tbuckley/cabot-search huggingface dataset:
Abstract 2961: AZD9592, an EGFR/cMET bispecific antibody-drug conjugate (ADC), demonstrates target-dependent efficacy in colorectal cancer (CRC) patient-derived xenograft (PDX) models
Authors: Ying Zheng, Edward Rosfjord, Simon Christ, Stephanie Zalesak-Kravec, Italia Grenga, Fernanda Arnaldez, Frank Comer, Lara McGrath
Journal: Cancer Research (2025)

Abstract Background: AZD9592 is a bispecific ADC designed to target both epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition tyrosine kinase receptor (cMET), delivering a topoisomerase 1 inhibitor payload to tumor cells. Despite recent advances in ADC development for CRC, such as the use of trastuzumab deruxtecan to treat HER2-positive CRC, a significant unmet need remains for novel therapeutic approaches, particularly for patients with limited targeted treatment options. Methods: We evaluated the antitumor efficacy of AZD9592 and explored biomarker-response relationships in CRC PDX models across a range of very low to high EGFR expression (optical density of membrane [OD] 6.7-162.6) and cMET expression (OD 18.5-142.6) measured by immunohistochemistry-quantitative continuous score (IHC-QCS), as well as other molecular features like oncogene drivers. Responses were defined as ≥30% tumor volume reductions from baseline. Results: AZD9592 demonstrated dose-dependent efficacy, with responses observed in 34.5% of models at 8 mg/kg and 14.8% at 4 mg/kg. Biomarker analyses of tumors revealed a significant association between cMET expression levels by IHC-QCS and responses at 8 mg/kg. cMET levels were significantly higher in AZD9592-responsive models than in antibody-responsive and isotype control-responsive models (p&amp;lt;0.02 for both). An optimized cMET expression cutoff had a predictive performance with an area under the curve of 0.73. Compared to wildtype tumors, response rates were not significantly different in tumors harboring mutations in oncogenes that share signaling pathways with EGFR and cMET and where clinical activity of EGFR antibody therapies is limited, including KRAS and BRAF. Moreover, response rates were not significantly different across tumors derived from patients with or without prior irinotecan treatment, a chemotherapy that also inhibits topoisomerase I. Proteomics identified additional molecular features associated with response. Conclusions: AZD9592 demonstrated dose-dependent antitumor activity in CRC PDX models, including KRAS-mutant and KRAS-wildtype tumors. These responses suggest opportunities for clinical development of AZD9592 in CRC and the potential for biomarker-guided patient selection. Citation Format: Ying Zheng, Edward Rosfjord, Simon Christ, Stephanie Zalesak-Kravec, Italia Grenga, Fernanda Arnaldez, Frank Comer, Lara McGrath. AZD9592, an EGFR/cMET bispecific antibody-drug conjugate (ADC), demonstrates target-dependent efficacy in colorectal cancer (CRC) patient-derived xenograft (PDX) models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2961.
Abstract 1057: Addressing challenges in integrating dietary factors into machine learning models for gastrointestinal cancer prediction in South Korean cohort
Authors: Daina Baublyte, Jeonghee Lee, Madhawa Gunathilake, Jeongseon Kim
Journal: Cancer Research (2025)

Abstract Introduction: Dietary factors are integral to cancer etiology but are underrepresented in predictive models for gastrointestinal (GI) cancer risk. Challenges such as limited availability and variability of dietary intake data hinder the development of effective machine learning (ML) models. This study investigates these challenges and develops practical solutions to enhance the integration of dietary data into GI cancer risk prediction using a South Korean cohort. Methods: We analyzed data from the Cancer Screenee Cohort, following 7, 862 adults (158 GI cancer cases and 7, 704 controls) over 16 years. Dietary data were collected using a validated food frequency questionnaire (FFQ), supplemented by clinical biomarkers and anthropometric measurements. ML models—logistic regression, random forests, gradient boosting machines, and support vector machines—were trained and evaluated using precision and F1 scores, focusing on predicting the minority class (GI cancer cases). A tailored data sampling and model training strategy was developed to address class imbalance and improve predictive performance. Results: Initial ML models faced performance challenges due to class imbalance and limited sample size, achieving zero precision for the case class and strong performance only for control class (control precision = 0.98). The proposed sampling and model training strategy enhanced minority-class predictions achieving a case class prediction precision of 0.78—a 78% improvement—while maintaining an overall F1 score of 0.75, reflecting a strong balance between overall model precision and recall. Conclusions: This study highlights the challenges of incorporating dietary factors into GI cancer prediction and underscores the importance of tailored approaches to address class imbalance in ML models. The proposed strategy substantially improved predictions for the minority class, offering practical insights for enhancing GI cancer screening and prevention through data-driven methods. Future work could explore incorporating additional dietary factors and testing the approach in larger populations to further validate its applicability. Citation Format: Daina Baublyte, Jeonghee Lee, Madhawa Gunathilake, Jeongseon Kim. Addressing challenges in integrating dietary factors into machine learning models for gastrointestinal cancer prediction in South Korean 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 1057.
