tbuckley/cabot-search huggingface dataset:
Abstract 4288: Discovery of a small molecule inhibitor of ADAR1 for cancer immunotherapy
Authors: Zijun Chen, Liqiang Shen, Qi Zhao, Jing Lu, Weiliang Li, Wen Jin, Xiang Ji, Mengchao Shi, Haowei Zhu, Lin Wang, Leduo Zhang, Xianqi Kong, Dawei Chen, Tianlun Zhou, Jiasheng Lu
Journal: Cancer Research (2025)

Adenosine deaminase acting on RNA 1 (ADAR1) is a critical enzyme that catalyzes the conversion of adenosine to inosine in double-stranded RNA (dsRNA). By modifying endogenous dsRNA, ADAR1 prevents erroneous recognition by cytoplasmic dsRNA sensors, including MDA5, PKR, and ZBP1. Inhibition of ADAR1’s deaminase activity can activate MDA5-mediated innate immune responses and stimulate interferon production, while blocking ADAR1’s RNA-binding activity can induce PKR-mediated translational shutdown and cell death. Emerging evidence suggests that silencing ADAR1 enhances tumor responsiveness to immune checkpoint inhibitors, highlighting ADAR1 as a promising target in cancer immunotherapy. In this study, we aimed to develop small-molecule inhibitors of ADAR1 as potential therapeutic agents for ADAR1-dependent cancers. A primary RNA-editing assay was established to screen a library of 265,000 compounds, leading to the identification of 505 initial hits. These hits underwent triage validation involving target engagement studies, cell-based editing assays, and selectivity profiling. Among the validated compounds, RP04459 emerged as a lead candidate for further investigation. RP04459 effectively inhibited ADAR1’s RNA-editing activity in both biochemical and cellular assays. Treatment with RP04459 activated downstream interferon-β signaling in an MDA5-dependent manner, confirming its immunostimulatory potential. Detailed point mutation studies revealed the binding site of RP04459 on the ADAR1 protein, providing insight into its mechanism of action. The identification of RP04459 as a selective ADAR1 inhibitor underscores its potential to enhance immune-based therapies for cancers reliant on ADAR1 activity. Further preclinical evaluation of RP04459 may pave the way for novel therapeutic strategies in cancer immunotherapy Citation Format: Zijun Chen, Liqiang Shen, Qi Zhao, Jing Lu, Weiliang Li, Wen Jin, Xiang Ji, Mengchao Shi, Haowei Zhu, Lin Wang, Leduo Zhang, Xianqi Kong, Dawei Chen, Tianlun Zhou, Jiasheng Lu. Discovery of a small molecule inhibitor of ADAR1 for cancer immunotherapy [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 4288.
Abstract 4691: Concurrent EGFR inhibition and radiotherapy potentiates radioresistance in <i>TP53</i>-mutated endometrial cancer
Authors: Gabriella Smith, Aaron Petty, Roberto Vargas
Journal: Cancer Research (2025)

Abstract Introduction: Endometrial cancers (EC) that harbor TP53 mutations portend a worse clinical prognosis. EGFR inhibition has emerged as a potential radio-sensitizing strategy, particularly in NSCLC and HNSCC, however, its effect in TP53-mutated tumors is mixed. As emerging data demonstrates that TP53 mutations may confer radioresistance in endometrial cancer, we explored the role of EGFR inhibition as a novel radio-sensitizing strategy in this disease site. Methods: To evaluate the effect of EGFR inhibition on radiation response, we employed the parental EC cell line, Hec1B (TP53 R248Q mutation). Cells were treated with increasing doses of the EGFR inhibitor, erlotinib, while concurrently exposed to varying doses of radiation. Cells were treated for 48 hours with erlotinib, and viability was assessed with CellTiter-Glo. IC50 values were determined using GraphPad Prism software. Drug synergy was determined using the Bliss independence model. A MeanR test was also used to compare the predicted response (additive) of the Bliss model to our data. All experiments were carried out in triplicate. Results: The IC50 value of erlotinib alone was 14.4uM. At 6Gy of radiation, the IC50 of erlotinib was 23.1uM. Per the Bliss independence model, erlotinib was not observed to have a synergistic effect with radiotherapy. However, the MeanR test of the deviation from additivity demonstrated antagonism with an F-statistic of 6.46, p = 0.02. Conclusion: Concurrent use of erlotinib potentiates radioresistance. Novel therapeutic and sequencing radio-sensitizing strategies remain to be elucidated in TP53 mutated EC. Citation Format: Gabriella Smith, Aaron Petty, Roberto Vargas. Concurrent EGFR inhibition and radiotherapy potentiates radioresistance in TP53-mutated endometrial 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 4691.
