tbuckley/cabot-search huggingface dataset:
Abstract 6027: 89Zr-matuzumab and 225Ac-matuzumab as a theranostic for epidermal growth factor receptor-positive KRAS wild-type colorectal and breast cancer xenografts
Authors: Florence Anjong Tikum, Humphrey Fonge, Fabrice Njotu, Hanan Babeker, Jessica K. Pougoue, Nikita Henning, Alireza Doroudi
Journal: Cancer Research (2024)

Abstract Background: About 80% of colorectal cancer (CRC) and 50 % of Triple-Negative breast cancer (TNBC) patients overexpress epidermal growth factor receptor (EGFR). Mutations in the KRAS oncogene (present in 40% of mCRC) lead to constitutive over-activation of EGFR and drive de novo resistance to anti-EGFR drugs. Here, we propose to target KRAS-mutant/BRAF mutant EGFR positive mCRC and TNBC using 225Ac-labeled matuzumab, a humanized anti-EGFR monoclonal antibody. Methods: p- -SCN-macropa was used to conjugate matuzumab for radiolabeling with 225Ac and SCN-deferoxamine was used to conjugate matuzumab for labelling with 89Zr. The radioimmunoconjugates were characterized by flow cytometry, HPLC and iTLC. in vitro cytotoxicity was evaluated in EGFR-positive mCRC, TNBC cell lines and 3D spheroids with different levels of EGFR density. Tumor growth was monitored using digital caliper. Mice were treated with either 10 MBq of 89Zr-matuzumab for imaging or three doses of 13 KBq/dose administered of 225Ac-matuzumab 10 days apart. In vivo study endpoint was tumor volume greater than or equal to 1500 mm3. Results: Flow cytometry showed about 95% binding to the cells in all EGFR-positive colorectal cell lines (DLD-1, SW620, SNU-C2B, HT-29) and breast cancer cell lines (MDA-MB-468, MDA-MB-231). in vitro studies showed enhanced cytotoxicity of 225Ac-matuzumab compared with matuzumab. IC50 in the MDA-MB-468 cell line for 225Ac-matuzumab (1.86 ± nM) was 35 times more effective than matuzumab (65.25± 7 nM). Similar trends were observed in the other KRAS-mutant mCRC cell lines and breast cancer cell lines. In 3D spheroid models, the IC50 of 225Ac-matuzumab (3.0 ± 2 nM) in MDA-MB-468, was 20.79 times more effective than matuzumab (62.3 ± 1.38 nM). Similar trends were observed for all the other spheroid models as well. High uptake of 89Zr-matuzumab was observed in both mCRC and TNBC xenografts. 225Ac-matuzumab slowed tumor growth rate in MDA-MB-468 and MDA-MB-231 tumors models compared with control antibody or non-treated controls for 30 days. This study is still ongoing and will last for 2 more months. Conclusion: 225Ac-matuzumab shows very promising outcomes in KRAS-mutant mCRC models and breast cancer models and warrants further investigation. Citation Format: Florence Anjong Tikum, Humphrey Fonge, Fabrice Njotu, Hanan Babeker, Jessica K. Pougoue, Nikita Henning, Alireza Doroudi. 89Zr-matuzumab and 225Ac-matuzumab as a theranostic for epidermal growth factor receptor-positive KRAS wild-type colorectal and breast cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6027.
Abstract 3533: Spatially Resolved Laser-Activated Cell Sorting (SLACS) and AI integration for enhanced pathological analysis and biomarker discovery
Authors: Haewook Jang, Amos Chungwon Lee, Sumin Lee, Sunghoon Kwon
Journal: Cancer Research (2024)

