tbuckley/cabot-search huggingface dataset:
Abstract 346: Trop-2 induces apoptosis via transcriptional activation of TRAIL, FAS-FASL, CD40-TNFRSF5
Authors: Saverio Alberti, Emanuela Guerra, Antonino Moschella, Martina Ceci, Ludovica Pantalone, Roberta Di Pietro, Marco Trerotola
Journal: Cancer Research (2024)

Abstract Trop-2 is a transmembrane signal transducer that activates cancer growth and metastatic diffusion (1). However, this does not occur in all tumor types, as Trop-2 is associated to better disease outcome in some cancers, e.g. breast and lung tumors. A prototypic pattern of Trop-2 expression in normal multistratified epithelia, e.g. epidermis, esophagus, is that of preferential expression in non-proliferating, terminally differentiated cells. The corresponding expression gradient parallels that of induction of programmed cell death, e.g. in the corneum layer of skin keratinocytes. This led us to explore Trop-2 function as a trigger of apoptosis. We thus assessed NS-0 myeloma Trop-2 transfectants for apoptosis induction by dynamic cell morphometry and quantification of membrane blebbing and cell fragmentation. This was shown to be preceded by phosphatidyl-serine membrane exposure, and was followed by nuclear pyknosis and karyorrhexis. DNA fragmentation was shown by TUNEL and DNA laddering, and was accompanied by a dramatic increase of apoptotic death of Trop-2-expressing cells. Transcriptomic analysis at early time points of apoptosis induction indicated overexpression of TRAIL, FAS/FASL and CD40/TNFRSF5 transmembrane death receptors. This paralleled upregulation of downstream death-inducing signaling complex components and of executioner Caspases 8 and 3, suggesting Trop-2 as a trigger of extrinsic apoptosis pathways. Apoptosis induction translated into diminished tumor growth in vivo, which was shown to be proportional to Trop-2 expression levels. However, apoptosis induction was found to parallel stimulation of NS-0 cell growth and of defence mechanisms from apoptosis, as increased levels of inhibitory transcription factors, Rb-binding protein, survivin, Myd-118. These findings suggest a previously unappreciated balance between stimulation of cell growth and triggering of cell death by Trop-2, and may pave the way for selective anticancer therapy approaches in Trop-2-expressing cancers.(1) Trerotola M. et al., Neoplasia 23: 415-428 (2021). Citation Format: Saverio Alberti, Emanuela Guerra, Antonino Moschella, Martina Ceci, Ludovica Pantalone, Roberta Di Pietro, Marco Trerotola. Trop-2 induces apoptosis via transcriptional activation of TRAIL, FAS-FASL, CD40-TNFRSF5 [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 346.
Abstract 1748: Dearth of smoking-induced mutations in oncogene-driven NSCLCs despite smoking exposure
Authors: Chen-Yang Huang, Nanhai Jiang, Meixin Shen, Gillianne Lai, Aaron C. Tan, Amit Jain, Stephanie P. Saw, Mei-Kim Ang, Quan Sing Ng, Darren Wan-Teck Lim, Ravindran Kanesvaran, Eng-Huat Tan, Wan Ling Tan, Boon-Hean Ong, Kevin L. Chua, Devanand Anantham, Angela Takano, Tony KH Lim, Wai Leong Tam, Ngak Leng Sim, Anders J. Skanderup, Daniel S.W. Tan, Steven G. Rozen
Journal: Cancer Research (2024)

