tbuckley/cabot-search huggingface dataset:
Abstract 2315: AI-enabled precision oncology era: Advanced and interactive interpretation of next-gneneration sequencing (NGS) reports
Authors: Hui Chen, Zanmei Xu, Lijuan Chen, Mingmin Wang, Peng Zhang, Fei Pang, Kai Wang
Journal: Cancer Research (2024)

Abstract Background: Next-generation sequencing (NGS) has been widely adopted in clinical practice, but there are still unmet needs among physicians regarding the interpretation and application of NGS reports. These needs include selecting multi-targeted and combination therapies, keeping up with evolving treatment options and clinical trial results, and incorporating personalized medicine based on real clinical cases. Methods: To address these challenges, we propose using large language model (LLM) to analyze and interpret clinical questions, perform semantic searches in a high-quality database, and provide customized prompts and logical outputs. Our knowledge base includes diagnostic and treatment details for 600+ tumor subtypes, 620,000+ entries, 2,000+ drug details, and 440,000+ clinical trials. The database is updated automatically using a fact engine and medical literature sources. Personalized gene interpretation is incorporated using pretraining, cosine similarity, and context learning prompts. Results: Our tool, named "SmartMTB", enables personalized interpretation of genomic testing reports for precision oncology. Users input the latest clinical features using a selection-based or question-and-answer approach. The tool identifies the treatment stage and genomic variations, provides information on mutation frequencies, sensitivity and resistance of targeted and immunotherapies, and priority selection strategies for multi-gene mutations. It matches similar clinical cases and provides real-time updates on treatment options and clinical trial literature. It also facilitates patient matching for clinical trials and considers economic factors. Conclusion: We present a groundbreaking artificial intelligence (AI) tool in cancer care that revolutionizes precision oncology. This AI system, trained on extensive datasets, swiftly and accurately analyzes and interprets complex genomic and clinical data. It enables clinicians to make informed decisions about personalized treatment strategies, significantly improving patient outcomes in cancer therapy. Citation Format: Hui Chen, Zanmei Xu, Lijuan Chen, Mingmin Wang, Peng Zhang, Fei Pang, Kai Wang. AI-enabled precision oncology era: Advanced and interactive interpretation of next-gneneration sequencing (NGS) reports [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 2315.
Abstract 4200: A novel 3D culture platform, <i>E-slice</i>, retains intact tumor microenvironment and tumor infiltrating immune cells
Authors: Viridiana Leyva-Aranda, Thomas Gallup, Jose Maldonado, Corina Margain, Sang Yun, David Gallup, Min Kim, Kyuson Yun
Journal: Cancer Research (2024)

Abstract Human cancer tissue is a complex ecosystem with heterogeneous cell types that communicate with each other dynamically to promote tumor progression and immune evasion. Hence, experimental systems that destroy or select for cancer cells in culture have often failed to accurately predict clinical responses of new drugs. Therefore, a technology that can retain the intact tumor microenvironment (TME) and accurately predict cancer patient’s response to anti-cancer treatments, including immunotherapies, will greatly benefit patients and dramatically reduce the cost of new drug development. E-slice is a proprietary 3D human tumor culture platform that maintains individual patient tumor’s unique ecosystem and the TME ex vivo for up to 30 days. It is generated by making thin sections of intact, fresh tumor tissues and culturing them in serum-free, defined media. As such, immune components and the TME in E-slices faithfully recapitulate human tumors ex vivo. We demonstrate that E-slices can be used to: 1) measure viability changes upon anti-cancer agent treatment longitudinally; 2) retain the native TME and tissue architecture since E-slices are never dissociated or artificially reconstituted; 3) culture any solid tumor types from patient needle biopsy cores or surgical samples, PDX, or mouse models; 4) perform high content drug screening on human tissues; 5) discover secreted biomarkers and to 6) discover or validate molecular mechanisms of action or therapy resistance; and 7) measure immunotherapy responses ex vivo from human tissues. Importantly, it has been shown to accurately predict individual patient treatment responses to chemotherapies and targeted therapies in 4-8 days, paving the way for evidence-based personalized treatment selections in a clinically actionable time frame. Furthermore, single cell RNA-sequencing analysis demonstrates that E-slices can retain the viability and molecular phenotypes of tumor infiltrating immune cells for up to 8 days ex vivo, providing a unique platform to study human tumor-immune interactions and evaluate efficacy of immune modulators on human tumor tissues ex vivo. Citation Format: Viridiana Leyva-Aranda, Thomas Gallup, Jose Maldonado, Corina Margain, Sang Yun, David Gallup, Min Kim, Kyuson Yun. A novel 3D culture platform, E-slice, retains intact tumor microenvironment and tumor infiltrating immune cells [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 4200.
Abstract 4786: Colorectal cancer screening rates among deaf, deafblind, and hard of hearing adults aged 45 to 75 years old
Authors: Regina M. Wang, Sowmya R. Rao, Erika J. Bergeron, Emmanuel C. Perrodin-Njoku, Poorna Kushalnagar
Journal: Cancer Research (2024)

