and the development and maintenance of secondary lymphoid organs and high endothelial venules (HEVs). FAP is highly prevalent in various solid tumors, making it a suitable target for drugs intended to accumulate within the tumor stroma. By restricting LTBR activation specifically to the tumor microenvironment (TME) via FAP targeting, RO7567132 is designed to modulate the tumor stroma to induce HEV differentiation, increase immune cell infiltration via upregulation of adhesion molecules and chemokines and and induce the formation of tertiary lymphoid structures (TLS) specifically at the tumor site, while avoiding widespread LTBR activation and minimizing toxicity. Clinical evidence shows that an increased immune infiltrate, the presence of TLS or the presence of HEVs correlate with better prognosis and better response to cancer immunotherapies in several tumor indications. RO7567132 induced a dose-dependent and FAP-dependent increase in the expression of adhesion molecules on the surface of endothelial cells, as well as an increase in the secretion of immune cell-attracting chemokines in vitro. In preclinical mouse models, the murine surrogate of RO7567132 induced the activation of tumor blood vessels, their differentiation into HEVs and the upregulation of inflammatory and immune pathways that resulted in increased infiltration of T and B cells into the tumor and elevated serum levels of CXCL13. Treatment with the murine surrogate of RO7567132 led to tumor growth inhibition in a breast cancer model and showed greater efficacy when combined with the murine surrogate of atezolizumab in both breast cancer and fibrosarcoma models. Additionally, in a slow-growing orthotopic mouse colorectal cancer model, treatment with the murine surrogate of RO7567132 increased the content of immune cells (T and B cells) and HEVs in tumors and induced the formation of immune cell niches resembling TLS. RO7567132 was well tolerated in both a 2-week non-GLP Maximum tolerated dose/Dose range-finding (MTD/DRF) study and a 4-week GLP toxicology study in cynomolgus monkeys at doses up to 10 mg/kg, with no associated adverse findings. RO7567132 is currently being tested in an open-label, multicenter, dose-escalation, randomized, phase1 study (NCT06537310) to evaluate safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of RO7567132, as a single agent and in combination with atezolizumab in participants with advanced and/or metastatic solid tumours. Citation Format: Roberta Bianchi, Leo Kunz, Michelle Brydon, Dario Speziale, Ralf Hosse, Juliana Bessa, Chr","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"18 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122948","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 1143: Reliable skeletal muscle area quantification and clinical data integration for predicting cancer cachexia","authors":"Sabeen Ahmed, Nathan Parker, Margaret Park, Daniel Jeong, Lauren Peres, Evan W. Davis, Jennifer B. Permuth, Erin Siegel, Matthew B. Schabath, Yasin Yilmaz, Ghulam Rasool","doi":"10.1158/1538-7445.am2025-1143","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-1143","url":null,"abstract":"Background: Cancer cachexia, a metabolic disorder marked by severe muscle loss and common among certain types of cancers, significantly impacts prognosis and quality of life in patients. A core feature of cachexia is skeletal muscle mass reduction, which can be efficiently monitored by assessing the skeletal muscle area (SMA) in computed tomography (CT) scans routinely performed in cancer care. However, manual annotation of SMA on CT scans is labor-intensive and time-consuming, while existing automated tools often suffer from variability in accuracy and lack full automation, limiting their clinical utility. To address these challenges, we developed a reliable and fully automated pipeline to deliver consistent, accurate measurements. By integrating SMA and skeletal muscle index (SMI) with clinical data, our approach facilitates multimodal survival analysis and cachexia prediction, generating insights that empower clinicians to enhance patient care. Method: We trained two deep learning (DL) models (nnU-Net 2D) using annotated CT images of the mid and end-third lumbar (L3) level from 50 gastroesophageal and 15 pancreatic cancer patients. Models were trained using 5-fold cross-validation to ensure robustness. To ensure reliability at inference, uncertainty estimation methods, model ensembling, dropout, and post-hoc calibration, were employed. Metrics such as variance, entropy, and coefficient of variation quantified model uncertainty, and a threshold-based approach flagged high-error SMA estimations for expert review. Our pipeline processes axial CT series, identifies L3 slices, annotates skeletal muscle, generates uncertainty maps, and SMA/SMI estimates. We combined the radiology derived SMA/SMI with clinical features to form multimodal data, which was used for survival analysis and prediction of cachexia at the time of cancer diagnosis using a multi-layer perceptron (MLP) model. Results: On the gastroesophageal dataset, the DL model achieved an average Dice score of 97.80% ± 0.93% for skeletal muscle segmentation. Across the pancreatic, colorectal, and ovarian datasets, the DL model's SMA estimates differed with a median of 2.48% compared to manual expert segmentation. Uncertainty metrics demonstrated strong correlations with SMA estimation differences, with correlation coefficients of 0.83 (variance), 0.76 (entropy), and 0.73 (coefficient of variation). The multimodal MLP model for cachexia prediction achieved 70% accuracy and an F1 score of 76.92%. The multimodal survival analysis showed significant improvements in concordance index compared to using clinical data alone, with increases of 5.6% on the pancreatic, 5.9% on the colorectal, and 1.5% on the ovarian dataset. Conclusion: Our automated, uncertainty-aware tool offers a robust and reliable solution for monitoring skeletal muscle changes, enabling diagnosis and intervention in managing cancer cachexia. Citation Format: Sabeen Ahmed, Nathan Parker, Margaret Park, Daniel Jeong, Lauren Peres, E","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122959","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 LB145: Identification of potent DIAPH3 variants as a powerful biomarker for targeting Native Hawaiian colorectal cancer population","authors":"Sudhir Kumar Rai, Isam Mohd-Ibrahim, Yuanyuan Fu, Asmita Pandey, Li Ma, Yu Chen, Yujia Qiu, Mayumi Jijiwa, Masaki Nasu, Hua Yang, Youping Deng","doi":"10.1158/1538-7445.am2025-lb145","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-lb145","url":null,"abstract":"Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths in the U.S. population, but minority groups experience significant disparities. Native Hawaiians (NH), who make up 0.4% of the U.S. population, face a higher mortality rate compared to Whites, with a rate of 52 per 100,000 in males (vs. 44 per 100,000) and 37 per 100,000 in females (vs. 34 per 100,000). This elevated CRC death rate among both NH males (52 vs. 44) and females (37 vs. 34) compared to the non-NH population highlights CRC as a major health disparity in the NH community. This disparity underscores the need for effective cancer strategies to address both the disease and related inequities. In this study, we conducted DNA and RNA sequencing on tissue samples from Native Hawaiians, including 41 colorectal cancer (CRC) samples and 41 control samples, obtained from the University of Hawaii Cancer Center (UHCC) Biorepository. Our analysis revealed notably high mutation rates in the Diaphanous-Related Formins 3 (DIAPH3) gene. The mutation profile of DIAPH3 was distinct from that of other ethnic groups, prompting us to focus on identifying specific DIAPH3 variants that could be targeted for this population. Given the varied roles of DIAPH3 across different cancer types, we expanded our analysis to assess DIAPH3 expression in Pan-cancer datasets, cancer cell lines, and NH-CRC formalin-fixed paraffin-embedded (FFPE) tissue samples. These samples exhibited elevated DIAPH3 mRNA expression and protein levels. TNM (Tumor, Node, Metastasis) plots revealed higher DIAPH3 expression in tumor samples compared to controls. Although DIAPH3 survival curves for COAD and READ cancers showed elevated expression, the difference was not statistically significant, suggesting that DIAPH3 may act as a potential prognostic biomarker for Native Hawaiian CRC patients with high expression. Building on these observations, we investigated DIAPH3 expression in CRC cell lines by overexpressing full-length wild-type DIAPH3. Our results indicated that DIAPH3 functions as a tumor-promoting gene, as demonstrated by cell migration, wound healing assay, clonogenic and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assays. In contrast, silencing DIAPH3 with siRNA suppressed CRC cell growth. We hypothesize that the loss of specific regions within the DIAPH3 coding sequence could influence the progression of CRC in the Native Hawaiian population. Based on these preliminary findings and the unique DIAPH3 mutation profile observed in Native Hawaiians, we plan to develop DIAPH3 variants that mirror these mutations for further characterization using in vitro functional assays. Ultimately, this research aims to improve our understanding of the disproportionately high CRC mortality rates among Native Hawaiians and inform the development of strategies to address these disparities. Specifically, the identification of potent DIAPH3 variants could provide valuable early detection biomarkers and","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122988","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 ND01: AMG 410: An H/NRAS-sparing pan-KRAS inhibitor with dual GTP(on)/GDP(off)-state activity for the treatment of diverse KRAS-mutant tumors","authors":"Brian A. Lanman, Ryan P. Wurz, Rati Verma, Tao Osgood, Kevin Gaida, Deanna Mohn, Ying-Chu Chen, Gilbert Diaz, Anne Y. Saiki, Paul E. Hughes, Christopher Mohr, Amit Vaish, Yanyan Tudor, Upendra P. Dahal, Prashant Agarwal, Christine Mollica","doi":"10.1158/1538-7445.am2025-nd01","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-nd01","url":null,"abstract":"KRAS is one of the most frequently mutated oncogenes in human cancer (present in ∼25% of cancers). Recent approvals of covalent KRAS G12C inhibitors (KRAS G12Ci) have demonstrated that this once “undruggable” target can now be inhibited with small-molecule allosteric inhibitors to deliver meaningful clinical benefit. Approved inhibitors (sotorasib & adagrasib) are only effective for tumors harboring the KRAS G12C mutation, however, and major unmet need remains for the larger population of patients (∼140k patients/year, USA) that bear other oncogenic KRAS mutations (e.g., KRAS G12D, G12V, etc.). Leveraging insights from KRAS G12Ci, we here report the structure- and property-based design of a non-covalent “pan-KRAS” inhibitor, AMG 