tbuckley/cabot-search huggingface dataset:
Abstract 4247: Discovery of GH3595: a novel allosteric DHX9 inhibitor for cancer therapy
Authors: Faridoon Faridoon, Jiapeng Li, Jiyue Zheng, Xiang Wang, Guiping Zhang
Journal: Cancer Research (2025)

Abstract DExH-Box helicase 9 (DHX9), also known as RNA helicase A (RHA), belongs to the DExD/H-Box superfamily II of helicases. Due to its fundamental roles in processes such as transcription and maintenance of genomic stability, DHX9 has emerged as a key regulator in various cancer types. Specifically, microsatellite instable (MSI) cancers, such as MSI-high (MSI-H) colorectal cancer, and tumors with defective homologous recombination exhibit a strong dependency on DHX9, suggesting that targeting DHX9 could offer a significant therapeutic opportunity. Employing fragment-based drug design, we have discovered GH3595, a novel allosteric DHX9 inhibitor that selectively targets the DHX9 protein. In vitro, GH3595 displayed a low nM potency in ATPase and helicase activity assays, which translated to specific low nM inhibition of MSI-H colorectal cancer and BRCA loss of function breast cancer proliferation. In vivo, GH3595 demonstrated favorable pharmacokinetic properties in different species and showed an acceptable safety profile. Furthermore, daily oral dosing of GH3595 led to the regression of MSI-H xenograft tumors without adverse effects on body weight. More importantly, GH3595 induced dose-dependent intra-tumoral circular RNA induction, showing a well-correlated PK/PD/Efficacy relationship. In summary, we report the discovery and characterization of GH3595, a potent and selective inhibitor of DHX9, which effectively disrupts DHX9-mediated signaling pathways. These findings highlight its significant therapeutic potential for the treatment of malignancies characterized by microsatellite instability or deficiencies in homologous recombination. Citation Format: Faridoon Faridoon, Jiapeng Li, Jiyue Zheng, Xiang Wang, Guiping Zhang. Discovery of GH3595: a novel allosteric DHX9 inhibitor for cancer therapy [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 4247.
Abstract 1804: An innovative dual-payload ADC combining topoisomerase 1 inhibitor and a tubulin inhibitor efficiently overcomes drug resistance
Authors: Ailin Shan, Chun Deng, Peng Zou, Shuai Song, Jiaqiang Cai, Tongtong Xue
Journal: Cancer Research (2025)

Antibody Drug Conjugates (ADC) have achieved great success as anti-cancer therapies, with 15 ADC drugs approved in global market. Despite the initial response to ADC treatment, drug resistance and tumor relapse inevitably happen due to the high heterogeneity in advanced tumors. The mechanism of resistance can be due to downregulation of drug targets, upregulation of multi-drug resistance mechanisms, such as ABCB1/ABCG2 and others. Overcoming these resistance mechanisms are a big challenge to next-generation ADC development for cancer therapy. To address these challenges, MediLink has developed an innovative dual-payload ADC with two payloads of different MOAs: a topoisomerase 1 inhibitor and a tubulin inhibitor. Two conjugation methods were developed: (1) Tubulin inhibitor payload-linkers were conjugated at specific lysine sites of antibody while Topo1i payload-linker were conjugated with free cysteine thiols via TMALIN® Technology, resulting in a dual-payload ADC with DAR of 2 and 8 for each payload-linker, respectively. (2) Reduced antibody conjugates with pre-mixed or step wisely added Topo1i payload linker and Tubulin payload linker in different proportions to obtain any desired ratio of the two different payloads. ADC characterization showed good stability, homogeneity and precise DAR values for the conjugation of both payload-linkers to Trastuzumab. In vitro, the dual-payload Her2 ADC demonstrated strong cytotoxicity against tumor cells with different levels of Her2 expression, especially in cells overexpressing ABCB1 and ABCG2, and Enhertu-resistant tumor cells. In vivo, the dual-payload ADC exhibited superior efficacy in Enhertu-resistance CDX model and Her2 low CDX models. In summary, we developed dual-payload ADCs with intention for resolving topo1 inhibitor induced tumor resistance issues. The dual-payload Her2 ADC demonstrated potent in vitro and in vivo anti-tumor activities, showing the potential to overcome the multidrug resistant mechanism and Enhertu resistance. Citation Format: Ailin Shan, Chun Deng, Peng Zou, Shuai Song, Jiaqiang Cai, Tongtong Xue. An innovative dual-payload ADC combining topoisomerase 1 inhibitor and a tubulin inhibitor efficiently overcomes drug resistance [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 1804.
Abstract 1354: Identification of <i>GREM-1</i> and <i>GAS6</i> as specific biomarkers for cancer-associated fibroblasts derived from patients with non-small cell lung cancer
Authors: Bo-Guen Kim, Kyunghee Park, Mina Hwang, Hyewon Lee, Kyung-Mi Park, Junsu Choe, Sun Hye Shin, Byeong-Ho Jeong, Kyungjong Lee, Jung Hee Lee, Yeong Jeong Jeon, Jong Ho Cho, Hong Kwan Kim, Woong-Yang Park, Sang-Won Um
Journal: Cancer Research (2025)