Abstract 2868: Preclinical evaluation of LM-350: An innovative anti-CDH17 antibody drug conjugate for gastrointestinal cancer therapy
Authors: Wentao Huang, Jin Li, Xia Qin, Da Fei, Runsheng Li
Journal: Cancer Research (2025)

Abstract Background: Cadherin 17 (CDH17) is a membrane cell adhesion protein selectively expressed in gastrointestinal cancers, including colorectal (CRC), gastric (GC), and pancreatic cancers (PC). Its expression in normal intestinal epithelial cells is limited. LM-350, a CDH17-targeted antibody-drug conjugate (ADC), is composed of a humanized monoclonal antibody (LM-150) conjugated to the next-generation topoisomerase I inhibitor LDX2 via a cleavable linker, with a drug-antibody ratio of 8. Methods: Target binding activity, specificity, and cross-species reactivity of LM-350 was evaluated by flow cytometry. Internalization was evaluated using an acidic pH-sensitive dye, with fluorescence signal detection via flow cytometry. Cytotoxicity and bystander effects were evaluated using the CellTiter-Glo luminescent cell viability assay. In vivo anti-tumor activity of LM-350 was evaluated in CDH17-positive CRC and GC cell line-derived xenografts (CDX) and patient-derived xenografts (PDX). Immunohistochemistry was used to assess CDH17 expression in tumor tissues. Results: LM-350 demonstrated concentration-dependent binding to CDH17-expressing human CRC and GC cells, with EC50 values ranging from 0.13 to 0.94 nM, which was comparable to the un-conjugated monoclonal antibody LM-150. LM-150 exhibited high specificity and binding affinity to monkey CDH17 but not to rodent CDH17. In addition, LM-350 induced concentration and time dependent cellular internalization and potent cytotoxic effects in CDH17-positive cells. In vivo, LM-350 treatment at doses of 3 or 6 mg/kg significantly inhibited or regressed tumor growth in multiple CRC and GC xenograft models, with tumor growth inhibition rates ranging from 70% to 129%. Conclusion: The novel ADC LM-350 targeting CDH17 exhibited potent anti-tumor activity in vitro and in CRC and GC xenograft models. LM-350 demonstrated high therapeutic potential in CDH17-positive gastrointestinal cancers, particularly in CRC and GC. Citation Format: Wentao Huang, Jin Li, Xia Qin, Da Fei, Runsheng Li. Preclinical evaluation of LM-350: An innovative anti-CDH17 antibody drug conjugate for gastrointestinal 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 2868.