Abstract This study focuses on the integration of Artificial Intelligence (AI) with Spatially Resolved Laser-Activated Cell Sorting (SLACS) for enhanced pathological analysis and biomarker discovery. The primary approach involves using AI to automatically analyze slide images, identifying critical areas associated with diseases such as cancer or cells emitting specific signals. AI algorithms efficiently segment these significant regions or cellular groups, facilitating targeted analysis. Following the AI-driven segmentation, SLACS comes into play, isolating the identified cells from the slide for further examination. This precise sorting allows for the focused study of cells relevant to disease processes, enhancing the efficiency and accuracy of pathological analysis. The separated samples obtained through SLACS are then subjected to detailed analysis. This step is crucial for understanding the cellular mechanisms at play in disease states and for the identification of potential biomarkers. These biomarkers are vital for developing targeted therapeutic strategies and advancing personalized medicine. By combining AI's advanced image processing and pattern recognition capabilities with the precision of SLACS, this integrated approach significantly improves the identification and analysis of disease-related cellular characteristics. It streamlines the process of isolating and studying specific cell populations, contributing to a deeper understanding of disease mechanisms and progression. In conclusion, the synergistic application of AI and SLACS represents a significant advancement in pathological research and biomarker discovery. This methodology not only enhances the accuracy of disease marker identification but also opens new avenues for research and clinical application. Citation Format: Haewook Jang, Amos Chungwon Lee, Sumin Lee, Sunghoon Kwon. Spatially Resolved Laser-Activated Cell Sorting (SLACS) and AI integration for enhanced pathological analysis and biomarker discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3533.
Abstract 3169: The role and mechanism of m6A methylation modification of LncRNA-ATB in regulating the invasion and metastasis of colorectal cancer
Authors: Yu Lang#, Jia-Lin Lin#, Jia-Peng Kang, Lu Yang, Dan Zhou, Can-Bin Fang*, Feng Ye*, Wei-wei Tang*
Journal: Cancer Research (2024)

Abstract Background: The epigenetic modification of LncRNA N6-methyladenosine (m6A) methylation plays a wide role in the invasion and metastasis of various malignant tumors. However, the role of LncRNA-ATB m6A methylation modification in colorectal cancer (CRC) has not been systematically elucidated. Methods: Detect the regulatory effect of ALKBH5 on LncRNA-ATB by Luciferin reporter gene. LncRNA-ATB expression was detected by IHC and qPCR in CRC tissues and cells. Transwell and scratch tests were used to detect the effect of ALKBH5 overexpression after LncRNA-ATB knockdown and replacement on the invasion and migration ability of CRC cells. Western blotting was used to detect the expression changes of MMPs proteins. Results: ALKBH5 could regulate the methylation level of the LncRNA-ATB 3’ UTR region (p&amp;lt;0.05). ALKBH5 overexpression in CRC cells led to a significant decrease in the expression level of LncRNA-ATB (p&amp;lt;0.05). LncRNA-ATB exhibited elevated expression in CRC cells and demonstrated significantly higher levels in CRC tissues compared to paracancerous tissues (p&amp;lt;0.05), indicating the potential tumor-promoting effect of LncRNA-ATB in CRC, with the mechanism possibly regulated by ALKBH5-mediated m6A demethylation. ALKBH5 overexpression inhibited the proliferation and migration of CRC cells after LncRNA-ATB knockdown. However, this inhibitory effect was attenuated upon LncRNA-ATB rescue, accompanied by an increase in MMP9 and a decrease in TIMP1. Conclusion: LncRNA-ATB plays a crucial role in ALKBH5-mediated m6A demethylation, regulating the invasion and metastasis of CRC. The ALKBH5-LncRNA-ATB m6A demethylation-MMPs signaling axis has been identified as a key regulatory pathway promoting CRC migration. m6A modification of lncRNA-ATB modulated by ALKBH5 provides a theoretical basis for novel therapeutic strategies for patients with metastatic CRC. FUNDING: This study was supported by the National Natural Science Foundation of China (Grant No. 81702414), Natural Science Foundation of Fujian Province of China (Grant No. 2020J05306) and Xiamen Science and Technology Planning Project (Grant No. 3502Z20194003). Citation Format: Yu Lang#, Jia-Lin Lin#, Jia-Peng Kang, Lu Yang, Dan Zhou, Can-Bin Fang*, Feng Ye*, Wei-wei Tang*. The role and mechanism of m6A methylation modification of LncRNA-ATB in regulating the invasion and metastasis of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3169.
Abstract 3266: Plk1 promotes Pdcd4 degradation to enhance enzalutamide resistance in prostate cancer
Authors: Qing Wang, Qiongsi Zhang, Yanquan Zhang, Xiaoqi Liu, Hsin-Sheng Yang
Journal: Cancer Research (2024)