Abstract Background: Deaf, deafblind, and hard of hearing (DDBHH) individuals who use American Sign Language (ASL), a subpopulation of the disability, experience disparities concerning cancer screening and cancer-related health outcomes. For this study, we explored colorectal cancer screening rates among DDBHH survey respondents in comparison to rates found in the hearing population. Materials and Methods: Using the National Cancer Institute Health Information National Trends Survey in ASL (Kushalnagar et al., 2015), we surveyed participants 18+ years old using the Center for Deaf Health Equity at Gallaudet University’s database of over 2,500 DDBHH participants from all over the USA, including Hawaii and Puerto Rico. We used the U.S. Preventive Services Task Force (USPSTF) guidelines’ age cutoffs to assess adherence to colorectal cancer screenings. Results: Survey response rate within three weeks of mail out in July 2023 was 12%. A total of 405 DDBHH adult participants answered screening questions for colorectal cancer in ASL and English. Overall, 43.7% self-reported screening adherence for age-eligible (45-75 years) colorectal cancer screening; 54.7% reported never having a colorectal cancer screening. Similarly-aged hearing adults reported 58.7% adherence in the English version of the National Health Interview Survey (NHIS). Discussion: With the 43.7% adherence rate, the DDBHH community is lagging behind colorectal cancer screenings compared to the general population of hearing adults. Estimating the colorectal cancer screening rates among the DBHH community and understanding the reasons for these existing disparities is important to achieve screening adherence of 68.3%, the target set by the Healthy People 2030. Such research will aid the Center for Deaf Health Equity to actively work with the community to improve strategies to increase colorectal cancer screening. Citation Format: Regina M. Wang, Sowmya R. Rao, Erika J. Bergeron, Emmanuel C. Perrodin-Njoku, Poorna Kushalnagar. Colorectal cancer screening rates among deaf, deafblind, and hard of hearing adults aged 45 to 75 years old [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 4786.
Automatic multi-view pose estimation in focused cardiac ultrasound
Authors: João Freitas, João Gomes-Fonseca, Ana Claudia Tonelli, Jorge Correia-Pinto, Jaime C. Fonseca, Sandro Queirós
Journal: Medical Image Analysis (2024)

Focused cardiac ultrasound (FoCUS) is a valuable point-of-care method for evaluating cardiovascular structures and function, but its scope is limited by equipment and operator's experience, resulting in primarily qualitative 2D exams. This study presents a novel framework to automatically estimate the 3D spatial relationship between standard FoCUS views. The proposed framework uses a multi-view U-Net-like fully convolutional neural network to regress line-based heatmaps representing the most likely areas of intersection between input images. The lines that best fit the regressed heatmaps are then extracted, and a system of nonlinear equations based on the intersection between view triplets is created and solved to determine the relative 3D pose between all input images. The feasibility and accuracy of the proposed pipeline were validated using a novel realistic in silico FoCUS dataset, demonstrating promising results. Interestingly, as shown in preliminary experiments, the estimation of the 2D images' relative poses enables the application of 3D image analysis methods and paves the way for 3D quantitative assessments in FoCUS examinations.
Abstract 124: Validation of humanized TL1A mice for advancing preclinical research
Authors: Chong Li, Shujin Zhang, Zhi Zhang, Jia Feng, James Jin, Yibo Du
Journal: Cancer Research (2024)

