tbuckley/cabot-search huggingface dataset:
Abstract 3953: FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms tumor
Authors: Yongdong Su, Garrett Cooper, Katie Skinner, Hong Yin, Jason Yustein, Sumin Kang, Andrew Hong
Journal: Cancer Research (2025)

Abstract Favorable Histology Wilms tumor (FHWT) is the most common pediatric kidney cancer and those with relapsed FHWT continue to have poor prognoses. A challenge in the field of FHWT research is the lack of faithful preclinical in vitro models for both primary and relapsed tumors. This prevents us from understanding the biology of FHWT and introducing new targeted therapies into FHWT clinical trials. We recently established 10 FHWT cell lines, including one from a relapsed case, which faithfully recapitulated the genome and transcriptome of the primary tumor. However, challenges persist in maintaining the long-term growth of these cell lines, limiting our insight into the functional study of FHWT. Through comparison of the transcriptome of the FHWT primary tumor samples to their respective cell lines, we identified upregulation of fibroblast growth factor 8 (FGF8) expression in primary tumors. We then performed functional genomics to study the role of FGF8 in FHWT. We found that the splice variants, FGF8b or FGF8f, are required for the maintenance of FHWT cells. Re-introducing these two splice variants using either exogenous addition or endogenous overexpression led to increased viability and passaging of FHWT cell line models by an average of 100% and 30%, respectively. Further, we found that overexpressing FGF8b or FGF8f led to increased clonogenicity and invasion in vitro and led to tumor formation in vivo. Our mechanistic studies suggest that FGF8 drives a stemness and proliferation program through a non-canonical KRAS/MAPK pathway: FGF8b and FGF8f overexpression activates MEK1/2 without activating Erk1/2 while still promoting ETV1 and ETV4, leading to increased cell proliferation. Abrogation of MAPK pathway in vitro using MEK inhibitors led to decreased viability in cells overexpressing FGF8b and FGF8f. Together, our study highlights the oncogenic effect of FGF8 in FHWT and links FHWT to an unexpected non-canonical MAPK pathway. Citation Format: {Authors}. {Abstract title} [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 XX.
Abstract 4608: Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors
Authors: Kimberly J. Briggs, Andre Mignault, Jordi Rodon, Victor Moreno, David Spigel, Capucine Baldini, Candace Haddox, Angela Hirbe, Ignacio Garrido-Laguna, Ibiayi Dagogo-Jack, Emiliano Calvo, Alexander Spira, Matthew R. Tonini, Douglas A. Whittington, Steven A. Lombardo, Binzhang Shen, Hannah Stowe, Shangtao Liu, Hongxiang Zhang, Satoshi Yoda, Brian Doyon, Wenhai Zhang, Minjie Zhang, Kevin M. Cottrell, Samuel Meier, Yi Yu, Teng Teng, Heidi Rego, Jennifer Morawiak, Heather DiBenedetto, Ellen Hooper, Adam Crystal
Journal: Cancer Research (2025)

Abstract Homozygous deletion of the MTAP gene occurs in 10-15% of all human cancers. To benefit this large patient population, MTA-cooperative PRMT5 inhibitors, including TNG908, TNG462, and TNG456 were developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Clinical trial eligibility for most MTA-cooperative PRMT5 inhibitors is restricted to patients with tumors with confirmed MTAP loss either detected by next-generation sequencing or immunohistochemistry. MTAP loss most commonly occurs as a co-deletion event with the proximal CDKN2A gene and the chromosomal 9p breakpoints are not uniform. Previously, we reported that homozygous loss of only the terminal exon (exon 8), an event reported to occur in only 0.5% of MTAP-deleted tumors, is insufficient for complete loss of MTAP activity in preclinical assays. Here, we report initial evidence for the clinical impact of MTAP truncations, as opposed to complete deletion, on the activity of MTA-cooperative PRMT5 inhibitors. Citation Format: Kimberly J. Briggs, Andre Mignault, Jordi Rodon, Victor Moreno, David Spigel, Capucine Baldini, Candace Haddox, Angela Hirbe, Ignacio Garrido-Laguna, Ibiayi Dagogo-Jack, Emiliano Calvo, Alexander Spira, Matthew R. Tonini, Douglas A. Whittington, Steven A. Lombardo, Binzhang Shen, Hannah Stowe, Shangtao Liu, Hongxiang Zhang, Satoshi Yoda, Brian Doyon, Wenhai Zhang, Minjie Zhang, Kevin M. Cottrell, Samuel Meier, Yi Yu, Teng Teng, Heidi Rego, Jennifer Morawiak, Heather DiBenedetto, Ellen Hooper, Adam Crystal. Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors [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 4608.