410, which binds to the most clinically relevant KRAS mutants (e.g., G12D, G12V, G13D; IC50 values = 1-4 nM) via the same allosteric pocket employed by approved KRAS G12C inhibitors. AMG 410 shows potent antiproliferative activity in KRAS-mutant cells (median IC50 = 12 nM). Importantly, AMG 410 is highly specific for KRAS, demonstrating greater than 100-fold selectivity against both HRAS and NRAS, differentiating AMG 410 from pan-RAS inhibitors through its ability to avoid anti-proliferative effects in non-KRAS-transformed cells (median IC50 >5 µM). In contrast to “on”-state-only inhibitors, AMG 410 is a dual GTP(on)- and GDP(off)-state inhibitor (KD(GDP-state) = 1 nM; KD(GTP-state) = 22 nM), enabling blockade of KRAS signaling in a cycling state-independent manner, while also allowing AMG 410 to block proliferation in wildtype KRAS-amplified tumor cells. AMG 410 demonstrates strong pre-clinical efficacy, robustly lowing phosphorylated ERK levels throughout dosing cycles and achieving tumor stasis or regression across a broad set of colorectal, pancreatic, and lung cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models harboring a diverse set of KRAS mutant alleles including G12D, G12V, G12C, & G13D. AMG 410 also shows enhanced in vivo efficacy in combination with other targeted therapies or immunotherapy and good pre-clinical tolerability, highlighting the potential of an HRAS- and NRAS-sparing pan-KRAS inhibitor to show improved efficacy and clinical tolerability in the combination setting. Based on a promising non-clinical safety and efficacy profile, a first-in-human study with AMG 410 in a range of solid tumor indications (CRC, PDAC, NSCLC) is planned. Citation Format: Brian A. Lanman, Ryan P. Wurz, Rati Verma, Tao Osgood, Kevin Gaida, Deanna Mohn, Ying-Chu Chen, Gilbert Diaz, Anne Y. Saiki, Paul E. Hughes, Christopher Mohr, Amit Vaish, Yanyan Tudor, Upendra P. Dahal, Prashant Agarwal, Christine Mollica. AMG 410: An H/NRAS-sparing pan-KRAS inhibitor with dual GTP(on)/GDP(off)-state activity for the treatment of diverse KRAS-mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, an","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"56 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122995","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 6207: Trends in breast cancer incidence-based mortality among US women aged 20-49 by molecular subtypes and race","authors":"Yueshiu Lyu, Suleepon Uttamapinan, Adetunji T. Toriola","doi":"10.1158/1538-7445.am2025-6207","DOIUrl":"https://doi.org/10.1158/1538-7445.am2025-6207","url":null,"abstract":"Background: Breast cancer incidence is rising in women aged 20-49 years, yet data on trends in mortality for this age group are limited. Mortality varies by several factors, underscoring the need for comprehensive analyses. We, therefore, investigated trends in breast cancer incidence-based mortality (IBM) by race and molecular subtypes. Methods: We performed a population-based study of women aged 20-49 years diagnosed with breast cancer between 2010 and 2020 using SEER 17-registry data. We applied IBM method to evaluate mortality trends by molecular subtype and race/ethnicity. We used Joinpoint regression models to identify changes in IBM trends, using annual percent changes (APC). Additionally, we evaluated breast cancer survival rates by race/ethnicity. Results: We analyzed data on 11,661 breast cancer deaths among women aged 20-49 years. Overall, IBM declined from 9.70/100,000 in 2010 to 1.47/100,000 in 2020. The declines occurred in all subtypes and racial/ethnic groups, with some differences in the points of inflexion. IBM for luminal A decreased consistently from 2010, with more marked decline from 2017 (APC, -32.88; 95%CI, -55.17 to -21.30). TNBC followed a similar pattern, with marked decline in 2018 (APC, -32.82; 95%CI, -41.47 to -17.79). Non-Hispanic Black (NHB) women had the highest IBM in 2010 (16.56/100,000) and 2020 (3.41/100,000) compared with Non-Hispanic White (NHW) women (9.18/100,000 in 2010 and 1.16/100,000 in 2020). Declines in IBM in NHB women become pronounced from 2016 (APC, -24.15; 95% CI -34.36 to -17.92), narrowing the gap with other racial groups. Significant declines in IBM for non-Hispanic Asian/Pacific Islander (API) women started earlier from 2013, compared to 2017 for NHW, non-Hispanic American Indian/Alaska Native, and Hispanic women. Survival analyses showed that NHB women had the worst survival outcomes, while NHW and non-Hispanic API had the best. Conclusion: IBM among US women aged 20-49 years with breast cancer declined significantly from 2010 to 2020, with variations by molecular subtype and race/ethnicity. The rapid decline in IBM after 2016-2018 likely reflects advancements in breast cancer management, particularly in novel treatments. Although NHB women still have the highest IBM, the differences have narrowed in recent years. Efforts should continue to focus on further enhancing access to early screening for high-risk women and effective treatment to fully mitigate racial disparities in mortality. Citation Format: Yueshiu Lyu, Suleepon Uttamapinan, Adetunji T. Toriola. Trends in breast cancer incidence-based mortality among US women aged 20-49 by molecular subtypes and race [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): nr 6207.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"33 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123125","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}