Abstract The androgen receptor (AR) signaling pathway plays critical role in the development of prostate cancer (PCa), including castration-resistant prostate cancer (CRPC). As a result, androgen signaling inhibitors (ASIs) like abiraterone and enzalutamide (ENZ) have emerged as the first-line treatment for CRPC. Nevertheless, the limited success of ASIs underscores the urgency of developing new approaches for managing CRPC patients who have become unresponsive to ASIs. Programmed cell death 4 (Pdcd4) is a tumor suppressor, which is frequently down-regulated during PCa progression. It has been shown that reduced Pdcd4 expression promotes both AR-dependent and AR-independent growth in PCa. In this study, we found that down-regulation of Pdcd4 led to acquisition of ENZ resistance in PCa. We also observed that down-regulation of Pdcd4 resulted in activation of mTORC2 activity. Additionally, knockdown of Rictor, a component of mTORC2 complex, enhanced sensitivity to ENZ treatment in PCa. These findings suggested that activation of mTORC2 due to Pdcd4 loss contributes to ASI resistance in PCa. To understand how Pdcd4 is down-regulated in the PCa, we identified that polo-like kinase (Plk1) phosphorylated Pdcd4 at Ser239. Phosphorylation of Pdcd4 by Plk1 led to ubiquitin-mediated proteasomal degradation of Pdcd4. Over-expression of the phosphomimic Pdcd4(S239D) in 22Rv1 cells promoted tumor cell growth in cultured cells and mice. Taken together, our data suggest that targeting Plk1/Pdcd4/mTORC2 signaling axis holds promise as a strategy to overcome ENZ resistance in PCa. Citation Format: Qing Wang, Qiongsi Zhang, Yanquan Zhang, Xiaoqi Liu, Hsin-Sheng Yang. Plk1 promotes Pdcd4 degradation to enhance enzalutamide resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3266.
Abstract 2177: Postbiotic metabolites secreted by L. acidophilus reduce DNA damage in an experimental model of Barrett’s tumorigenesis
Authors: Divya Joshi, Claudia Andl
Journal: Cancer Research (2024)

Abstract The origins of esophageal adenocarcinoma (EAC) are commonly attributed to the progression from gastroesophageal reflux disease (GERD) to Barrett’s Esophagus (BE) and finally to esophageal adenocarcinoma. During GERD, various types of bile induce oxidative stress and generate reactive oxygen species (ROS), resulting in DNA damage and inflammation in cells. Although there has been much research documenting the shift in the esophageal microbiome from gram-positive to gram-negative bacteria during this progression, there has also been an observed increase in the presence of Lactobacillus, a gram-positive commensal bacterium with probiotic qualities, in the esophagus during the progression from GERD to BE and eventually to EAC. Our previous research has demonstrated the ability of Lactobacillus spp. to not only colonize the esophagus under in vitro conditions of GERD, but also their anti-inflammatory and anti-genotoxic properties on esophageal cells exposed to bile. To assess the extent of reflux-induced DNA damage and oxidative stress during the progression of BE, we exposed two BE cell lines, CP-B and BAR-T, and the EAC cell line FLO-1 to ox bile or deoxycholic acid. Both bile types demonstrated significant increases in phosphorylated H2AX, as a marker for pronounced DNA damage repair. Next, we supplemented both live L. acidophilus and its postbiotic metabolites to cells exposed to ox bile and deoxycholic acid. We show a significant reduction in DNA damage as measured by pH2AX with both the live treatment and the treatment with postbiotic metabolites when compared to untreated, bile-exposed cells at various stages of BE and EAC. Ongoing experiments include assessing anti-genotoxic effects of postbiotic metabolites through DNA repair protein RAD51, reductions in oxidative stress though ROS marker 8-oxo-guanine, and anti-inflammatory effects through NFkB-associated inflammation. BE and EAC cell viability and proliferation upon bile exposure and postbiotic metabolite administration will also be assessed. This study aims to determine the supplementation with Lactobacillus postbiotic metabolites in the prevention and intervention of esophageal adenocarcinoma development. Citation Format: Divya Joshi, Claudia Andl. Postbiotic metabolites secreted by L. acidophilus reduce DNA damage in an experimental model of Barrett’s tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2177.
Abstract 6132: Exploring genomic complexity in lung cancer at the Tijuana/California border: A real-world perspective through liquid biopsy comprehensive genomic profiling
Authors: Jorge Alberto Guadarrama-Orozco, Jennifer Ramirez-Puente, Elizabeth Dominguez-Gonzalez
Journal: Cancer Research (2024)