Abstract 5624: The antiviral, Daclatasvir, disrupts ASCL1-EZH2 signaling and impairs survival of neuroendocrine prostate cancer cells
Authors: Rohith Guddeti, Jitender Monga, Craig Rogers, Dhananjay Chitale, Shirish Gadgeel, Jagadananda Ghosh
Journal: Cancer Research (2025)

Abstract Management of neuroendocrine prostate cancer (NEPC) is extremely difficult not only because available therapeutic regimens cannot effectively kill NEPC cells but also due to the aggressive, highly metastatic nature of NEPC cells to invade distant organs. Development of effective therapeutic agents for NEPC is urgently needed but is suffering from lack of proper understanding about critical and selective molecular targets. Recent molecular analyses revealed that the pseudokinase, Tribbles 2 (TRIB2), is consistently overexpressed both in the treatment emergent as well as de novo NEPC cells and tumors and plays a critical role in the survival and maintenance of neuroendocrine characteristics in NEPC cells. Daclatasvir (DCV), an FDA-approved antiviral agent, was found to directly bind and destabilize TRIB2 protein and prime it for degradation via activation of proteasomes. However, the extent to which DCV impacts the viability and lineage characteristics in NEPC cells remain unclear. We report here that DCV inhibits the growth and survival of NEPC cells by inducing caspase-mediated apoptosis. Mechanistically, DCV disrupts the TRIB2 downstream signal transduction cascade which involves the proneuronal transcription factor, Achaete-scute homolog 1 (ASCL1) and the epigenetic regulator, Enhancer of zeste homolog 2 (EZH2). Interestingly, inhibition of the ASCL1-EZH2 signaling axis by DCV showed an increase in the protein level of the androgen receptor (AR). Moreover, we found that DCV at lower, sub-lethal doses synergize with AR inhibitors, such as enzalutamide, to enhance NEPC cell death, suggesting improved efficacy of these two classes of anticancer agents in combination. Since DCV is well-tolerated in humans, and is approved for treatment of viral hepatitis, our findings position DCV as a promising therapeutic agent for NEPC, a highly aggressive, drug-resistant subtype of prostate cancer with extremely limited therapeutic options. Citation Format: Rohith Guddeti, Jitender Monga, Craig Rogers, Dhananjay Chitale, Shirish Gadgeel, Jagadananda Ghosh. The antiviral, Daclatasvir, disrupts ASCL1-EZH2 signaling and impairs survival of neuroendocrine prostate cancer cells [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 5624.
Abstract 4422: Targeting MLK4 in herceptin-resistant breast cancer
Authors: Subhasis Das, Jingjing Sun, Song Li, Basabi Rana, Ajay Rana
Journal: Cancer Research (2025)

Abstract Mixed Lineage Kinases play a significant role in cancer biology, including breast cancer, by influencing key cell proliferation, survival, and metastasis signaling pathways. Targeting MLKs offers a promising therapeutic strategy, especially in cancers with dysregulated MLK activity. We have reported that one of the members of the mixed lineage kinase (MLK) family, MLK3 kinase activity, was necessary to mediate the cytotoxic effect of anti-HER2 therapies (i.e., Herceptin and Lapatinib). Activation of MLK3 using C6-ceramide nanoparticles caused massive cell death and apoptosis in Herceptin-resistant breast tumors. Recently, we observed that another MLK family member, MLK4, was overexpressed in human HER2+ breast cancer Herceptin-resistant breast tumors and Herceptin-resistant cancer cell lines, suggesting that MLK4 could play a functional role in developing HER2-therapy resistance. Interestingly, MLK4 gene knockdown in Herceptin-resistant breast cancer cell lines significantly caused cell death and apoptosis. Knockdown of MLK4 in Herceptin-resistant SkBr3 &amp; BT474 cell lines downregulated p-HER2 (Y1221/1222, Y1248), p-AKT (S473), pCDC2 (Y15) and arrested cells in G2-M phase suggesting MLK4 regulates HER2 activation, and cell cycle progression. Overexpressing MLK4 in Herceptin-sensitive cells further activated the HER2-PI3K-Akt pathway, leading to Herceptin resistance. Surprisingly, MLK4 and HER2 endogenously interacted, and an in vitro kinase assay showed that MLK4 phosphorylates the intracellular domain of HER2 at Tyrosine 1221 and 1222 sites (Y1221/2), indicating that MLK4-induced phosphorylation could activate HER2 downstream signaling. Finally, MLK4 knockdown using siMLK4-loaded nanoparticles in an in vivo mouse PDX model demonstrated significant tumor regression and apoptosis. These results suggest that MLK4 upregulation is necessary for Herceptin resistance in HER2-positive breast tumors. Considering our in vitro and in vivo data, we plan to develop a specific inhibitor of MLK4, which could be used clinically to treat Herceptin-resistant HER2+ metastatic breast cancer. Citation Format: Subhasis Das, Jingjing Sun, Song Li, Basabi Rana, Ajay Rana. Targeting MLK4 in herceptin-resistant 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 4422.
