tbuckley/cabot-search huggingface dataset:
Abstract 909: A new chemokine identified as a key player of tumor immune microenvironment remodeling in β-catenin mutated hepatocellular carcinoma
Authors: Justine Vaché, Camille Dantzer, Isabelle Mahouche, Ramazan Akyol, Adel Hammoutene, Paulette Bouliac-Sage, Valérie Paradis, Violaine Moreau, Clotilde Billottet
Journal: Cancer Research (2025)

Abstract The emergence of immunotherapy has revolutionized the treatment landscape for advanced hepatocellular carcinoma (HCC), significantly enhancing patient survival. However, accumulating evidence indicates that two-thirds of HCC harboring oncogenic mutations in the β-catenin coding gene (CTNNB1) exhibit resistance to immunotherapy. These tumors are largely devoid of immune infiltrates, highlighting a critical mechanism of immune escape. To investigate this phenomenon, we developed two 3D liver cancer spheroid models using a β-catenin-wild-type cell line (Huh7) and a β-catenin-mutated cell line (HepG2) co-cultured with PBMC (Peripheral Blood Mononuclear Cells). Flow cytometry analyses revealed that β-catenin mutation significantly impairs immune cell infiltration, particularly by Natural Killer (NK) cells. Our global transcriptomic analysis conducted in HepG2 cell line identified a specific chemokine, referred to here as CXX*, which is downregulated by mutated-β-catenin. In 2D and 3D cultured models, depletion of the mutated β-catenin in HepG2 cells led to an increase in CXX expression and secretion while β-catenin pathway overactivation in Huh7 cells induced its decrease. As CXX is known to recruit NK cells, we investigated the impact of its depletion or overexpression on immune cell infiltration in Huh7 and HepG2 spheroids. Our results demonstrated that CXX indeed plays a key role in the recruitment of NK cells in both models. In silico transcriptomic analysis of HCC patient cohorts corroborated these findings, revealing reduced CXX expression and diminished NK cell markers in tumors harboring β-catenin mutations, with these two results being positively correlated. Additionally, we report both a decrease in CXX expression and a reduced infiltration of NK cells in tumor sections from HCC patients with β-catenin mutation. Preliminary data obtained from supernatants of HCC patient Precision-Cut Liver Slices (PCLS) also revealed a reduction of CXX secretion by PCLS obtained from patients bearing the β-catenin mutation. In conclusion, our results identify CXX as a novel negative target of oncogenic β-catenin and provide new insights into how β-catenin mutations reshape the tumor microenvironment of HCC, enabling immune evasion. *A patent is in progress. Citation Format: Justine Vaché, Camille Dantzer, Isabelle Mahouche, Ramazan Akyol, Adel Hammoutene, Paulette Bouliac-Sage, Valérie Paradis, Violaine Moreau, Clotilde Billottet. A new chemokine identified as a key player of tumor immune microenvironment remodeling in β-catenin mutated hepatocellular carcinoma [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 909.
Abstract 1253: Single-cell analysis reveals intricate subclonal heterogeneity and evolution in response to standard of care treatments in glioblastoma
Authors: Yueshan Zhao, Xiaoyu Lu, Verah Nyarige, Junfei Zhao, Gonzalo Lopez, Ann Forslund, Maria Ortiz-Estevez, Jorge Benitez-Hernandez, Wei Zhang, Celia Fontanillo, Kai Wang, Ha Dang
Journal: Cancer Research (2025)

Abstract Glioblastoma multiforme (GBM) is the most common and lethal brain cancer. Standard of care treatments (SOC) are limited to surgery, radiation and chemotherapies, providing an average overall survival of only ∼16 months. Tumor heterogeneity and cellular plasticity are major contributions to treatment resistance in this disease. We constructed an integrated patient-level and cohort-level framework and analyzed single-nucleotide RNA sequencing data in matched primary and recurrence specimens to understand tumor heterogeneity, evolution, and drug resistance in SOC treated GBM patients (N=23). Patient-level tumor analysis revealed distinct tumor cell transcriptional subclones representing widespread intra-patient heterogeneity. Tumor evolution analysis from primary to recurrence revealed diverse treatment responses representing sensitive, intrinsic resistant, and acquired resistant subclones. Further characterization of tumor subclones and clustering analyses indicated that tumor heterogeneity under SOC treatments was linked to diverse biological mechanisms including neural development and oncogenic pathways, contributing to varying levels of subclonal resistance. Our analysis also highlighted intrinsic resistance was prominent as primary tumors often harbored substantial proportion of resistant tumor cells. This insight on resistant status at cell level then allowed us to compare resistant to sensitive cells and identify both established and potentially novel mechanisms of SOC resistance that were not always obvious in the comparison between primary and recurrence samples. These included activation of PI3K/AKT, MAPK, TGF-β, EMT, and WNT signaling pathways. Taken together, our novel analytical strategy revealed complex tumor heterogeneity and evolution landscape in SOC treated GBM, offering insights on potential mechanisms driving these phenomena and providing a resource for further exploration and development of therapeutic strategies. Citation Format: Yueshan Zhao, Xiaoyu Lu, Verah Nyarige, Junfei Zhao, Gonzalo Lopez, Ann Forslund, Maria Ortiz-Estevez, Jorge Benitez-Hernandez, Wei Zhang, Celia Fontanillo, Kai Wang, Ha Dang. Single-cell analysis reveals intricate subclonal heterogeneity and evolution in response to standard of care treatments in glioblastoma [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 1253.
