tbuckley/cabot-search huggingface dataset:
Abstract 5217: Interaction of cancer associated fibroblasts and apoptotic cancer cells reduces macrophage survival and promotes reprograming of tumor associated macrophages
Authors: Jihee Lee Kang, Kyungwon Yang, Kiyoon Kim
Journal: Cancer Research (2025)

Recent studies highlight the critical role of cancer-associated fibroblasts (CAFs)- tumor-associated macrophages (TAMs) interactions in tumorigenesis. In prior work, we demonstrated that the interaction between CAFs and apoptotic cancer cells can inhibit tumor growth and metastasis. However, the molecular mechanisms underlying the crosstalk between CAFs reprogrammed by apoptotic cancer cells and TAMs are incompletely understood. In this study, we show, using immunohistochemistry in primary tumors, that intratumoral injection of conditioned medium (CM) from lung CAFs exposed to apoptotic cancer cells reduces the density of tumor-associated macrophages (TAMs) and the proportion of M2 TAMs. Additionally, this treatment shifts M2 TAMs toward an M1-like phenotype within the tumor microenvironment (TME). Furthermore, CM from apoptotic cancer cell-exposed CAFs promotes STAT1 phosphorylation in M2 TAMs. Depletion of WISP-1 from the CM reversed these effects, emphasizing its pivotal role. These findings suggest that CM from apoptotic cancer cell-exposed CAFs may provide a promising therapeutic strategy for targeting TAMs in the TME. Citation Format: Jihee Lee Kang, Kyungwon Yang, Kiyoon Kim. Interaction of cancer associated fibroblasts and apoptotic cancer cells reduces macrophage survival and promotes reprograming of tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5217.
Abstract 1578: Preclinical evaluation of BLB-101, a topoisomerase-inhibitor-based anti-CLDN6/9 antibody-drug conjugate featuring a proprietary hydrophilic linker
Authors: Suk Hyung Lee, Alice Juang, Aastha Jain, Jun Liu, Wen Zhang, Zuoan Yi, Darren Buchwald, Alice Chen
Journal: Cancer Research (2025)

Abstract Claudin 6 (CLDN6) is a tight junction protein that is highly expressed in various human cancers, including ovarian and endometrial cancers, while it is not found in normal adult tissues. Claudin 9 (CLDN9), which shares significant homology with CLDN6, displays similar expression patterns, being nearly absent in normal tissues but upregulated in ovarian and endometrial cancers. We propose to target both CLDN6 and CLDN9 simultaneously to enhance anti-tumor efficacy and broaden treatment options for more patients. We successfully discovered an antibody that binds with high affinity to CLDN6 and CLDN9 while sparing other claudin family members. The humanized version of this candidate antibody demonstrates stronger binding and higher internalization compared to a benchmark antibody currently in clinical development. BLB-101 is an antibody-drug conjugate (ADC) candidate featuring a topoisomerase-inhibitor-based payload optimized in-house with a proprietary hydrophilic linker. Design features of the linker enable efficient delivery of hydrophobic drug payloads and low likelihood of off-target endocytosis. BLB-101 has drug-to-antibody ratio of 8 (DAR8), demonstrates enhanced potency, favorable in vivo PK, and excellent plasma stability. In vitro studies revealed that BLB-101 ADC quickly internalizes in CLDN6+ or CLDN9+ cancer cells. BLB-101 exhibited strong cytotoxic effects across several cancer cell lines, including PA-1 and JEG-3. In addition, we confirmed the bystander killing effect of BLB-101 under a coculture condition of CLDN6-positive cells and negative cells in vitro. Furthermore, BLB-101 maintains the mAb's capability to induce antibody-dependent cellular cytotoxicity. In xenograft models expressing CLDN6, BLB-101 treatment led to a substantial reduction in tumor size. Additionally, repeated administration of BLB-101 was well tolerated in both mice and in non-human primates. Together, these findings provide strong support for the continued development of BLB-101directed against CLDN6/CLDN9 positive tumors. Citation Format: Suk Hyung Lee, Alice Juang, Aastha Jain, Jun Liu, Wen Zhang, Zuoan Yi, Darren Buchwald, Alice Chen. Preclinical evaluation of BLB-101, a topoisomerase-inhibitor-based anti-CLDN6/9 antibody-drug conjugate featuring a proprietary hydrophilic linker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1578.