Abstract 7257: Humanized GDF15 model for simulating weight loss induced by GDF15 secretion in tumors
Authors: Jay Zhang, Suman Zhao, Ruili Lv, Yongshun Li, Saina Ma, Yanling Wang
Journal: Cancer Research (2025)

Abstract GDF15, also known as growth differentiation factor-15, is expressed by multiple tissues and secreted into the serum. It regulates numerous physiological processes, such as affecting food intake and causing weight loss, by binding to the receptor GFRAL. Under normal physiological conditions, GDF15 levels are low; however, its expression significantly increases under pathological conditions such as diabetes and cancer. In some special types of advanced cancers, GDF15 levels can rise and trigger anorexia-cachexia syndrome. We created humanized B-hGDF15 mice by replacing the mouse GDF15 gene with the human GDF15 gene in situ. Additionally, we established a B-hGDF15 MC38 cell line by inserting an exogenous promoter and the human GDF15 CDS sequence at the mouse GDF15 locus in MC38 cells. RT-PCR was conducted to detect mRNA levels of hGDF15 in B-hGDF15 mice, confirming the absence of mouse Gdf15 expression and the presence of human GDF15 expression. We performed ELISA to detect the protein expression levels of hGDF15 in B-hGDF15 mice and B-hGDF15 MC38 humanized cell line, confirming successful expression of the hGDF15 protein. When B-hGDF15 mice were inoculated with B-hGDF15 MC38, tumor model was developed successfully, and a trend of body weight loss was observed compared with the wild-type MC38 group. Subsequently, we performed an efficacy experiment in B-hGDF15 mice inoculated with B-hGDF15 MC38. After 7 days of inoculation, the mice were grouped based on body weight and tumor size, and the treatment group received 10 mg/kg of a ponsegromab analog on the same day. We observed significant weight gain in the treated group compared to the control group, indicating that B-hGDF15 mice and B-hGDF15 MC38 provide an excellent preclinical in vivo model for testing GDF15-targeted drugs. Citation Format: Jay Zhang, Suman Zhao, Ruili Lv, Yongshun Li, Saina Ma, Yanling Wang. Humanized GDF15 model for simulating weight loss induced by GDF15 secretion in tumors [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 7257.
Abstract 5643: Aryl hydrocarbon receptor agonist ZSTK3744 overcomes chemotherapy resistance in TNBC
Authors: Takahiro Ohashi, Kayoko Kawai-Asami, Sayuri Terada, Kotomi Akatsuka, Yuko Nagata, Shinsuke Hiramoto, Tsubasa Nagasaki, Eika Higashi, Ryuichiro Ohshita, Keiko Fukushima
Journal: Cancer Research (2025)

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis compared with other subtypes. Due to the lack of therapeutic targets, such as hormone receptors and human epidermal growth factor receptor 2, systemic chemotherapy remains the primary treatment option for TNBC. However, chemotherapy has limited benefits and some patients acquire resistance, further complicating treatment. New therapeutic approaches are urgently needed to overcome chemotherapy resistance in TNBC. ZSTK3744 is an aryl hydrocarbon receptor agonist developed as a novel therapeutic candidate for TNBC. ZSTK3744 has shown inhibitory effects on the proliferation of various cancer cell lines, including TNBC cell lines, in vitro. Moreover, it suppressed tumor growth in TNBC xenograft models. In this study, we evaluated the effects of ZSTK3744 on chemotherapy-resistant TNBC cells. Chemotherapy-resistant MDA-MB-468 cells, derived from TNBC, were developed through long-term exposure to adriamycin or paclitaxel. Compared to wild-type cells, the anti-tumor effects of adriamycin, paclitaxel, and eribulin were weakened in these resistant cells; however, ZSTK3744 maintained its efficacy. Transcriptome analysis was conducted to elucidate the mechanism of chemotherapy resistance, revealing alterations in several resistance-associated genes. In particular, upregulation of the ATP-binding cassette transporter 1 gene (ABCB1) was commonly observed in these cells. The anti-tumor effects of adriamycin, paclitaxel, and eribulin were reduced in cells with high ABCB1 expression, whereas those of ZSTK3744 were unaffected. Moreover, ZSTK3744 significantly inhibited tumor growth in xenograft models implanted with adriamycin-resistant MDA-MB-468 cells, showing a higher potency than eribulin. ZSTK3744 is a promising agent for overcoming chemotherapy-resistance in TNBC. Citation Format: Takahiro Ohashi, Kayoko Kawai-Asami, Sayuri Terada, Kotomi Akatsuka, Yuko Nagata, Shinsuke Hiramoto, Tsubasa Nagasaki, Eika Higashi, Ryuichiro Ohshita, Keiko Fukushima. Aryl hydrocarbon receptor agonist ZSTK3744 overcomes chemotherapy resistance in TNBC [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 5643.