Abstract 102: Identifying predictors of liver metastasis in small cell lung cancer using gene expression profiling
Authors: George Chrisafis, Mohit Arora, Nobuyuki Takahashi, Anish Thomas
Journal: Cancer Research (2025)

Abstract Small cell lung cancer (SCLC) is a highly aggressive, treatment-resistant form of lung cancer which carries an exceptionally poor prognosis. Patients with SCLC often present at an advanced stage due to the propensity of SCLC for early metastasis, with common sites including the brain, liver, adrenal glands, and bone. Liver metastasis has been identified as an independent prognostic factor for unfavorable response to chemotherapy, but specific steps in the liver metastatic cascade are yet to be described. Here, we seek to better characterize SCLC liver metastases by analyzing gene expression data from cell lines and patient biopsy samples. We analyzed data published in MetMap (Jin et al., 2020), which estimated organ-specific ‘metastatic potential’ of a variety of cell lines from the Cancer Cell Line Encyclopedia (CCLE). Gene set enrichment analysis revealed that SCLC cell lines with high liver metastatic potential exhibit significant positive enrichment of MYC signaling, oxidative phosphorylation, and Wnt/Beta-catenin signaling with negative enrichment of TNF-alpha signaling, inflammatory response, interferon response, and epithelial-to-mesenchymal transition. This pattern appears unique to SCLC cells compared with liver metastatic non-small cell lung cancer and colorectal cancer cells. Genes with differentially higher expression in SCLC lines with high liver metastatic potential were also found to play roles in embryonic organ and lung development. Cell lines with low liver metastatic potential exhibited increased expression of genes involved in pathways related to natural killer (NK) cell mediated immunity, suggesting the important role for innate immunity in preventing liver metastasis. This observation was confirmed in multiple datasets of SCLC patient biopsies, with higher expression of NK cell activating genes associated with a more favorable prognosis. Additionally, chromosome 3p deletion was more frequently observed in liver metastatic cell lines, and in primary patient tumors, the presence of a 3p deletion (plus 5q non-deletion) was associated with the presence of liver metastasis. Genes and pathways identified by this analysis, following experimental validation, could serve as potential therapeutic targets to predict and disrupt the liver metastatic cascade. Citation Format: George Chrisafis, Mohit Arora, Nobuyuki Takahashi, Anish Thomas. Identifying predictors of liver metastasis in small cell lung cancer using gene expression profiling [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 102.
Abstract 2876: BR116: An antibody drug conjugate targeting CDH17 for gastrointestinal cancer therapy
Authors: Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Yiqun Li, Cindy Wu, Lei Nie, Haibin Wang, Gang Chen
Journal: Cancer Research (2025)

Abstract Cadherins are Ca2+-dependent cell adhesion molecules that mediates cell-to-cell adhesion and plays a key role in tissue development. Classical cadherins, such as E-cadherin (CDH1), N-cadherin (CDH2), P-cadherin (CDH3), and VE-cadherin (CDH5) are implicated in cancer progression, invasion, and metastasis when their expression or function changes. CDH17 (Cadeherin-17, LI-cadherin) is a structurally unique member of the cadherin superfamily, with seven extracellular EC repeats, a transmembrane domain, and a shorter cytoplasmic domain. Originally discovered in rat liver and intestine, CDH17 is also called liver and intestine cadherin. In humans, the expression of CDH17 is mainly limited to the digestive tract, including the duodenum, jejunum, ileum, colon, pancreas, and is rarely detected in other tissues. In the intestinal epithelium, CDH17 is mainly localized to lateral and basolateral cell membranes. CDH17 overexpression is observed in various gastrointestinal malignancies, such as gastric cancer, colorectal cancer, bile duct cancer, pancreatic cancer and hepatocellular carcinoma, with almost no expression in normal tissues and organs. High expression of CDH17 is also associated with poor prognosis. The tumorigenic role of CDH17 involves interaction with α2β1 integrin to regulate cell adhesion, proliferation and migration, particularly in colon cancer liver metastasis, making CDH17 a promising therapeutic target in cancer research. BR116 is a novel anti-CDH17 ADC that consists of a humanized, highly specific monoclonal antibody, stably conjugated to an innovative topoisomerase I inhibitor with hydrophilic linker. Notably, our unique conjugation platform CysX™ offers site-specific, stable and irreversible conjugation. CysX™ not only prevents payload detachment during circulation and reducing the off-target toxicity, improved therapeutic window, but also enables a uniformed drug-to-antibody ratio (DAR) of 4. The toxin was carefully selected based on the target characterization and cancer cell sensitivity. BR116 has demonstrated remarkable antitumor activity in both in vitro and in vivo studies. Preclinical evaluations have shown strong safety profile in cynomolgus monkeys, indicating its potential as a therapeutic treatment for gastrointestinal cancers. With its enhanced safety profile and promising efficacy, BR116 holds significant potential for further clinical development. BR116 is aiming to file for an IND in 2025. Citation Format: Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Yiqun Li, Cindy Wu, Lei Nie, Haibin Wang, Gang Chen. BR116: An antibody drug conjugate targeting CDH17 for gastrointestinal 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 2876.