Abstract 3277: Investigating the link between metabolic reprogramming and immune modulation in tumors: exploring the therapeutic potential of BPM31510
Authors: Maria-D. Nastke, Sylwia Stopka, Abbas Khojestah, Juan J. Aristizabal-Henao, Archna Ravi, Kaila M. Bennett, Niven R. Narain, Lawrence Recht, Michael A. Kiebish, Stephane Gesta
Journal: Cancer Research (2025)

Abstract BPM31510, a CoQ10-lipid nanoparticle, has been shown in previous studies to deliver supraphysiological levels of oxidized CoQ10 to tumors, leading to the induction of mitochondrial Reactive Oxygen Species (ROS) and subsequent apoptotic cell death. Since mitochondrial metabolism is crucial for immune cell function, we investigated whether BPM31510 could influence the tumor microenvironment (TME) to influence immune-mediated tumor elimination. In tumor models such as MC38 and PAN02, we have demonstrated that BPM31510 induces cytotoxic T cell infiltration while concurrently reducing tumor-associated macrophages (TAMs). Additionally, in a rat glioblastoma (GBM) model, BPM31510 was found to metabolically reprogram tumors, further suggesting a potential link between immune modulation and metabolic changes within the TME. These findings support the hypothesis that BPM31510’s ability to reprogram tumor metabolism and induce T cell infiltration may be interconnected. This dual mechanism positions BPM31510 as a promising therapeutic for enhancing immune responses in 'immunologically cold' tumors, such as GBM and pancreatic cancer. To explore this connection further, we propose focused studies in syngeneic murine models to examine how BPM31510’s immune-modulatory and metabolic effects interact within the TME. These studies will involve detailed analysis of both tumor and lymphoid tissues using advanced flow cytometry and TIMSTOF FLEX spatial omics technology. The goal is to investigate how different dosing and scheduling regimens of BPM31510 impact the relationship between tumor metabolism, immune cell phenotype, and immune activity. Ultimately, this study aims to provide new insights into optimizing BPM31510 treatment strategies, potentially enhancing the effectiveness of immune-based therapies for these difficult-to-treat cancers. By understanding how BPM31510 influences both the immune landscape and metabolic reprogramming of tumors, we hope to develop more effective therapeutic approaches for 'cold' tumors like GBM and pancreatic cancer. Citation Format: Maria-D. Nastke, Sylwia Stopka, Abbas Khojestah, Juan J. Aristizabal-Henao, Archna Ravi, Kaila M. Bennett, Niven R. Narain, Lawrence Recht, Michael A. Kiebish, Stephane Gesta. Investigating the link between metabolic reprogramming and immune modulation in tumors: exploring the therapeutic potential of BPM31510 [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 3277.