Abstract 5630: Ecubectedin as a promising therapeutic agent against gastric cancer through WNT/β-Catenin modulation
Authors: Alejandro Losada, Marta Martínez Diez, Eugenio Bustos-Morán, Ismael Fernández-Miranda, Maria José Guillen, Pablo M. Avilés, Marcelo Lima Ribeiro, Carmen Cuevas
Journal: Cancer Research (2025)

Gastric cancer continues to be a major global health challenge due to its high mortality rate, with over half of patients showing significant dysregulation of the WNT/β-catenin pathway. Ecubectedin, a novel transcriptional inhibitor, has shown potent antiproliferative effects across several solid tumors. The aim of this study was to characterize the molecular effects of ecubectedin in gastric cancer, both in vitro and in vivo, focusing on transcriptomic analysis of key regulatory pathways. Ecubectedin´s antineoplastic activity was evaluated through MTT assays in a representative panel of 15 gastric cancer cell lines. Eight cell lines were chosen to assess the effects of ecubectedin on the transcriptome following a 6-hour exposure to 50 nM. Ecubectedin´s in vivo antitumor effects were evaluated in HGC-27 xenograft mouse models. Ecubectedin demonstrated potent antitumor activity in vitro, with GI50 values in the low nanomolar range (from 0.3 to 8 nM). Ecubectedin exerts a potent effect as a transcription inhibitor, leading to significant repression of 2,775 genes. Gene set enrichment analysis revealed that Ecubectedin disrupted key signaling pathways, especially WNT/β-catenin. At the protein level, Ecubectedin (50 nM) modulated the WNT/β-catenin pathway and inhibited TCF/β-catenin-mediated transcription. In vivo, a single i.v. dose of Ecubectedin (0.6 mg/kg) inhibited tumor growth by 61% after 7 days in both RNA-seq and in vivo protein data (from tumors in ecubectedin-treated mice) support that ecubectedin represses WNT/β-catenin signaling. In conclusion, ecubectedin shows strong antitumor activity against gastric cancer, modulating the often-dysregulated WNT/β-catenin pathway, highlighting its potential as a promising therapeutic for further clinical exploration. Citation Format: Alejandro Losada, Marta Martínez Diez, Eugenio Bustos-Morán, Ismael Fernández-Miranda, Maria José Guillen, Pablo M. Avilés, Marcelo Lima Ribeiro, Carmen Cuevas. Ecubectedin as a promising therapeutic agent against gastric cancer through WNT/β-Catenin modulation [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 5630.