Abstract TL1A, or Tumor Necrosis Factor-Like Ligand 1A, plays a pivotal role in regulating the immune system and has garnered considerable attention in the field of cancer research. Studies have shown that TL1A can impact the tumor microenvironment via inflammatory signaling, immunosuppression, and tumor growth and survival. Targeting TL1A or its downstream effects could offer new avenues for cancer treatment and immunotherapy. To this end, we generated a human TL1A knock-in (B-hTL1A) mouse model. Human TL1A gene expression in B-hTL1A mice was confirmed by RT-PCR. TL1A protein expression was not altered following TL1A humanization in B-hTL1A mice as shown by flow cytometry. Lastly, soluble human TL1A was detected in B-hTL1A mice by ELISA. Due to the purported role of TL1A in mucosal immunity, efforts to induce inflammatory bowel disease in this humanized model are currently underway. Taken together, we established a preclinical B-hTL1A mouse model for the evaluation of TL1A-targeted immunotherapy. Citation Format: Chong Li, Shujin Zhang, Zhi Zhang, Jia Feng, James Jin, Yibo Du. Validation of humanized TL1A mice for advancing preclinical research [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 124.
Abstract 4216: Indication agnostic evaluation of CAR T cell function using patient-derived immunocompetent tumoroid modelling platform
Authors: Damieanus O. Ochola, Huckie Dell Mundo, Preethi Samuel, Natalia Korkorina, Bhuvanesh Dave
Journal: Cancer Research (2024)

Abstract Introduction: Engineered T cells redirected towards tumor-specific cytotoxicity is a promising immunotherapeutic modality that has been well characterized for efficacy against B cell malignancies and evaluated in multiple tumor types. However, the development and optimization of CAR T cell therapies requires a rigorous preclinical model for the evaluation of CAR T cell function, tumor killing, cytokine production, and memory responses. Experimental Procedure: We are evaluating our model platform Custom Organoid Modelling Platform for Accurate and Speedy SolutionS (COMPASS 2) as a comprehensive platform for testing developmental and functional stages of CAR T cells including activation, memory, and exhaustion. We are performing qualitative and quantitative analyses of surface markers to recapitulate the complexity of human cancer. Additionally, since CAR T cells mediate crosstalk with other immune components in the TME, we also evaluate and monitor the presence of B cells, NK cells, macrophages, and endogenous T cells. Triple Negative Breast Cancer (TNBC); Immunophenotyping (IP); Immunofluorescence (IF); Fluorescence Activated Cell Sorting (FACS); T regulatory (Treg). Summary of Results: Our evaluation of COMPASS 2 for functional testing of CAR T cells demonstrates the feasibility of the platform in preclinical CAR T cell evaluation. We showed T cell infiltration and analyzed cytokine production that may alter tumor cells and TME. Crosstalk with other immune cells will be evaluated. We are currently evaluating the tumor volume changes using an EGFRvIII-targeted CART cell therapy on TNBC model systems, followed by apoptosis and EGFR analysis using FACS. Conclusion: Our COMPASS 2 model platform enables studies that require recapitulating hurdles to CAR therapy, including antigen escape, T cell dysfunction and trafficking; to reveal an essential role of the endogenous immune response mediating the antitumor effect following CAR therapy. Citation Format: Damieanus O. Ochola, Huckie Dell Mundo, Preethi Samuel, Natalia Korkorina, Bhuvanesh Dave. Indication agnostic evaluation of CAR T cell function using patient-derived immunocompetent tumoroid modelling platform [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 4216.
Abstract 4244: Clinical response assessment of immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer using a T cell organoid coculture system
Authors: Ju Hee Oh, Eun Hye Choi, Ji Eun Lee, Eun Ji Nam
Journal: Cancer Research (2024)