Abstract 1673: Advancing bladder cancer treatment with live attenuated salmonella ZH9: from monotherapy to combination strategies
Authors: Nicholas Glanville, Claudia Prevosto, Sonia Domingos-Pereira, Lenka Polak, Victoria Morel, Marine Leblond, Gregory Verdeil, Denise Nardelli-Haefliger, Livija Deban
Journal: Cancer Research (2025)

Abstract For over 30 years, microbial immunotherapy with Bacillus Calmette-Guérin (BCG) has been the standard-of-care for non-muscle invasive bladder cancer (NMIBC). Global demand for BCG however exceeds supply and BCG therapy is associated with disease recurrence and high treatment burden. Most novel bladder cancer treatments in development either target BCG unresponsive patients as second line or are administered in combination with BCG and thus share its shortcomings. There remains a significant need for innovative therapies to replace BCG in bladder cancer treatment, and live-attenuated Salmonella Typhi ZH9 presents a promising alternative, both as a monotherapy and as a combination partner. Efficacy of ZH9 was investigated in syngeneic mouse MB49 and p53-/Pten- GEMM orthotopic tumor models in which animals were treated in the bladder via catheterization, with or without combination intraperitoneal anti-PD-L1 or anti-PD-1 treatment. Immune responses were characterized by flow cytometry and histology analyses of bladder tissue. Intravesical ZH9 monotherapy following orthotopic MB49 tumor inoculation demonstrated significant survival benefit compared to both vehicle control and BCG treatments. A single administration of ZH9 was sufficient for efficacy, inducing far greater magnitude and duration of immune responses than standard-of-care BCG, and resulting in systemic anti-tumor immunity that protected against both local bladder and distant MB49 tumors. Combination of local ZH9 treatment with regimens of checkpoint inhibitor antibodies anti-PD-L1 (MB49 model) and anti-PD-1 (GEMM model) that were otherwise ineffective, led to significant efficacy, suggesting local Salmonella ZH9 treatment can synergize with systemic immunotherapies. These data support Salmonella ZH9 as an effective first-line monotherapy and checkpoint inhibitor combination therapy for bladder cancer, with potential to reduce treatment burden on patients, lower associated healthcare costs and to ease microbial therapy supply constraints due to a scalable manufacturing process. Clinical evaluation of ZH9 in a Phase 1b study evaluating safety, pharmacology, and early efficacy in NMIBC is ongoing. Citation Format: Nicholas Glanville, Claudia Prevosto, Sonia Domingos-Pereira, Lenka Polak, Victoria Morel, Marine Leblond, Gregory Verdeil, Denise Nardelli-Haefliger, Livija Deban. Advancing bladder cancer treatment with live attenuated salmonella ZH9: from monotherapy to combination strategies [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 1673.
Abstract 4180: Insights into HuR as a modulator of aerobic glycolysis in triple-negative breast cancer
Authors: Arundhathi Dev J R, Ajay Gogia, Sandeep R. Mathur, Ashutosh Mishra, Chandra Prakash Prasad
Journal: Cancer Research (2025)

Abstract The RNA-binding protein Human Antigen R (HuR/ELAVL1) is ubiquitously expressed and plays a pivotal role in post-transcriptional gene regulation by stabilizing and enhancing the translation of mRNAs containing U/AU-rich elements. Its overexpression, particularly in the cytoplasm, has been implicated in various cancers, where it drives critical processes such as proliferation, survival, angiogenesis, and metastasis. As a key modulator of oncogenic pathways, HuR represents a significant target for understanding cancer progression and developing novel therapeutic strategies. The present study investigates the oncogenic role of HuR in TNBCS, an aggressive subtype of breast cancer. Meta-analysis with TNBC dataset (Liu-2014) correlated high HuR protein expression with reduced patient survival (p=0.028). Immunohistochemistry performed in 40 TNBC patient tissue showed an overexpression of HuR (77%) and its downstream target MMP9(55%). Disrupting the RNA binding activity of HuR with the HuR specific inhibitor CMLD2 resulted in the downregulation of HuR and its downstream targets CDK2, MMP9, and β-catenin in TNBC cell lines MDA-MB-231 and MDA-MB-468. Inhibition of cytoplasmic HuR was validated via immunofluorescence and cell fractionation followed by immunoblotting. HuR inhibition compromised proliferation, migration, invasion, extracellular acidification, clonogenicity (2D and 3D), and EMT (downregulated E-Cadherin, N-Cadherin, and Vimentin) in TNBC cells. Exploratory transcriptomics via nCounter XT showed that HuR inhibition in MDA-MB-231 altered the profile of glycolytic genes in addition to other pathways such as cell cycle, DNA damage repair, amino acid synthesis etc. In accordance, the expression of the glycolytic genes LDHA, PFKP and MCT4 was reduced upon CMLD2 treatment at mRNA and protein level in both the TNBC cell lines. Pretreatment with CMLD2 impaired the tumor forming ability of 4T1 in vivo. Consistent results were obtained on HuR siRNA knockdown. To our knowledge, this is the first report that explores HuR as a positive regulator of aerobic glycolysis in TNBCs. Inhibition of HuR by CMLD2 provides a rationale to consider it as a potential anticancer agent for TNBCs. Citation Format: Arundhathi Dev J R, Ajay Gogia, Sandeep R. Mathur, Ashutosh Mishra, Chandra Prakash Prasad. Insights into HuR as a modulator of aerobic glycolysis in triple-negative breast cancer [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 4180.