Abstract Background/Aims: Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor stroma. They are primarily associated with tumor maintenance and promotion via diverse mechanisms in cancer. Using RNA sequencing, we conducted an analysis aimed at distinguishing distinct markers indicative of CAFs compared to normal fibroblasts (NFs) within the context of non-small cell lung cancer (NSCLC) across diverse conditions. Methods: We conducted RNA sequencing analysis on 22 CAFs and 11 NFs from patients with NSCLC. CAFs and NFs were isolated and cultured from tumor tissues (primary tumor or metastatic lymph nodes) and from the most distant non-tumor tissues of the resected lungs, respectively, in NSCLC patients. We performed bulk-RNA sequencing analysis using total RNA from cultured cell pellets of CAFs or NFs. Differential expression, gene set enrichment and CAF subpopulation prediction analyses were performed. Results: Notably, COL11A1, GREM1, CD36, and GAS6 showed higher expression in CAFs than in NFs, whereas TNC and CXCL2 were more highly expressed in NFs. CD36 levels were elevated in CAFs from lymph nodes (LN-CAFs) compared with those from lung specimens (Lung-CAFs) and NFs. COL11A1 levels in Lung-CAFs surpassed those in LN-CAFs and NFs. Both GREM1 and GAS6 showed strong expression in Lung-CAFs and LN-CAFs relative to NFs. CAFs exhibited features of the myofibroblast CAF subpopulation, whereas NFs displayed traits of the antigen-presenting CAF subtype. Conclusions: In NSCLC, GREM1 and GAS6 can be valuable diagnostic and therapeutic targets for CAFs from primary tumors and metastatic sites; they warrant further study. Citation Format: Bo-Guen Kim, Kyunghee Park, Mina Hwang, Hyewon Lee, Kyung-Mi Park, Junsu Choe, Sun Hye Shin, Byeong-Ho Jeong, Kyungjong Lee, Jung Hee Lee, Yeong Jeong Jeon, Jong Ho Cho, Hong Kwan Kim, Woong-Yang Park, Sang-Won Um. Identification of GREM-1 and GAS6 as specific biomarkers for cancer-associated fibroblasts derived from patients with 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 1354.
Abstract 1426: Mechanism study of METTL3/HIF-2α positive feedback loop promoting multidrug resistance in anaplastic thyroid carcinoma
Authors: Junya Ning, Jinpu Yu
Journal: Cancer Research (2025)