Abstract 1090: Multiomic analysis of Taiwanese NSCLC: insights from a predominantly non-smoking cohort
Authors: Hsu-Ching Huang, Samira Masoudi, Daniel Halmos, Chien-jung Huang, Yu-Chao Wang, Yi-Chen Yeh, Yung-Hung Luo, Han-Shui Hsu, Yuh-Min Chen, Chun-Ku Chen, Sandip Patel, Albert Hsiao
Journal: Cancer Research (2025)

Abstract Introduction: We curated multiomic data including whole exome sequencing (WES) and high-resolution chest CT from patients diagnosed with NSCLC, and evaluated the potential for a multitask deep learning algorithm to predict tumor mutational status and WES signatures from CT. Materials and Methods: Taipei Veterans General Hospital (TVGH) initiated a multi-omic databank integrating clinical, radiological, pathological, and genomic data from NSCLC patients. A predefined pipeline identified INDEL and SNP mutations with high or moderate impact using Ensembl Variant Effect Predictor (VEP). PCA reduced dimensionality of the WES binary data, and t-SNE was used for clustering and visualization. Chest CT was performed using scanners with ≥ 20 detector rows, at end-inspiration with 120 kV, automated exposure control, and a 50 cm field of view. Patients were split 80% for training and 20% for validation. 3D CT image data centered on lesions were rotated, resampled and cropped. A 3D ResNet-18 network, pre-trained on Kinetics-400, was used for predicting common NSCLC mutations (EGFR, TP53), and the first and second principal component coefficients. Results: A total of 317 patients were included, with 74% non-smokers.(Table 1) Of 109 LDCT detected nodules, only 27 were from smokers. PCA of 12, 023 gene mutations identified five principal components. t-SNE visualized the clustered distribution of the top three genes with the highest weights: EGFR, TP53, and RBM10, along with tumor mutation burden (TMB) and EGFR co-mutation status. Performance of the deep learning algorithm in the validation set (n=63) showed: EGFR mutation prediction: AUROC 71%, PPV 71%; TP53 mutation prediction: AUROC 76%, NPV 94%, sensitivity 0.84, specificity 0.72.Pearson correlation for prediction of the coefficients of the genetic signature principal components from CT images were 0.37 and 0.47. Conclusion: Deep learning algorithms can infer genetic mutation signatures from CT radiologic features. Further optimization is needed. Citation Format: Hsu-Ching Huang, Samira Masoudi, Daniel Halmos, Chien-jung Huang, Yu-Chao Wang, Yi-Chen Yeh, Yung-Hung Luo, Han-Shui Hsu, Yuh-Min Chen, Chun-Ku Chen, Sandip Patel, Albert Hsiao. Multiomic analysis of Taiwanese NSCLC: insights from a predominantly non-smoking cohort [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 1090.