Abstract Endometrial cancers with the mismatch repair deficiency (MMR-D) phenotype exhibit characteristics such as an increased burden of tumor mutations and the presence of tumor-infiltrating lymphocytes (TILs) involved in tumor invasion. While monotherapy using immune checkpoint inhibitors (ICIs) has shown clinical improvement in MMR-D endometrial cancer (EC), observed response rates ranging from 30% to 50% suggest the existence of inherent resistance mechanisms. One notable feature of MMR-D tumors is the high proportion of tumor-infiltrating lymphocytes (TILs) encompassing various lymphocytes with diverse effects on immune interactions. Therefore, we aim to assess the feasibility of a self T-cell-tumor organoid co-culture platform for individual MMR-D endometrial cancer patients. We provide evidence that co-culturing self-tumor organoids with peripheral blood lymphocytes can be utilized to evaluate ICI responsiveness in MMR-D endometrial cancer patients. The application of a specific T-cell organoid co-culture platform to a cohort of patient resistant to monotherapy ICIs offers a means to anticipate the timing for minimal immunotherapeutic intervention and the appropriate timing for combination therapy. Citation Format: Ju Hee Oh, Eun Hye Choi, Ji Eun Lee, Eun Ji Nam. Clinical response assessment of immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer using a T cell organoid coculture system [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 4244.
Abstract 1970: Discovery and characterization of potent and selective HER2 exon20 insertion mutant inhibitors
Authors: Ho Yeon Nam, Sun Young Jang, Jiyoung Jeon, HyungSeok Yoo, Jooyun Byun, Gunwoo Lee, Youngjoo Lee, Yu-Yon Kim, Soye Jeon, Young Gil Ahn
Journal: Cancer Research (2024)