Abstract 3567: Immunotherapy combined with chemotherapy versus biomarker-guided immunotherapy: A cost-effectiveness analysis
Authors: Fubing Wu, Feilong Zhao, Ding Zhang, Wen Huang
Journal: Cancer Research (2025)

Abstract Background. PD-L1 and TMB are established biomarkers for predicting immunotherapy efficacy. However, with the substantial reduction in the cost of domestic PD-L1 testing, the value of expensive genetic testing compared to its limited benefits has become a pertinent question. Methods. Data from 309 NSCLC receiving immunotherapy and 156 NSCLC undergoing chemotherapy in CHOICE-01 clinical trial were analyzed. Using a decision tree model, patients were categorized into All-in group receiving immunotherapy combined with chemotherapy, and two control groups guided by TMB and PD-L1, respectively. Cost-effectiveness was assessed using Incremental Cost-Effectiveness Ratio (ICER). Results. The decision tree comprised three chance nodes: All-in combinational therapy, TMB-guided, and PD-L1-guided strategies (Table 1 Table 1. Structure and parameters of the decision tree. Decision Probability, % Regimen ORR mean, % ORR Distribution Adjusted mean utility All-in 100 Comb 65.70 Beta(203, 106) R: 0.698 NR: 0.567 TMB TMB-H: 30.96 Comb 72.73 Beta(56, 21) R: 0.698 NR: 0.567 TMB-L: 69.04 Chemo 45.88 Beta(39, 46) R: 0.690 NR: 0.547 PD-L1 Pos: 65.16 Comb 68.00 Beta(136, 64) R: 0.698 NR: 0.567 Neg: 34.84 Chemo 39.62 Beta(21, 32) R: 0.690 NR: 0.547 ). The TMB-H group exhibited the highest response rate, followed by the PD-L1 positive group, both exceeding an overall response rate of 65.7%. Utility values for partial response (PR), stable disease (SD), and progressive disease (PD) were retrieved from previous studies, then adjusted by weighted average of SD and PD distribution and adverse reaction-related disutility. After model evaluation, the All-in, TMB-guided, and PD-L1 guided strategies yielded utility of 0.653, 0.638, and 0.628, respectively. Corresponding costs were ¥3, 202, ¥3, 833, and ¥11, 395. Given the decreasing utility and increasing cost across the strategies, calculating the ICER was deemed unnecessary. Conclusion. The All-in strategy demonstrated the highest utility and lowest cost, indicating it as the most cost-effective option for patients considering immunotherapy combined with chemotherapy. However, as this study focused on ORR, it only reflects short-term cost-effectiveness. Further investigation into long-term cost-effectiveness regarding survival outcomes is warranted. Citation Format: Fubing Wu, Feilong Zhao, Ding Zhang, Wen Huang. Immunotherapy combined with chemotherapy versus biomarker-guided immunotherapy: A cost-effectiveness analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3567.
Abstract 5243: Peripheral Foxp3high regulatory T cells develop into tumor-associated counterparts by proinflammatory cytokines and act as prognostic biomarker in patients with hepatoma
Authors: Wei-Ting Ku, Chien-Hao Huang, Jayashri Mahalingam, Cheng-Heng Wu, Tsung-Han Wu, Jian-He Fan, Chung-Wei Su, Po-Ting Lin, Chien-Wei Peng, Wei Teng, Wen-Juei Jeng, Wen-Juei Jeng, Wei-Ting Chen, Chen-Chun Lin, Shi-Ming Lin, I-Shyan Sheen, Yung-Chang Lin, Chun-Yen Lin
Journal: Cancer Research (2025)

CD4+ regulatory T cells (Tregs) play a critical role in the progression of hepatocellular carcinoma (HCC). However, indiscriminate depletion of Tregs risks triggering autoimmunity. While previous research highlights the phenotypic and functional heterogeneity of Treg subpopulations, a unified classification system remains elusive. This study aims to characterize Treg subtypes in HCC patients using single-cell CITE-seq and validate their clinical relevance and prognostic potential. CITE-seq profiling of 51,067 CD4+ T cells from eight HCC patients identified distinct Treg populations in tumor, non-tumor, and peripheral blood samples. Validation studies conducted on 96 HCC patients and 53 healthy donors using flow cytometry, functional assays, and clinical data revealed a peripheral Foxp3high Treg subset that preferentially migrates to tumor sites. Upon infiltration, these Tregs undergo terminal differentiation, exhibiting heightened activation, immunosuppressive functions, and increased expression of LAYN and TRM-associated genes. Proinflammatory cytokines within the tumor microenvironment further amplify Foxp3 expression