Abstract 2540: Biodistribution and dosimetry of FAPI-46 in mouse model of colorectal carcinoma with PET and SPECT imaging
Authors: Johanna Rokka, Henrik Vaherto, Susanne Bäck, Jussi Rytkönen
Journal: Cancer Research (2025)

Abstract Fibroblast Activation Protein (FAP) is overexpressed in cancer-associated fibroblasts of many epithelial cancers. In nonmalignant conditions FAP is overexpressed in wounds healing, inflammatory and fibrotic tissues, whereas in healthy adult tissue FAP expression is low. Radiolabeled FAP Inhibitors (FAPIs) are used in clinic for imaging and/or radiotherapy. FAPIs are usually conjugated to a DOTA chelating site which allows the use of both diagnostic and therapeutic radionuclides. In this study we investigated the radiochemical properties, pharmacokinetics and dosimetry of FAPI-46 in after Lu-177 or Ga-68 labelling in preclinical mouse model of colorectal carcinoma. FAPI-46 (non-GMP grade) was radiolabeled with Ga-68 and Lu-177 using previous described synthesis with slight modifications (Loktev et al., J Nucl Med 2019). Radiochemical purity was determined with radio-HPLC (LabLogic). A colon cancer mouse model was created by inoculating 5x106 HCT116 cells in 100 µl 50% matrigel subcutaneously (s.c.) in the interscapular area of NMRI-Foxn1nu male mice. Approximately two weeks post inoculation, animals were randomized into groups based on tumor volume (n = 2-4 / timepoint). Animals were dosed with 177Lu-FAPI-46 or 68Ga-FAPI-46, scanned with SPECT (Mediso) or PET (Sedecal) up to 90 minutes. Simultaneously satellite animals were terminated and sampled for gamma counting (Perkin Elmer) at 30-, 60- and 90-minutes post injection. Image analysis was performed with PMOD software. Dosimetry calculations will be performed with OLINDA 2.0. 68Ga- and 177Lu-FAPI-46 were produced with high radiochemical yield and purity. Nuclear imaging of radiolabeled FAPI-46 with both radiolabels shows fast kinetics and excretion via kidney as shown in literature. The dosimetry calculations are still ongoing. FAPI is suitable for multipurpose imaging and there is a great interest towards this molecule in the fields of imaging and oncology. The same precursor structure can be labeled with more than one radionuclide with high radiochemical yield and purity. Citation Format: Johanna Rokka, Henrik Vaherto, Susanne Bäck, Jussi Rytkönen. Biodistribution and dosimetry of FAPI-46 in mouse model of colorectal carcinoma with PET and SPECT imaging [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 2540.
Abstract 1384: Mitochondrial complex I inhibition enhances chemotherapy efficacy in melanoma
Authors: Semmer Ali, Mehrdad Zarei, Luke D. Rothermel, Jordan M. Winter
Journal: Cancer Research (2025)

Abstract Background: Melanoma, characterized by the uncontrolled proliferation of melanocytes, is one of the most common types of cancer in the United States. Despite improvement in therapeutics, it remains a formidable adversary in oncology due to its aggressive resistance to treatment and propensity for metastasis. Metabolic reprogramming is a hallmark of cancers implicated in resistance to therapies. Previous efforts have focused on targeting glycolysis, while mitochondrial oxidative phosphorylation (OXPHOS) and TCA metabolism remain underexplored in melanoma research due to limited understanding of contexts in which OXPHOS is required for cancer cell growth and survival. Methods: To determine the impact of chemotherapies (Temozolomide and Cisplatin) on cellular metabolism, metabolomics profiling was performed using liquid chromatography-mass spectrometry (LC-MS) and bioenergetics analyses. Therapeutic responses were studied with chemotherapy in combination with a complex I inhibitor (Phenformin and IACS-010759). In vivo studies investigating the combination of complex I inhibitors and Temozolomide were conducted in immunocompetent C57BL/6J mice. Murine YUMM1.7 melanoma cell allografts were established to evaluate tumor growth and therapeutic efficacy through tumor volume analysis. Results: Our study examined OXPHOS diversity across different melanoma cell lines, identifying those with high and low mitochondrial OXPHOS activity. We found that melanoma cells exhibit significant mitochondrial dependency as evidenced by increased TCA cycle intermediates, ATP production, and oxidative capacity in response to chemotherapy. Additionally, melanoma cells increase mitochondrial electron transport chain (ETC) complex I as an adaptive response to chemotherapy. Pharmacological inhibition of ETC complex I synergizes with conventional anti-melanoma chemotherapy in preclinical models. Furthermore, the combination of complex I inhibitors and Temozolomide proved to be the most effective treatment in vivo, significantly suppressing tumor growth in a murine melanoma model compared to either treatment alone. The combination therapy was well-tolerated, with no observed reduction in body weight, indicating minimal systemic toxicity. Conclusion: These findings underscore the clinical promise of employing mitochondrial complex I inhibition as part of a combined therapeutic approach to enhance chemosensitivity for individuals with advanced and refractory melanoma. Citation Format: Semmer Ali, Mehrdad Zarei, Luke D. Rothermel, Jordan M. Winter. Mitochondrial complex I inhibition enhances chemotherapy efficacy in melanoma [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 1384.