Abstract 2896: Transforming treatment paradigms: A cutting-edge polθ Inhibitor (DWP223) targeting PARP resistance in BRCA-mutant cancers
Authors: Juno Kim, Jie Luo, Bin Cao, Ling Zhao, Xiaojing Zhang, Xiaohua Lin, Xiaojing Lin
Journal: Cancer Research (2025)

Abstract A significant portion of tumors with BRCA1 or BRCA2 mutations exhibit only weak responses to PARP inhibitor (PARPi) treatment, and often develop resistance to PARPi over time. Both Polθ and PARP1 play critical roles in MMEJ for DNA double-strand break repair, and Polθ inhibition holds the potential to overcome PARPi resistance driven by BRCA reversion mutations. To address these challenges, we have developed DWP223, a novel selective and potent Polθ inhibitor. This compound can be used as a single agent or in combination with PARPi to treat tumors harboring BRCA mutations.DWP223 has shown potent and selective inhibition of BRCA-deficient cell proliferation in vitro, achieving an IC50 value below 20 nM, while demonstrating minimal impact on parental cell lines. In vivo, DWP223 monotherapy is effective at doses as low as 30 mg/kg, and when used in combination with PARP inhibitors, it induces over 50% tumor regression at a lower dose. Notably, even at high doses, DWP223 is well-tolerated, with no observable weight loss or hematological toxicity in animal models.Furthermore, DWP223 extends therapeutic potential by exhibiting synthetic lethality in tumors deficient in non-homologous recombination (HR), broadening its application to patients without homologous recombination repair (HRR) mutations. The compound’s favorable pharmacokinetic profile and robust safety data across multiple species underscore its suitability for clinical development, highlighting the opportunity to reduce hematological toxicity and target PARP inhibitor-resistant cancers.Collectively, DWP223 represents a promising therapeutic candidate, either as a standalone treatment or in combination with PARPi, for targeting HR-deficient cancers and potentially overcoming PARPi resistance. DWP223 is advancing toward IND filing in 2025. Citation Format: Juno Kim, Jie Luo, Bin Cao, Ling Zhao, Xiaojing Zhang, Xiaohua Lin, Xiaojing Lin. Transforming treatment paradigms: A cutting-edge polθ Inhibitor (DWP223) targeting PARP resistance in BRCA-mutant cancers [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 2896.
Abstract 1817: Overcoming tumor hypoxia in MPNSTs using an implantable micro-catheter
Authors: Samual Hatfield, Ryan Courtney, Emily Witt, Jianling Bi, James Byrne
Journal: Cancer Research (2025)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are a devastating and rare type of tumor, accounting for 5-10% of all soft-tissue sarcomas, with a 5-year overall survival rate of only 50%. A key contributing factor to the poor outcomes is treatment resistance due to tumor hypoxia. Despite efforts to mitigate tumor hypoxia as a therapeutic strategy, significant challenges remain, including the kinetics of oxygenation, peak partial pressures achieved, and the safety of existing methods. Here, we report on an implantable system for direct intratumoral oxygen injection that synergizes with radiotherapy. We demonstrate that tumor oxygenation using this system slows tumor growth and extends survival in a mouse model of MPNST. Six-to-eight-week-old female C57BL/6J mice bearing subcutaneous right-flank MPNST allograft tumors were separated into four treatment cohorts: oxygen infusion + radiation, radiation, oxygen infusion, and no treatment. For mice receiving oxygen infusion, the center of the tumor was catheterized once tumors reached a volume of 200 mm3. Intratumoral oxygen infusion was achieved using a syringe pump to deliver oxygen at a partial pressure of 50 mmHg. The microcatheters were then removed, and a single 15 Gy radiation dose was administered using a small animal radiation research platform. Following treatment, tumor growth was monitored and measured three times weekly using calipers. Tumor volume was approximated using the formula V = 0.5 × length (L) × width (W)2, where