Abstract Objective: This study explores the application of liquid biopsy with next-generation sequencing (NGS) in profiling the genomic landscape of lung cancer patients from the Tijuana/California Border region. Specifically, we employ blood-based comprehensive genomic profiling (CGP) to assess the complexity of the genomic profile in these patients. Materials and Methods: From April 2019 to November 2023, 37 lung cancer patients from Tijuana underwent profiling using the FoundationOne®Liquid CDx (F1LCDx®) assay, focusing on circulating tumor DNA (ctDNA). The assay, which spans 324 cancer-related genes and genomic signatures, provides insights into tumor fraction (TF) and blood-based tumor mutational burden (bTMB). Variants were classified based on the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT). Results: A notable 88.6% of patients exhibited at least one detectable alteration in plasma. The most frequently mutated genes were TP53 (51.3%), EGFR (16.2%), DNMT3A (13.5%), and KRAS (10.8%). Tumor mutational burden (TMB) was assessable in 9 out of 37 patients, with values ranging from 0 to 10 mut/Mb. According to ESCAT classification, 63.1% of samples revealed potentially actionable alterations (Tier I-II), while an additional 24.1% harbored alterations for which approved drugs are available in other cancer types (Tier III). Conclusion: Liquid biopsy NGS emerges as a viable and valuable strategy for guiding personalized therapy. Given restricted accessibility to new drugs or clinical trials in Mexico, the use of blood-based CGP may enhance the identification of druggable alterations, thereby increasing the likelihood of accessing targeted drugs or enrolling in clinical trials. Citation Format: Jorge Alberto Guadarrama-Orozco, Jennifer Ramirez-Puente, Elizabeth Dominguez-Gonzalez. Exploring genomic complexity in lung cancer at the Tijuana/California border: A real-world perspective through liquid biopsy comprehensive genomic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6132.
Abstract 7509: Evaluation ofHER-2 expression on circulating tumor cells as a real time biomarker in advanced breast cancer
Authors: Jayant Khandare, Gourishankar Aland, Saloni Andhari, Ganesh Khutale, Prathamesh Patil, Tanvi Deshpande, Meghana Garbhe, Vikas Jadhav, Aravindan Vasudevan, Sreeja Jayant
Journal: Cancer Research (2024)

Abstract Introduction: Breast cancer accounts for 12.5% of all new annual cancer cases worldwide. Cases classified as HER2-positive tend to proliferate, metastasize, and often lead to relapse. HER-2 is the most valid tumor marker, used as a diagnostics and prognostic biomarker in metastatic breast cancer (MBC). Thus, analysis of expression of HER-2 on CTCs can offer a real time dynamic biomarker for treatment options between endocrine therapy versus chemotherapy in advanced breast cancer. Functional assays on CTCs with HER-2 biomarker offer evolving biomarkers especially when the tissue is not accessible and inadequate. Methods: Retrospectively, 179 breast cancer patients' blood was analyzed for the presence of CTCs using the OncoDiscover® platform approved by Drug Controller General of India (CDSCO). Consisting of immunomagnetic multi-components mediated by anti EpCAM antibodies. The isolated cells were immunostained consisting of a nuclear dye DAPI, CK-18, CD45 and HER-2 antibodies. CTCs were identified by the presence of HER-2 + ve, CK 18 + ve, DAPI + ve and CD 45 -ve staining. Validation of HER-2 expression on the CTCs was analyzed based on the linear intensity gradients of the fluorescence signals. CTCs were termed as HER-2 -ve based on weak or no detectable fluorescence signal and termed +ve based on high fluorescence signal. Results: Among the cohort of 179 patient samples, 63.68 % samples showed the presence of CTC (CTC ranged from 1-7). 47.84% of these CTCs showed the expression of HER-2 signal. The mean value for fluorescence intensity for expression of HER-2 in CTCs was found to be 3.23. The observed mean fluorescence intensity for HER-2 expression further emphasizes the robustness of CTCs as a viable source for molecular characterization. Conclusion: Integration of HER-2 analysis on CTCs into the clinical assessment of metastatic breast cancer, may offer a non-invasive, real-time strategy for profiling and possibly paving the way for more precise and tailored therapeutic interventions. Citation Format: Jayant Khandare, Gourishankar Aland, Saloni Andhari, Ganesh Khutale, Prathamesh Patil, Tanvi Deshpande, Meghana Garbhe, Vikas Jadhav, Aravindan Vasudevan, Sreeja Jayant. Evaluation ofHER-2 expression on circulating tumor cells as a real time biomarker in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7509.
Abstract 898: Deep learning-based cell types scores in tumor microenvironment estimated by H&amp;E images associated with PD-L1 status in lung adenocarcinoma
Authors: Seungho Cook, Haenara Shin, Jaemoon Koh, Hongyoon Choi, Kwon Joong Na
Journal: Cancer Research (2024)