Abstract 2556: Therapy-induced senescent cancer cells facilitate immune evasion in cancer by promoting PD-L1 upregulation through a ribophorin 1-dependent pathway
Authors: Hyun Jung Hwang, Donghee Kang, Jisoo Shin, Jonghun Jung, Soyeon Ko, Kyung Hee Jung, Soon-Sun Hong, Ji Eun Park, Myung Jin Oh, Hyun Joo An, Wen-Hao Yang, Young-Gyu Ko, Minji Choi, Jong-Ho Cha, Jae-Seon Lee
Journal: Cancer Research (2025)

Abstract Cancer senescence induced by conventional chemotherapy and radiotherapy, characterized by limited proliferation, drug resistance, and a senescence-associated secretory phenotype, is increasingly recognized as a contributor to cancer relapse and the development of an immunosuppressive tumor microenvironment. However, the relationship between cancer senescence and anti-tumor immunity remains poorly understood. In this study, we demonstrate that senescent cancer cells upregulate PD-L1 expression by enhancing its transcription and glycosylation. We identify ribophorin 1 as a key regulator of PD-L1 glycosylation during cancer senescence. Ribophorin 1 depletion significantly reduces PD-L1 levels through the ER-lysosome-associated degradation pathway, rendering senescent cancer cells more susceptible to T-cell-mediated killing. Furthermore, ribophorin 1 depletion suppresses tumor growth by decreasing PD-L1 levels and enhancing cytotoxic T lymphocyte (CTL) activity. Additionally, targeting ribophorin 1 or using anti-PD-1 therapy effectively reduces the number of senescent cancer cells in irradiated tumors and suppresses cancer recurrence by activating CTLs. These findings clarify how senescent cancer cells evade T-cell immunity following treatment, contributing to cancer recurrence. Our results highlight the therapeutic potential of targeting senescent cancer cells as a strategy in cancer treatment. Citation Format: Hyun Jung Hwang, Donghee Kang, Jisoo Shin, Jonghun Jung, Soyeon Ko, Kyung Hee Jung, Soon-Sun Hong, Ji Eun Park, Myung Jin Oh, Hyun Joo An, Wen-Hao Yang, Young-Gyu Ko, Minji Choi, Jong-Ho Cha, Jae-Seon Lee. Therapy-induced senescent cancer cells facilitate immune evasion in cancer by promoting PD-L1 upregulation through a ribophorin 1-dependent pathway [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 2556.
Abstract 1648: LT-010366, a first-in-class orally bioavailable KRAS G12D degrader in the treatment of multiple KRAS G12D-mutated cancer models <i>in vitro</i> and <i>in vivo</i>
Authors: Shuang Yan, Zhengqing Ye, Haiji Chen, Chenli Ding, Juan Xu, Yan Feng
Journal: Cancer Research (2025)

Abstract Recent successes in targeting KRASG12C have provided both insight and inspiration for targeting alternative KRAS mutants. Among KRAS mutations, KRAS G12D is the most frequent driver mutated isoform and is found in approximately 34% of patients with pancreatic ductal adenocarcinoma (PDAC), 12% of patients with colorectal cancer (CRC), 4% of patients with lung adenocarcinoma, and in a subset of patients with other solid tumors. We have developed LT-010366 as a first-in-class orally bioavailable KRAS G12D degrader with high potency and selectivity. In In vitro degradation assays, LT-010366 demonstrated extraordinary degradation activities with DC50 of 0.96-2.55 nM and efficiency (Dmax) over 95% against KRAS protein in multiple cancer cell lines harboring KRAS G12D mutation, as well as remarkable inhibition of p-ERK with IC50 of 0.52-26.06 nM in those cell lines. In cell proliferation assays, LT-010366 showed a strong antiproliferative potency with IC50s of 0.12-15.77 nM and max inhibition of 74.42-98.4% in tested KRAS G12D mutant cancer cell lines. Moreover, LT-010366 selectively degrades KRAS, sparing HRAS and NRAS. In CDX tumor, daily oral administration of LT-010366 exhibited potent antitumor activities in both PDAC (PK-59) and CRC (GP2D) models