length and width correspond to the x and y measurements of the tumor in mm. Animals were euthanized, and tumors were harvested once their volume reached 2000 mm3. In a separate cohort of mice, tumors were resected one hour after irradiation, formalin-fixed, paraffin-embedded, and stained for γ-H2AX foci. Intratumoral oxygen infusion combined with radiation inhibited tumor growth and extended the median survival of mice with MPNSTs from 13 days (no treatment) to 25 days (oxygen infusion + radiation). Additionally, there was a significant increase in γ-H2AX foci per nucleus in tumors treated with oxygen infusion + radiation compared to radiation alone. We demonstrate that direct intratumoral oxygenation can radiosensitize MPNSTs in a mouse model. The significant reduction in tumor growth observed in mice receiving oxygen infusion + radiation, compared to radiation alone, suggests that tumor oxygenation may improve outcomes when combined with current standard-of-care therapies. Citation Format: Samual Hatfield, Ryan Courtney, Emily Witt, Jianling Bi, James Byrne. Overcoming tumor hypoxia in MPNSTs using an implantable micro-catheter [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 1817.
Abstract 1799: Harnessing the GlycOBI® enabling technologies: next-generation site-specific glycan ADCs with versatile DAR to enhance therapeutic index
Authors: Teng-Yi Huang, Ka-Shu Fung, Yu-Chao Huang, Chi-Sheng Shia, Chi-Huan Lu, Nan-Hsuan Wang, Ya-Chi Chen, Ming-Tain Lai
Journal: Cancer Research (2025)

The GlycOBI® enabling technologies represent a novel approach for the development of antibody-drug conjugate (ADC) to achieve site-specific glycan conjugation through the proprietary dual-action enzyme EndoSymeOBI®. This innovative technology is capable of attaining homogeneous ADC at specific drug-to-antibody ratio (DAR) while maintaining antibody integrity and function. A key feature of the technology is its exclusive linker, which has a unique design to enhance payload stability and enable selective release in the tumor microenvironment, thereby potentially broadening the therapeutic index. The ADCs that use the GlycOBI® enabling technologies are shown to be highly homogeneous while achieving uniform DAR configurations. These next generation ADCs, combined with optimized and novel linker designs, exhibit superior pharmacokinetics, stability, and antitumor activity compared to conventional ADCs in various animal models. The technology supports mono-specific and multi-specific antibodies, expanding its versatility for various therapeutic modalities. The flexibility of DAR configurations and proprietary linker design further demonstrate the technologies’ adaptability across diverse payload classes, including cytotoxic agents, immunomodulators, and degraders. In preclinical models, OBI-902 (TROP2 GlycOBI® DAR4 ADC) and OBI-904 (Nectin-4 GlycOBI® DAR8 ADC), both using Exatecan, a potent topoisomerase 1 inhibitor as the payload, have demonstrated promising antitumor activities. Notably, OBI-904, with its DAR8 format, exhibits superior activities in animal models, including in low antigen expressing tumor models, compared to approved and other benchmark Nectin-4 ADCs. Further, both ADCs maintained their stability and avoided antibody aggregation. Both candidates are targeted for IND submissions in 2025, representing an important milestone in advancing the GlycOBI® ADCs to the clinics. The integration of glycan engineering, EndoSymeOBI®, and a novel linker design establishes the GlycOBI® suite of technologies as a robust and adaptable solution to address the current ADC limitations. These advancements underscore its transformative potential in driving the next generation of therapeutics. Citation Format: Teng-Yi Huang, Ka-Shu Fung, Yu-Chao Huang, Chi-Sheng Shia, Chi-Huan Lu, Nan-Hsuan Wang, Ya-Chi Chen, Ming-Tain Lai. Harnessing the GlycOBI® enabling technologies: next-generation site-specific glycan ADCs with versatile DAR to enhance therapeutic index [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 1799.