Abstract Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for over 85% of all cases. Among NSCLC, approximately 2-4% of patients have mutations in the HER2, a member of the ErbB family of receptor tyrosine kinases and key proliferation driver, with exon 20 insertions making up about 90% of these mutations. HER2 exon mutations can have various alterations, and among them, the most common HER2 mutation is in-frame insertions in exon 20, especially the A775_G776insYVMA insertion/duplication. These mutations can affect the structure and function of the HER2 protein and may contribute to tumor development and growth. HER2 mutations have often shown resistance to EGFR tyrosine kinase inhibitors (TKIs), further highlighting the need for HER2-specific treatments. Also, inhibitors targeting HER2 mutations are selective, meaning they specifically target HER2 alterations without causing toxicities or affecting EGFRWT. Therefore, there is a need for the development of selective HER2 exon20 insertion mutant inhibitors. Herein, Hanmi has identified selective HER2 exon20 insertion mutant small molecule inhibitors, designed based on affinity and binding mode starting from a known crystal structure using GLIDE (Schrödinger), and the screening for the viability of cell lines including HER2A775_G776insYVMA, HER2G776delinsVC , HER2WT and EGFRWT was investigated. Hanmi's HER2 exon20 insertion mutant inhibitors selectively target mutant HER2 receptor tyrosine domains through shared binding, sparing EGFRWT and minimizing EGFR-related toxicities. With highly selectivity against EGFRWT and desirable pharmacokinetic properties, the Hanmi compounds inhibit HER2 mutant cells and HER2 mutant enzymes. Additionally, the compounds have an oral administration-compatible DMPK profile and demonstrated anti-tumor activity in HER2 mutant and HER2WT tumor xenograft mice. In conclusion, based on our study, Hanmi compounds, a novel HER2 exon20 insertion mutant inhibitors could be suggested as an appropriate therapeutic agent for inhibitory activity against HER2 exon20 insertion mutant NSCLC. Citation Format: Ho Yeon Nam, Sun Young Jang, Jiyoung Jeon, HyungSeok Yoo, Jooyun Byun, Gunwoo Lee, Youngjoo Lee, Yu-Yon Kim, Soye Jeon, Young Gil Ahn. Discovery and characterization of potent and selective HER2 exon20 insertion mutant inhibitors [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 1970.
Abstract 1988: Mass spectrometry profiling identifies ENO2 as a driver of lenvatinib resistance in hepatocellular carcinoma
Authors: Sukbum Kim, Jia-Jian Loh, Huajian Yu, Ki-Fong Man, Kai-Yu Ng, Terence Kin-Wah Lee, Clive Yik-Sham Chung, Stephanie Ma
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, and lenvatinib is a multi-kinase inhibitor approved by the FDA as a first-line drug for advanced HCC since 2018. Lenvatinib demonstrated antitumor activity with a higher objective response rate, longer progression-free survival, and time to progression in a non-inferiority trial compared with sorafenib. However, the clinical benefits of lenvatinib remain limited as acquired resistance to lenvatinib during HCC treatment is inevitable. This highlights the need to understand the molecular mechanisms of lenvatinib resistance and to explore new therapeutic approaches to overcome this resistance. Tumor lineage plasticity, a recognized hallmark of cancer, is a phenomenon in which tumor cells dedifferentiate into a more stemness state to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the mechanism by which cellular plasticity contributes to lenvatinib resistance remains elusive. In this study, we employed proteomic mass spectrometry to investigate altered proteins in two pairs of parental lenvatinib-sensitive and their corresponding trained lenvatinib-resistant HCC cell lines. This analysis revealed that upregulation of enolase 2 (ENO2), a glycolytic enzyme that catalyzes the dehydration and conversion of 2-phosphoglycerate to phosphoenolpyruvate, is a critical contributor. ENO2 upregulation is frequently observed in HCC and is strongly correlated with aggressive clinical features, including poor survival, advanced tumor stage, and poor differentiation status. We further showed that ENO2 upregulation in HCC is positively correlated with stemness and hepatic progenitor marker signatures, as well as hypoxia, and subsequently demonstrated that ENO2 is regulated by hypoxia/HIF-1α, with hypoxia response element sequences located in the ENO2 promoter region. Research is underway to investigate the functional role and underlying molecular mechanisms associated with ENO2-driven lenvatinib resistance and cellular plasticity in HCC. Citation Format: Sukbum Kim, Jia-Jian Loh, Huajian Yu, Ki-Fong Man, Kai-Yu Ng, Terence Kin-Wah Lee, Clive Yik-Sham Chung, Stephanie Ma. Mass spectrometry profiling identifies ENO2 as a driver of lenvatinib resistance in hepatocellular carcinoma [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 1988.
Abstract 1820: Investigating the anticancer effects and pharmacological mechanisms of phenanthridine Amaryllidaceae alkaloid in bladder cancer
Authors: Yu-Chi Su, Mei-Chuan Chen
Journal: Cancer Research (2024)

Abstract Bladder cancer (BC) ranks as the tenth most common malignancy worldwide. Despite the improved five-year survival rate of around 80% for bladder cancer patients, 25% of cases progress to muscle-invasive bladder cancer with associated metastases, leading to a notable five-year survival of 5%. This underscores the urgent clinical necessity for the development of novel therapeutic strategies in the management of bladder cancer. In this study, we demonstrate the anticancer potential of a phenanthridine Amaryllidaceae alkaloid (PAA), and investigate its underlying mechanisms in bladder cancer. The data demonstrates the selective cytotoxicity of PAA towards bladder cancer cells, revealing IC50 values of 2.47 μM in RT112 cells and 8.99 μM in normal uroepithelial SV-HUC-1 cells. Protein array analysis further showed that PAA attenuated phosphorylation of several kinases, which functions as critical regulators of cell survival and proliferation. PAA induces S phase retardation and increases the phosphorylation of ATM, potentially enhancing DNA damage capability. Furthermore, PAA induced apoptosis, as evidenced by the accumulation of sub-G1 cells and caspase activation. In summary, our findings demonstrate that PAA exerts diverse effects on cell cycle regulation and apoptosis. These results suggest that PAA holds promise as a potential candidate for the treatment of bladder cancer. Citation Format: Yu-Chi Su, Mei-Chuan Chen. Investigating the anticancer effects and pharmacological mechanisms of phenanthridine Amaryllidaceae alkaloid in bladder 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 1820.