Abstract 4814: Development of a novel claudin-6-targeting CAR-T cell
Authors: Ana Shahpazir, Siret Tahk, Paule Hermet, Anu Ustav, Robin Pau, Gaily Kivi, Mario Plaas, Andres Männik, Joan Teyra, Mart Ustav, Tanel Mahlakōiv
Journal: Cancer Research (2025)

Abstract Chimeric antigen receptor (CAR) T cell therapies have achieved remarkable efficacy in treating B cell malignancies but have shown limited clinical success in patients with solid tumors. A key challenge in advancing these therapies lies in the identification and targeting of highly tumor-specific antigens to ensure both safety and efficacy. In this study, we employed HybriFree B-cell cloning technology and phage display to discover antibodies targeting Claudin-6 (CLDN6), an oncofetal protein selectively expressed in subsets of ovarian, lung, endometrial, and testicular cancers, with minimal or no expression in healthy adult tissues. To generate a robust immune response, chickens were immunized with virus-like particles (VLPs) displaying a high-density presentation of transmembrane CLDN6. Monoclonal antibodies specific to CLDN6 were subsequently screened for their specificity towards CLDN6 using VLPs bearing other Claudin family members. The most promising specific binders that were able to discriminate between binding of CLDN6 and CLDN9 were humanized via the Qumanize platform and incorporated into a second-generation CAR construct with a 4-1BB costimulatory domain and CD3ζ signaling domain. CLDN6-specific CAR T cells were then generated and evaluated for their cytotoxicity in tumor models of ovarian, lung, and gastric cancers. Two CLDN6-specific CARs exhibited highly specific recognition and efficient lysis of cancer cells endogenously expressing CLDN6. Within 24 hours of co-culture, CLDN6 CAR T cells eliminated 80% of PA-1 cells and 60% of OV-90 cells. To assess T cell immune activation, cytokine secretion was measured upon co-culture with various target cells. Notably, IFN-γ secretion was observed exclusively when CLDN6 CAR T cells were co-cultured with CLDN6-positive targets, confirming their antigen specificity. This study underscores the utility of HybriFree technology and the Qumanize platform in generating highly specific and high-affinity CARs for tumor targeting. These findings present a promising avenue for developing next-generation immunotherapies for CLDN6-expressing solid tumors. Citation Format: Ana Shahpazir, Siret Tahk, Paule Hermet, Anu Ustav, Robin Pau, Gaily Kivi, Mario Plaas, Andres Männik, Joan Teyra, Mart Ustav, Tanel Mahlakōiv. Development of a novel claudin-6-targeting CAR-T cell [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 4814.