and the suppressive capacities of these cells. Mechanistic analysis implicated the CCL5/CCR5 signaling axis as essential for the recruitment of Foxp3high Tregs from peripheral blood to the tumor microenvironment. Peripheral Foxp3high Tregs strongly correlated with their tumor-infiltrating counterparts, suggesting their potential as a non-invasive biomarker. A threshold of peripheral Foxp3high Tregs/CD4+ T cells &amp;gt; 3.5% was found to predict overall survival and early recurrence, achieving AUROCs exceeding 0.75. In conclusion, peripheral Foxp3high Tregs transition into tumor-associated counterparts via the CCR5-CCL5 axis and proinflammatory cytokines, contributing to immunosuppression in HCC. Their abundance in peripheral blood correlates with tumor infiltration and clinical outcomes, underscoring their utility as a prognostic biomarker for HCC. Citation Format: Wei-Ting Ku, Chien-Hao Huang, Jayashri Mahalingam, Cheng-Heng Wu, Tsung-Han Wu, Jian-He Fan, Chung-Wei Su, Po-Ting Lin, Chien-Wei Peng, Wei Teng, Wen-Juei Jeng, Wen-Juei Jeng, Wei-Ting Chen, Chen-Chun Lin, Shi-Ming Lin, I-Shyan Sheen, Yung-Chang Lin, Chun-Yen Lin. Peripheral Foxp3 regulatory T cells develop into tumor-associated counterparts by proinflammatory cytokines and act as prognostic biomarker in patients with hepatoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5243.
Abstract 1827: Investigating the efficacy of 177-Lu therapeutics in a series of castrate resistant prostate cancer PDX models
Authors: Stefano Cairo, Benedetta Arno, Mara Gilardi, Hsiu-Wen Tsai, Juliana Maynard, Marianna Zipeto, Michael Ritchie
Journal: Cancer Research (2025)

Abstract Recent advancements in alpha and beta particle-emitting radiopharmaceuticals underscore the therapeutic potential of targeted radionuclide therapy, presenting a promising alternative for patients with advanced or metastatic disease where conventional treatments fall short. This field is pushing the boundaries of personalized medicine, allowing clinicians to tailor treatments to individual patients' genetic and molecular profiles, thereby improving outcomes. As translational research in radiopharmaceutical development progresses, it holds significant promise for redefining therapeutic options and setting new standards in patient care. Targeting and maintaining high specificity to chosen targets, such as PSMA, is crucial for the clinical success of novel radiopharmaceuticals. The development and translation of these therapies require a series of steps through the drug discovery pipeline, including selecting the right radionuclide, chemistry, model, and biomarkers for patient selection. Historically, radiopharmaceutical development has relied on cell lines. While cell-derived xenografts are cost-effective and essential for initial characterization, screening, biodistribution, and efficacy, clinically relevant pre-clinical models predictive of patient outcomes are indispensable for de-risking radiopharmaceutical development. Unfortunately, these models have been underutilized due to the limited availability of combined PDX and radiopharmaceutical capabilities. Here, we present an end-to-end approach for testing 177-Lu therapeutics, from dosimetry and biodistribution in cell lines to efficacy in metastatic castration-resistant PDX models. When treated with 177-Lu based prostate therapeutics, PDX models exhibited a diverse range of responses. RNA-seq and proteomics analyses confirmed that Champions Oncology metastatic castration-resistant prostate cancer PDX models expressed varying levels of PSMA, reflecting the patient population in clinical settings. Our results highlight the importance of integrating robust radiochemistry and biodistribution workflows with clinically relevant patient-derived models to derive translational insights and accelerate the development of radiopharmaceuticals. This comprehensive approach not only enhances the predictive power of pre-clinical models but also ensures that the therapeutic strategies developed are closely aligned with the clinical realities faced by patients. Citation Format: Stefano Cairo, Benedetta Arno, Mara Gilardi, Hsiu-Wen Tsai, Juliana Maynard, Marianna Zipeto, Michael Ritchie. Investigating the efficacy of 177-Lu therapeutics in a series of castrate resistant prostate cancer PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1827.