Abstract Research Background: Anaplastic Thyroid Carcinoma (ATC) is an extremely lethal malignant tumor, with patients having an average survival period of typically less than five months. For ATC patients, conventional treatment methods such as surgery and radioactive iodine therapy are not effective. To date, there is no widely recognized standard treatment protocol, which has resulted in no significant improvement in patient survival rates over the past several decades. In clinical treatment, chemotherapeutic drugs doxorubicin and cisplatin are the primary treatment methods. Additionally, research shows that the multi-targeted tyrosine kinase inhibitor lenvatinib is effective for some ATC patients. However, the reality is that many patients exhibit resistance to these drugs from the early stages of treatment, greatly limiting their potential to benefit from the therapy. Research Results: Our previous research data found that compared to differentiated thyroid cells and normal thyroid cancer cells, ATC cells have a higher degree of hypoxia, and ATC patients with high tissue hypoxia scores have a worse prognosis compared to those with low hypoxia scores; in vitro experiments demonstrated that hypoxic conditions can induce ATC cell resistance to cisplatin, doxorubicin, and lenvatinib. By comparing tissues with high and low hypoxia scores, we discovered significant enrichment of ABC transport proteins. In ATC tissues, hypoxia scores were significantly negatively correlated with METTL3 expression. Under hypoxic conditions, METTL3 in ATC cells downregulates HIF-2α, thereby reducing ABC transport protein expression. We further found that METTL3 catalyzes m6A methylation modification on HIF-2α RNA, and the "reading protein" YTHDF2 recognizes this modification and participates in RNA degradation, thus reducing HIF-2α RNA levels. Interestingly, we also discovered that HIF-2α can downregulate METTL3 expression through the histone demethylase KDM2B, which removes methylation marks from the 4th lysine of histone H3, thereby suppressing downstream gene transcription. Research Conclusion: In ATC cells, the hypoxic microenvironment upregulates KDM2B through the HIF-2α pathway. KDM2B downregulates METTL3 through its demethylation action, and METTL3 performs m6A methylation modification on HIF-2α RNA, which is then recognized by YTHDF2, ultimately downregulating HIF-2α expression. This positive feedback loop significantly upregulates the expression of ABC transport proteins involved in multidrug resistance, leading to resistance to drugs such as cisplatin, doxorubicin, and lenvatinib. Citation Format: Junya Ning, Jinpu Yu. Mechanism study of METTL3/HIF-2α positive feedback loop promoting multidrug resistance in anaplastic thyroid 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 1426.
Abstract 1721: AXL signaling promotes adaptive resistance to HER2 tyrosine kinase inhibitors in HER2 aberrant tumor cells
Authors: Masaki Ishida, Tadaaki Yamada, Yuki Katayama, Kazuo Yasumoto, Koichi Takayama
Journal: Cancer Research (2025)

Abstract Introduction: Human epidermal growth factor receptor 2 (HER2) is an oncogene target in various cancers, including lung, stomach, and breast cancers. Several HER2-tyrosine kinase inhibitors (TKIs) have been developed for clinical use in patients with tumors exhibiting HER2 aberrations. However, achieving complete tumor remission remains challenging. Therefore, identifying optimal combined therapeutic approaches with HER2-TKIs is crucial for improving clinical outcomes. This study focuses on elucidating the adaptive resistance mechanisms to HER2-TKIs and the therapeutic strategies needed to overcome this resistance. Methods: We conducted in vitro and in vivo experiments using HER2-aberrant tumor cell lines to evaluate the adaptive responses to HER2-TKIs. The involvement of AXL signaling was examined using MTT assays, western blotting, qPCR, and flow cytometer. Results: We showed that adaptive resistance to HER2-TKIs in HER2-aberrant tumors is mediated by AXL signaling, activation of which is induced by its ligand GAS6 production. Inhibition of AXL reduced the viability of HER2-aberrant tumor cells that overexpress AXL by enhancing apoptosis and cell cycle arrest induced by HER2 inhibition. This process contributed to adaptive resistance to HER2-TKIs in HER2-aberrant cancers through the Shc1BP-Shc1 axis, one of the adaptor proteins. HER2-TKIs induced the dissociation of ShcBP1 from Shc1, promoted the binding of Shc1 to AXL, and triggered the translocation of ShcBP1 to the nucleus, which is associated with the cell cycle. In xenograft models of AXL-overexpressing HER2-aberrant tumors treated with HER2-TKIs, initial combination therapy with an AXL inhibitor significantly reduced tumor size and delayed tumor regrowth compared to HER2-TKI monotherapy. Conclusion: These findings highlight the critical role of the GAS6-AXL signaling axis in intrinsic resistance to HER2-TKIs and the potential benefits of its inhibition in overcoming this resistance. Citation Format: Masaki Ishida, Tadaaki Yamada, Yuki Katayama, Kazuo Yasumoto, Koichi Takayama. AXL signaling promotes adaptive resistance to HER2 tyrosine kinase inhibitors in HER2 aberrant tumor 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 1721.
Abstract 4526: Safeguarding parathyroid glands during thyroidectomy using a real-time imaging agent
Authors: Jing Huang, Jialun Ding, Zhishan Guo, Kuan Liu
Journal: Cancer Research (2025)