Abstract 4593: Molecular and immunohistochemical classification of extrapulmonary small cell neuroendocrine carcinomas: A study of 181 cases
Authors: Radoslav Matej, Pavel Dundr, Klara Pavlickova, Marian Svajdler, Jan Hojny, Nikola Hajkova
Journal: Cancer Research (2025)

Abstract Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Most patients with EP-SCNC have metastatic disease upon presentation, and their average overall survival (OS) is less than 12 months. Our study aimed to conduct a complex analysis of EP-SCNC. One hundred and eighty-one EP-SCNC tissue samples were subjected to a complex analysis. One hundred and fifty-five tumors were pure EP-SCNC, while 26 were combined tumors. Immunohistochemistry for ASCL1, NEUROD1, YAP1, POU2F3, Rb1, p53, cyclin D1, p16, PTEN, DLL3, PD-L1, CD56, synaptophysin, chromogranin A, and INSM1 was performed, and 128 samples were analyzed molecularly using next generation sequencing (NGS), comprising DNA and RNA analysis. Detailed results on immunohistochemical and molecular analyses were provided for each primary origin of EP-SCNC separately. Median survival for the whole cohort of patients was 8.94 months. Patient age (≥ 70 years), tumor mutational burden (TMB) &amp;lt; 15, and TP53 and BRCA2 mutations were negative prognostic factors. High expression of ASCL-1 was associated with shorter OS, whereas high expression of YAP1 was associated with longer OS. Patients with genitourinary tumors had significantly better OS than those with gastrointestinal tract EP-SCNC tumors. Rb1 expression loss was detected more often in genitourinary tract SCNCs. In contrast, p16 overexpression was found more often in genitourinary tract SCNCs. POU2F3 expression was detected more often in combined tumors, whereas NEUROD1 was detected more often in pure EP-SCNC. Regarding “druggable markers, ” DLL3 was expressed in 66% of tumors and PD-L1 in 17.4%.Detailed analyses of different prognostic and predictive markers are needed to better understand EP-SCNC biology and create more personalized therapy to improve patient prognosis. Citation Format: Radoslav Matej, Pavel Dundr, Klara Pavlickova, Marian Svajdler, Jan Hojny, Nikola Hajkova. Molecular and immunohistochemical classification of extrapulmonary small cell neuroendocrine carcinomas: A study of 181 cases [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 4593.
Abstract 3930: Preclinical models of cancer cachexia: Bridging the gap to clinical applications
Authors: Hongyan Sun, Dan Zhou, Yunlong Jiang, Jianming Xu, Jing Zhao, Xiang Gao, Jun Wang
Journal: Cancer Research (2025)

Abstract Cancer cachexia (CC) is a multifactorial syndrome affecting up to 80% of advanced cancer patients. Characterized by unintentional weight loss, skeletal muscle wasting, and fat depletion, CC significantly impairs quality of life, treatment tolerance, and survival. Despite its prevalence, effective therapeutic options remain limited, underscoring the urgent need for preclinical models that closely mimic clinical symptoms to support drug development. Towards this end, we developed and validated a CC preclinical model with HT-1080 xenograft in NCG mice, which demonstrated hallmark CC features, including body weight loss, fat and muscle loss, as well as impaired physical performance. The tumor-bearing mice also displayed elevated hGDF15 levels (undetectable in non-tumor-bearing (NTB) mice), and significantly reduced cumulative food intake. In this study, we used Ponsegromab (anti-GDF15 monoclonal antibody) as a positive treatment for CC starting when mice had lost ∼7% body weight. At the end of the study, mice in hIgG1-treated control group suffered over 15% body weight loss, while the Ponsegromab treatment restored body weight to baseline levels. Although Ponsegromab treated mice remained lighter than NTB PBS controls, our data suggested that Ponsegromab treatment could significantly improve food intake and increase survival rates. Fat and muscle tissue weights, including gonadal, peri-renal, and inguinal subscapular white fat, as well as gastrocnemius and soleus muscles, were significantly reduced in the hIgG1-treated control group compared to baseline controls. Ponsegromab treatment preserved fat and muscle weights to levels similar to the baseline group. Motor function assessed via rotarod performance, and grip strength showed coordination and strength impairments in tumor-bearing mice, while Ponsegromab significantly improved grip strength and physical performance in comparison to the hIgG1-treated control group. In conclusion, our validated preclinical cachexia models closely align with clinical CC manifestations, providing a robust platform for the evaluation of novel therapeutic strategies. These models enable detailed exploration of CC mechanisms and support the development of effective interventions to mitigate cachexia and improve patient outcomes. Citation Format: Hongyan Sun, Dan Zhou, Yunlong Jiang, Jianming Xu, Jing Zhao, Xiang Gao, Jun Wang. Preclinical models of cancer cachexia: Bridging the gap to clinical applications [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 3930.