Abstract 2653: Non-muscle myosin II a role in breast cancer proliferation, invasion and metastasis
Authors: Wasim Feroz, Sarah Storr, Andrew Stiles, Marykate Kilroy, Olamide Ogunleye, Joan T. Garrett
Journal: Cancer Research (2025)

Abstract We recently identified non-muscle myosin IIa (NMIIA) as a novel binding partner for HER3 in HER2+ breast cancer cells. This interaction was observed through HER3 immunoprecipitation experiments following inhibition of the HER family, compared to vehicle control treatments. NMIIA, a hexameric protein, is encoded by the Myosin heavy chain 9 (MYH9) gene, which provides the heavy chain necessary for its structure and function. NMIIA plays a critical role in cytoskeletal dynamics and cellular mechanotransduction, processes implicated in cancer progression and metastasis. To investigate the clinical significance of NMIIA, we analyzed its protein expression in early-stage invasive breast cancer samples using immunohistochemistry. Tumor samples were stained with an antibody against NMIIA and subsequently stratified into two groups: the lower 50% and the upper 50% based on NMIIA expression levels. This stratification was performed by a trained pathologist. Focusing on patients with lymphovascular invasion (LVI), we found that those with high NMIIA expression levels exhibited significantly worse disease-specific survival compared to patients with low NMIIA levels (p = 0.010). Interestingly, no difference in survival was observed among LVI-negative patients, regardless of NMIIA expression levels (p = 0.948). These findings underscore a potential interplay between NMIIA expression and tumor vasculature, suggesting NMIIA may contribute to tumor progression in the presence of LVI. Ongoing studies aim to determine whether NMIIA is more highly expressed in matched brain metastases of breast cancer compared to their primary tumors, mirroring a pattern previously reported for HER3. This research will help elucidate NMIIA's role in metastatic progression and its potential as a therapeutic target. Additionally, we are exploring whether NMIIA contributes to breast cancer development in a mechanically sensitive manner using a novel parent NMII inhibitor compound. This compound has already led to the development of a small molecule inhibitor that has entered clinical trials, highlighting the translational potential of targeting NMIIA. Our findings suggest NMIIA as a key player in HER3 signaling and tumor progression, particularly in the context of LVI, and provide a foundation for further research into its mechanistic and therapeutic implications. Citation Format: Wasim Feroz, Sarah Storr, Andrew Stiles, Marykate Kilroy, Olamide Ogunleye, Joan T. Garrett. Non-muscle myosin II a role in breast cancer proliferation, invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2653.
Abstract 4991: Temporal trends in health-related quality of life (HRQoL) outcomes in fourth line or higher treatment for relapsed/refractory multiple myeloma (RRMM): A systematic literature review (SLR) and meta-analysis
Authors: Ken Hasegawa, Xavier P. Leleu, Taha Itani, Monique Giordana, Enrique Granados, Rebecca J. Chan, Ana Kostic, Jie Ting, Sean P. Harrigan, Michael J. Zoratti, Rahul Banerjee
Journal: Cancer Research (2025)

Abstract Background: The HRQoL of patients with RRMM is highly impacted by their disease and is typically only maintained with conventional treatments before deteriorating. We conducted an SLR and meta-analyzed temporal trends in HRQoL to contextualize findings from emerging immunotherapies for 4L+ RRMM such as chimeric antigen receptor T-cell (CAR T) therapies and bispecific antibodies (BsAb). Methods: MEDLINE, EMBASE, CENTRAL and the grey literature were systematically searched (Jan 2012 to Mar 2024) for studies of patients with 4L+ RRMM where HRQoL was measured according to either the EORTC QLQ-C30 or QLQ-MY20. Changes from baseline were described, by treatment category (CAR T, BsAb, and Other), using fixed-effect meta-analyses over one year of follow-up. Estimates were compared to minimally important differences (MIDs) to determine clinical meaningfulness. Results: We included 14 studies with QLQ-C30 (n=14) or QLQ-MY20 (n=11) outcomes at timepoints of interest (Table). In patients treated with CAR T, sustained clinically meaningful improvements were observed from 3 months onwards on the Physical functioning and Pain domains and from 4 months onwards on Global health status and the Social functioning, Fatigue, and Future perspective domains. Treatment with a BsAb tended to maintain baseline HRQoL over time, with some meaningful improvements in Emotional functioning, Physical functioning, Fatigue, and Pain. Meaningful deteriorations were seldom observed on any domain. Conclusions: This evidence base is evolving, and some findings are limited by few studies and small sample sizes. Nevertheless, our study demonstrated earlier and sustained improvement in key HRQoL domains among patients with 4L+ RRMM who receive CAR T. These findings are similar to the results of CAR T in other hematological settings and reflect improved general well-being post-CAR T. Citation Format: Ken Hasegawa, Xavier P. Leleu, Taha Itani, Monique Giordana, Enrique Granados, Rebecca J. Chan, Ana Kostic, Jie Ting, Sean P. Harrigan, Michael J. Zoratti, Rahul Banerjee. Temporal trends in health-related quality of life (HRQoL) outcomes in fourth line or higher treatment for relapsed/refractory multiple myeloma (RRMM): A systematic literature review (SLR) and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4991.