Abstract Parathyroid gland (PG) inadvertent damage or removal is a frequent complication of thyroidectomy, largely due to the difficulty of distinguishing PGs from surrounding thyroid gland (TG) during surgery. To address this challenge, we developed a novel imaging agent (IO-100) for real-time intraoperative PG visualization. Our study demonstrates that locally administered dark-colored IO-100 preferentially diffuse into TG while remaining excluded from tissue-dense PGs, creating a visually distinct contrast observable by surgeons. Through systematic in vivo optimization, intraoperative PG/TG contrast has been significantly enhanced, and PGs have been well identified and preserved. Importantly, local IO-100 administration was well-tolerated, showed no adverse toxicities exploiting the unique biodegradable property. These findings establish IO-100 as a promising safe and effective imaging agent for enhancing PG identification and minimizing damage/removal risk during thyroidectomy, providing a valuable tool for improving surgical outcomes. Citation Format: Jing Huang, Jialun Ding, Zhishan Guo, Kuan Liu. Safeguarding parathyroid glands during thyroidectomy using a real-time imaging agent [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 4526.
Abstract 5950: Assessment of response and overall survival (OS) for various systemic therapies in <i>ERBB2</i>-altered advanced urothelial carcinoma (aUC)
Authors: Jacob B. Leary, Thomas L. Enright, Dimitra Rafailia Bakaloudi, Rafee Talukder, Michael T. Schweizer, Jessica E. Hawley, Bruce Montgomery, Evan Y. Yu, Andrew C. Hsieh, Todd A. Yezefski, Petros Grivas, Ali Raza Khaki, Ruben Raychaudhuri
Journal: Cancer Research (2025)

Abstract Background: A subset of aUCs harbor ERBB2 alterations. While anti-HER2 therapies in HER2-over-expressing aUC have been promising, relationships between ERBB2 alterations and response to other systemic therapies are unclear. Based on available data, we hypothesized that ERBB2-altered aUC would respond less favorably to immune checkpoint inhibitor (ICI), enfortumab vedotin (EV), and sacituzumab govitecan (SG) than ERBB2-wildtype aUC. Methods: This single-center retrospective study included patients (pts) diagnosed with aUC between 5/6/2016 and 9/23/2022 who underwent panel-based somatic tumor sequencing (120 tissue-based, 9 ctDNA) and received ICI, EV, or SG in first line (1L) or as salvage (2L+). Pts were grouped as ERBB2alt aUC, including tumors harboring ERBB2 amplification (n=13) and/or ERBB2 mutation (n=9), and ERBB2-wildtype(wt) aUC (n=107). Observed response rate (ORR) and OS measured from each therapy start were evaluated. Kaplan-Meier method was used to calculate OS curves. Log-rank and Fisher’s exact tests were used to compare OS and ORR between groups, respectively. Results: 129 pts were evaluable for ERBB2 status; 22 (17%) were ERBB2alt. Baseline characteristics including age, sex, prior extirpative surgery rate, ECOG performance status, proportion of pts with liver metastases, and presence of de novo metastasis were similar between groups. One pt with ERBB2alt aUC received 1L EV; none received 1L SG. Results are shown in Table 1. Conclusions: In pts receiving 2L+ ICI, significantly higher ORR and longer OS were noted in pts with ERBB2alt vs ERBB2wt aUC, contrary to our hypothesis; ERBB2alt was also associated with higher ORR to 2L+ EV. Limitations include retrospective design, limited sample size and power for subsets, lack of randomization, selection/confounding biases, and lack of HER2 protein IHC assessment. Results are hypothesis-generating and need external validation. Citation Format: Jacob B. Leary, Thomas L. Enright, Dimitra Rafailia Bakaloudi, Rafee Talukder, Michael T. Schweizer, Jessica E. Hawley, Bruce Montgomery, Evan Y. Yu, Andrew C. Hsieh, Todd A. Yezefski, Petros Grivas, Ali Raza Khaki, Ruben Raychaudhuri. Assessment of response and overall survival (OS) for various systemic therapies in ERBB2-altered advanced urothelial carcinoma (aUC) [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 5950.
Abstract 1454: Investigating the expression of PTPRN2 and MT1X genes in glioblastoma cell migration using hydrogel-based models
Authors: Ananya Bharadwaj, Talia Sanazzaro, Stephanie K. Seidlits
Journal: Cancer Research (2025)