Abstract 3981: The GZMK CD8 T cells cluster defined by single-cell transcriptome profiling with innate-like functions is a predictor of survival in hepatocellular carcinoma patients
Authors: Wei-Ting Ku, Chien-Hao Huang, Jian-He Fan, Cheng-Heng Wu, Tsung-Han Wu, Wei Teng, Po-Ting Lin, Chung-Wei Su, Yung-Chang Lin, Chun-Yen Lin
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC), the sixth most common cancer globally in 2020, is closely associated with hepatitis B or C infections and non-alcoholic steatohepatitis (NASH). Despite advancements in surgical and systemic therapies for early and advanced stages, tumor relapse and poor prognosis remain significant challenges, necessitating improved therapeutic approaches. This study highlights the role of GZMK-expressing CD8+ T cells in HCC, identified through single-cell transcriptome profiling. These cells exhibit transcriptional profiles similar to hepatotoxic CD8+ T cells in chronic hepatitis B and innate-like CD8+ T cells in chronic hepatitis C. GZMK CD8+ T cells are enriched with tissue-resident memory traits and are detectable in peripheral blood and tumor tissues. Furthermore, within the tumor microenvironment, GZMK CD8 cells expressed surface receptors resembling those of NK cells, allowing them to release IFN-γ and exert non-antigen specific innate-like cytotoxic effects. These GZMK CD8+ T cells could be identified as CD38+HLA-DR+ CD8+ T cells by flow cytometry. These CD38+HLA-DR+ CD8+ T cells increased in the peripheral blood of HCC patients and accumulated in tumor tissue. Cytokines such as IL-12, IL-15, and IL-18 were shown to stimulate the proliferation of CD38+HLA-DR+ CD8+ T cells, enhancing their production of IFN-γ and granzyme B, as well as their expression of NK-like receptors and effector molecules. These bystander-activated CD38+HLA-DR+ CD8+ T cells, derived from effector memory (EM) and effector memory RA (EMRA) subsets, displayed cytotoxicity against K562 and THP-1 cell lines through DNAM-1, granzyme B, and perforin. A high GZMK CD8+ T cell signature was strongly associated with improved overall survival (OS) and progression-free survival (PFS) in the TCGA-HCC database. These findings suggest that GZMK CD8+ T cells have a significant impact on survival in HCC, possibly through their innate-like cytotoxic functions. This unique subset may serve as a biomarker and a potential therapeutic target in HCC management. Citation Format: Wei-Ting Ku, Chien-Hao Huang, Jian-He Fan, Cheng-Heng Wu, Tsung-Han Wu, Wei Teng, Po-Ting Lin, Chung-Wei Su, Yung-Chang Lin, Chun-Yen Lin. The GZMK CD8 T cells cluster defined by single-cell transcriptome profiling with innate-like functions is a predictor of survival in hepatocellular carcinoma patients [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 3981.
Abstract 5007: Integrated histology-genomic multimodel deep learning to predict prognosis in non-small-cell lung cancer
Authors: Yang Xu, Haimeng Tang, Xue Wu, Qiuxiang Ou
Journal: Cancer Research (2025)

Abstract Background: Deep learning (DL) provokes a paradigm shift in deciphering high-dimensional data for various clinical applications, and multimodal DL approaches show significant potential to integrate diverse datasets and enhance prediction accuracy. Despite these advancements, multimodal DL remains underutilized in prognostic assessment, particularly for non-small-cell lung cancer (NSCLC) patients. Methods: We analyzed whole-slide imaging (WSI; approximately 6,000 slides and ∼40,000,000 image tiles), whole exome sequencing (WES), and overall survival (OS) data from 2,366 NSCLC patients sourced from various online databases. A Sequential-Adapted Attention (SeAttn) model was developed to process WSI data, while multiple DL models were trained to analyze WES data and clinical features. Multimodel DL was then used to combine these learned features to predict long-term OS outcomes. The model was further confirmed using a validation (N=100) and a held-out test (N=101) cohort. Results: The SeAttn model exhibited strong predictive power for NSCLC histological subtypes, achieving an area under the curve (AUC) of 0.98 in the test cohort (P&amp;lt;0.0001). SeAttn-derived WSI features, baseline clinical characteristics, as well as WES-based genetic features were used individually to predict OS, yielding concordance indices (C-indices) ranging from 0.55 to 0.67. The combination of these multimodal features using a COX-based DL approach further improved the test cohort C-index to 0.71 (95% CI 0.14, P=0.002), with WSI, mutation gene-sets, and baseline clinical data as the top contributors. Notably, our multimodal DL model accurately predicted prognosis for up to 5 years post-diagnosis (P&amp;lt;0.05 for all time-dependent AUCs within 5 years in both validation and test cohorts), and our model could significantly stratify patients based on their OS (P=0.012 in the test cohort). Additionally, we identified and validated novel prognostic markers, including some genetic mutations, co-deletions, and amplification of two microRNA clusters. Conclusion: Our multimodal deep learning model demonstrates substantial predictive capacity for prognosis in NSCLC patients, providing a robust framework for integrating diverse clinical, genetic, and imaging data to yield accurate survival estimates and uncovering clinically relevant biomarkers to guide risk stratification. Our findings underscore the broader promise of multimodal DL, offering a scalable and data-driven approach that can be adapted for other cancers. Citation Format: Yang Xu, Haimeng Tang, Xue Wu, Qiuxiang Ou. Integrated histology-genomic multimodel deep learning to predict prognosis in non-small-cell lung 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 5007.