Abstract Purpose: The spatial distribution of cell types in the tumor microenvironment (TME) is associated with functional status of tumor immunology and eventually affects the response to immuno-oncology treatment. We have developed a deep learning model that was trained by integrating H&amp;E images of lung adenocarcinoma with spatial transcriptomic data. We applied this model to predict various cell types within the TME using only hematoxylin and eosin (H&amp;E) images to correlate with the PD-L1 status. Methods: A deep learning model to predict five cell types enrichment score maps from H&amp;E images was trained by spatial transcriptomics data combined with matched H&amp;E images. The five cell types of TME included B cells, T/NK cells, myeloid cells, fibroblasts, and epithelial cells. wAnother dataset based on tissue microarray (TMA) data of H&amp;E images of lung cancer patients (n = 94) was used to predict cell type enrichment scores associated with PD-L1 status estimated by TPS score. The cell type scores derived from the H&amp;E-stained lung cancer images were correlated with the PD-L1 status. Results: The cell types predicted by the model using H&amp;E image patches showed a significant correlation with those determined through spatial transcriptomic data, serving as an internal validation. All cell types (B cells, T/NK cells, myeloid cells, fibroblasts, and epithelial cells) from TMA cores showed significant differences according to the PD-L1 expression groups. The enrichment scores of B cells, T/NK cells, myeloid cells and fibroblasts were significantly higher in the PD-L1 high group. Conclusions: Our research introduces a deep learning model for precise cell type mapping within the tumor microenvironment and applied to H&amp;E-stained TMA cores. The relationship between PD-L1 status and the cell type enrichment scores within the tumor microenvironment, as predicted by the deep learning model analyzing H&amp;E images, demonstrates the potential for using H&amp;E-based characterization of the tumor microenvironment as a biomarker in immuno-oncology treatments. Citation Format: Seungho Cook, Haenara Shin, Jaemoon Koh, Hongyoon Choi, Kwon Joong Na. Deep learning-based cell types scores in tumor microenvironment estimated by H&amp;E images associated with PD-L1 status in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 898.
Abstract 3885: A ubiquitin-specific proximity labeling method to study drug-induced ubiquitylation
Authors: Hai-Tsang Huang, Ryan J. Lumpkin, Ryan W. Tsai, Katherine A. Donovan, Shuyao Su, Xu Zhao, James Chen, Eric S. Fischer, William R. Sellers
Journal: Cancer Research (2024)

Abstract Targeted protein degradation is a promising therapeutic paradigm that offers new ways to disrupt protein functions. Currently, most studies that characterize the pharmacological effects of protein degraders utilize target-specific assays and global proteomics. However, information on the direct molecular consequence of protein degraders, i.e., induced protein ubiquitylation, is often lacking. Here we report the development of E-STUB (E3-substrate tagging by ubiquitin biotinylation), a ubiquitin-specific proximity labeling method that identifies ubiquitylated substrates in proximity to an E3 ligase of interest. We demonstrated that E-STUB can accurately identify the ubiquitylated targets induced by protein degraders in both CRBN and VHL systems—two of the most utilized E3 ligases by heterobifunctional degraders—and is likely generalizable to other E3 ligases. While we observed a high level of consistency between ubiquitylation and degradation for the induced substrates, E-STUB also detected ubiquitylation of non-degraded targets, providing novel and complementary insights to global proteomics. We also envision that E-STUB could be specifically used for the development of chemical inducers of proximity that catalyze non-degradative ubiquitylation events. In summary, we expect that the E-STUB approach can be widely useful for studying the principles of chemically induced ubiquitylation and the advancement of targeted protein degradation. Citation Format: Hai-Tsang Huang, Ryan J. Lumpkin, Ryan W. Tsai, Katherine A. Donovan, Shuyao Su, Xu Zhao, James Chen, Eric S. Fischer, William R. Sellers. A ubiquitin-specific proximity labeling method to study drug-induced ubiquitylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3885.