Glioblastoma (GBM) is an aggressive brain tumor originating from glial cells and presents difficulty in treatment. GBM are highly heterogeneous, presenting a challenge in treatment. In addition, cells migrate away often as single cells from primary tumor sites making GBM impossible to be fully resected. GBM cells adapt their behavior based on the mechanical properties of their surrounding microenvironment, making it significant to investigate gene markers associated with these mechanical changes. Our recent efforts to investigate particular gene markers included using an interface hydrogel platform that replicates the local microenvironment from the tumor edge to peritumoral tissue. Using this model we successfully separated migratory and non-migratory cells. Results from single-cell RNA (scRNA) sequencing identified gene targets that were overexpressed within the migratory group. We found the gene PTPRN2, which plays a role in vesicle trafficking and exocytosis, was overexpressed in migratory cells. This could be a promising target for future therapeutic methods to limit glioblastoma cell migration. In addition to PTPRN2, we are exploring the role of MT1X, a gene in the metallothionein family, to validate these findings. We are currently investigating the expression of the PTPRN2 and MT1X genes using GBM xenograft mouse models. We have observed PTPRN2 expression in the GBM mouse models, with the highest expression detected in migratory cells compared to non-migratory cells in soft gel conditions. In the future, we plan to perform western blot analysis to further confirm PTPRN2 and MT1X protein expression and validate their roles as potential target proteins for GBM treatment. Citation Format: Ananya Bharadwaj, Talia Sanazzaro, Stephanie K. Seidlits. Investigating the expression of PTPRN2 and MT1X genes in glioblastoma cell migration using hydrogel-based 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 1454.
Abstract 2997: Cell-based assay platforms for NLRP3 inflammasome drug discovery
Authors: Jianghong Wu, Li Liang, Peter Gallagher, Yong Wan, Haiching Ma
Journal: Cancer Research (2025)

Abstract Inflammasomes have recently emerged as the exciting and promising drug targets for inflammatory disease therapy. The best characterized is the NLRP3 inflammasome. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3, adapter protein ASC, and inflammatory protease caspase-1 that responds to microbial infection, endogenous danger signals, and environmental stimuli. The assembled NLRP3 inflammasome can activate the protease caspase-1 to induce gasdermin D-dependent pyroptosis and facilitate the release of IL-1β and IL-18, which contribute to innate immune defense and homeostatic maintenance. We have established cell-based Caspase-Glo 1 Inflammasome Assay and NanoBRET target engagement intracellular NLRP3 assay for high throughput screening of inflammasome inhibitors. MCC950 is a cell-permeable, bioavailable, non-toxic sulfonylurea-derived compound. Here, we demonstrate that MCC950 inhibits LPS/Nigericin-induced caspase-1 activation and pyroptotic cell death in dose response mode in PMA primed THP-1 cells in Caspase-Glo 1 inflammasome and CellTiter-Glo viability assays. Our NanoBRET target engagement NLRP3 assay results show that MCC950 binds to cellular NLRP3 within 2 hours of incubation. Interestingly, NanoBRET NLRP3 residence time analysis in living cells indicates that a slow dissociation kinetics (long residence time) is observed for MCC950. Furthermore, Western blot analysis confirms that MCC950 blocks LPS/Nigericin-induced caspase-1 cleavage and activation in PMA primed THP-1 cells. Taken together, our results indicate Caspase-Glo 1 inflammasome and NanoBRET target engagement NLRP3 assays serve as great cell-based assay platforms to facilitate inflammasome drug discovery against inflammatory diseases. Citation Format: Jianghong Wu, Li Liang, Peter Gallagher, Yong Wan, Haiching Ma. Cell-based assay platforms for NLRP3 inflammasome drug discovery [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 2997.