with KRAS G12D mutation, resulting in profound tumor regression without body weight loss. In GP2D xenograft model, LT-010366 demonstrated dose-dependent tumor inhibition at the dose of 10 mg/kg, 30 mg/kg and 100 mg/kg PO, QD with TGI of 95.7%, 114.4% and 116.5% after 14-day treatment, respectively. In PK-59 model, LT-010366 demonstrated dose-dependent tumor inhibition at the dose of 3 mg/kg, 10 mg/kg and 30 mg/kg PO, QD with TGI of 69.3%, 116% and 126.8% after 15-day treatment, respectively. In GP2D model, LT-010366 also exhibited dose-dependent degradation of KRAS protein and demonstrated marked inhibition of downstream p-ERK and p-S6. In addition, LT-010366 also displays a high-quality drug-like profile. In summary, our results demonstrated that LT-010366 induced degradation of KRAS G12D protein, inhibition of KRAS downstream signaling mediators and exhibited antitumor activity in multiple KRAS G12D-mutated cancer cells in vitro and in vivo. LT-010366 is a promising therapeutic agent to be advanced to clinical development for patients with tumors harboring KRAS G12D mutation. Citation Format: Shuang Yan, Zhengqing Ye, Haiji Chen, Chenli Ding, Juan Xu, Yan Feng. LT-010366, a first-in-class orally bioavailable KRAS G12D degrader in the treatment of multiple KRAS G12D-mutated cancer models in vitro and in vivo [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 1648.
Abstract 1732: Mastering metastases by novel selective CDK9 Inhibitor ORI-15412
Authors: Gergana Galabova, Michael Almstetter, Nicole Brusis, Christiane Gilch, Roland Koestler, Julie Kondrotas, Jan Kubitzki, Henrik Kuhn, Federico Medda, Patricia Perez-Galan, Jean Tassel, Nadine Traube, Andreas Treml, David Wifling, Nasser Yehia, Peter Zegar, Michael Thormann
Journal: Cancer Research (2025)

Abstract Metastases, the leading cause of cancer-related morbidity and deaths, remain a major therapeutic challenge, highlighting the critical need for novel treatments. Our study evaluates the efficacy of ORI-15412, an oral and fully brain-penetrant CDK9 inhibitor developed by Origenis, designed to meet this need through selective inhibition of CDK9 and modulation of key pathways involved in cancer progression and metastasis. ORI-15412 was engineered using Origenis' proprietary technologies - MOREsystem®, MolMind®, BRAINstorm™, and Cippix® - for optimized blood-brain barrier penetration, selectivity, and potency. By targeting the pTEFb complex and downstream effectors, including phospho-RNA Pol II, MCL-1, and c-Myc, ORI-15412 induces apoptosis and suppresses osteoclast differentiation in cancer models. It also demonstrates dose-dependent reduction in NF-κB-dependent p52 expression, suggesting potential immune modulatory effects. In vivo studies using the aggressive intracardial MV4-11_luc metastatic mouse model showed that ORI-15412 achieved 95% tumor growth inhibition (TGI) and up to 99.99% reduction in metastasis across the brain, bones, bone-marrow, lymph nodes, and lungs. The drug was well-tolerated with no observed toxicity, and efficacy was dose-dependent, underscoring its potential for treating metastatic cancers. Having completed all IND-enabling safety and toxicity studies with NOAEL at efficacious doses, ORI-15412 is positioned as a clinical-ready candidate, offering a promising new approach for patients with metastatic cancers, particularly those with brain and bone involvement. Citation Format: Gergana Galabova, Michael Almstetter, Nicole Brusis, Christiane Gilch, Roland Koestler, Julie Kondrotas, Jan Kubitzki, Henrik Kuhn, Federico Medda, Patricia Perez-Galan, Jean Tassel, Nadine Traube, Andreas Treml, David Wifling, Nasser Yehia, Peter Zegar, Michael Thormann. Mastering metastases by novel selective CDK9 Inhibitor ORI-15412 [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 1732.