Tuneable Gelatin Methacryloyl (GelMA) hydrogels for the directed specification of renal cell types for hiPSC-derived kidney organoid maturation.
Authors: Shane Clerkin, Krutika Singh, Jessica L Davis, Niall J Treacy, Ivan Krupa, Emmanuel G Reynaud, Robert M Lees, Sarah R Needham, Delphi MacWhite-Begg, Jacek K Wychowaniec, Dermot F Brougham, John Crean
Journal: Biomaterials (2025)
Abstract 1738: Pan-inhibition of super-enhancer-driven oncogenic transcription by novel synthetic ecteinascidins yields potent anti-cancer activity
Authors: Julian Obid, Max Cigrang, Maguelone Nogaret, Frédéric Coin
Journal: Cancer Research (2025)

Abstract Transcriptional addiction is a cancer hallmark, defined as the strong dependence of cancer cells on the high transcriptional activity of specific oncogenes promoting their proliferation and survival. This phenomenon often involves the acquisition of large clusters of enhancers known as super-enhancers (SE), which are bound by extremely abundant levels of ubiquitous transcription factors that sustain the robust oncogenic expression. Despite recent efforts to develop compounds disrupting SE-driven oncogenic expression, such as CDK7 and BRD4 inhibitors, their clinical success has been limited due to poor pharmacokinetics and short half-lives. Skin cutaneous melanoma (SKCM) serves as a valuable model for studying transcriptional addiction, as melanoma cells can dynamically shift between various cellular states through transcriptional and epigenetic reprogramming, posing a challenge for current therapeutic strategies. To address this, we developed two novel synthetic ecteinascidin derivatives of lurbinectedin, a drug approved for the treatment of advanced small cell lung cancer. Our results demonstrate that these newly developed ecteinascidins, along with the parent compound lurbinectedin, exhibit potent anti-tumor effects against melanoma, both in vitro and in mouse xenografts models resistant to current therapies, leading to reduced tumor growth and prolonged animal survival. Mechanistically, our extensive RNA-seq and chem-map assays reveal that synthetic ecteinascidins significantly suppress SE-mediated oncogene expression in melanoma cells by directly binding to and inhibiting the promoters of genes encoding ubiquitous transcription factors and coactivators that are highly enriched at oncogenic SE sites. Overall, our study provides the first evidence that the clinically approved drug, lurbinectedin, as well as its derivatives, can target and disrupt SE-dependent oncogenes, highlighting their potential as therapeutic options for cancers with transcriptionally heterogeneous landscapes where conventional therapies face significant challenges. Citation Format: Julian Obid, Max Cigrang, Maguelone Nogaret, Frédéric Coin. Pan-inhibition of super-enhancer-driven oncogenic transcription by novel synthetic ecteinascidins yields potent anti-cancer activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1738.
Small Molecule Inhibition of SUMOylation Increases Expression from AAV Vectors Both During and After Initial Transduction in Mice
Authors: Maria C Seleme, Aradhana Kasimsetty, Young Hwang, Carole Lee, Aoife M Roche, Allysen C Henriksen, John K Everett, Frederic D Bushman, Denise E Sabatino
Journal: Molecular Therapy (2025)
Identification of a robust promoter in mouse and human hepatocytes by in vivo biopanning of a barcoded AAV library
Authors: Jonas Becker, Claire Domenger, Pervinder Choksi, Chiara Krämer, Conradin Baumgartl, Olena Maiakovska, Jae-Jun Kim, Jonas Weinmann, Georg Huber, Florian Schmidt, Christian Thirion, Oliver J Müller, Holger Willenbring, Dirk Grimm
Journal: Molecular Therapy (2025)