Abstract Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET, and fusions involving ALK and RET. We term these “non-smoking-related oncogenes” (NSROs). NSRO-driven tumors account for approximately half of NSCLCs in East Asia, and, alarmingly, their age-adjusted incidence is increasing for unknown reasons. In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers. However, the clonal architecture and genomic landscape of these tumors remain largely unexplored. Here, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. Overall, NSRO-driven NSCLCs in smokers and non-smokers had similar genomic landscapes and clonal architectures that were distinct from those in typical-smoking NSCLCs. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs. We confirmed this unexpected finding in two large NSCLC data sets from other geographic regions. However, we observed differences in the tumor transcriptomes of NSRO-driven NSCLCs in smokers and non-smokers, with tumors in smokers displaying higher transcriptomic activities related to regulation of the cell cycle. This suggested that smoking does have an impact on tumor phenotype in NSCRO-driven NSCLC, likely through non-genetic mechanisms. We concluded that NSRO-driven NSCLCs, whether in non-smokers or smokers, constitute an important disease entity that is very different from typical-smoking NSCLC. Citation Format: Chen-Yang Huang, Nanhai Jiang, Meixin Shen, Gillianne Lai, Aaron C. Tan, Amit Jain, Stephanie P. Saw, Mei-Kim Ang, Quan Sing Ng, Darren Wan-Teck Lim, Ravindran Kanesvaran, Eng-Huat Tan, Wan Ling Tan, Boon-Hean Ong, Kevin L. Chua, Devanand Anantham, Angela Takano, Tony KH Lim, Wai Leong Tam, Ngak Leng Sim, Anders J. Skanderup, Daniel S.W. Tan, Steven G. Rozen. Dearth of smoking-induced mutations in oncogene-driven NSCLCs despite smoking exposure [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 1748.
Abstract 1868: Target-dependent considerations for the design of bispecific T-cell engagers
Authors: Matt Mai, Raffi Tonikian, Peter Bergqvist, Alaa Amash, Nathalie Blamey, Gabrielle Conaghan, Valentine de Puyraimond, Patrick Farber, Allison Goodman, Ahn Lee, Jessica Fernandes Scortecci, Cindy-Lee Crichlow, Akram Khodabandehloo, Tova Pinsky, Kate Caldwell, Jessica Patterson, Philippe Pouliot, Davide Tortora, Oscar Urtatiz, Ping Xiang, Irene Yu, Kirstin Brown, Kelly Bullock, Andrea Chee, Stephanie K. Masterman, Neil Aubuchon, Lindsay Devorkin, Bryan C. Barnhart, Tim Jacobs
Journal: Cancer Research (2024)

Abstract In this study, we present data from four T-cell engager (TCE) programs in which we leveraged our highly diverse CD3-binding antibodies to generate functional bispecifics for each tumor target. By aggregating tumor-cell killing and cytokine data across four tumor targets with different properties and target expression levels, we have gained novel insights into target-specific considerations for the development of CD3 TCEs. TCEs recapitulate a synapse between T cells and target cells. T cell function downstream of this synapse is determined by the complex interplay between multiple independent factors. These include properties of the CD3- and tumor-binding arms, such as binding kinetics and epitope, as well as target-dependent factors such as cell type and target density. We used our diverse CD3 antibodies to engineer bispecific TCEs against four solid tumor targets: PSMA, B7-H4, 5T4, and the peptide-MHC target MAGE-A4. For each target, we engineered and characterized hundreds of bispecific molecules using high-throughput assays, including T-cell dependent tumor-cell killing, cytokine release, developability assessments, and structural studies. Here, we compare data from across these programs to elucidate the impact of target-dependent parameters on TCE function. These data provide important insights for the selection of appropriate TCE targets and efficient design of bispecific antibodies with high therapeutic potential. Citation Format: Matt Mai, Raffi Tonikian, Peter Bergqvist, Alaa Amash, Nathalie Blamey, Gabrielle Conaghan, Valentine de Puyraimond, Patrick Farber, Allison Goodman, Ahn Lee, Jessica Fernandes Scortecci, Cindy-Lee Crichlow, Akram Khodabandehloo, Tova Pinsky, Kate Caldwell, Jessica Patterson, Philippe Pouliot, Davide Tortora, Oscar Urtatiz, Ping Xiang, Irene Yu, Kirstin Brown, Kelly Bullock, Andrea Chee, Stephanie K. Masterman, Neil Aubuchon, Lindsay Devorkin, Bryan C. Barnhart, Tim Jacobs. Target-dependent considerations for the design of bispecific T-cell engagers [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 1868.
Abstract 6961: The cell adhesion molecule ninjurin 2 modulates tumorigenesis, inflammatory response and metabolism via modulating and pyroptosis
Authors: Jin Zhang, Weici Zhang, Xinbin Chen
Journal: Cancer Research (2024)

Abstract The nerve injury induced protein 2 (NINJ2) belongs to a family of homophilic adhesion molecules and was initially found to be involved in nerve regeneration. However, the role of NINJ2 in other cellular process are not well studied. Here, by generating a Ninj2-deficient mouse model, we showed that mice deficient in Ninj2 have a short lifespan and are prone to spontaneous tumors, systemic inflammation and metabolic defects. To better understand the metabolic traits that contributes to these phenotypes, we performed comprehensive carbohydrate and lipid metabolic analyses. Indeed, carbohydrate metabolic analyses indicated that NINJ2-deficiency led to defects in monosaccharide metabolism along with accumulation of multiple disaccharides and sugar alcohols. Similarly, lipidomic analyses indicated that Ninj2 deficiency altered patterns of several lipids including triglycerides, phospholipids and ceramides. To identify a cellular process that associate with these metabolic defects, we examined the role of Ninj2 in pyroptosis, a programmed cell death that links cancer, inflammation and metabolic disorders. Indeed, we found that loss of NINJ2 promotes pyroptosis by activating the NLRP3 inflammasome. Taken together, these data reveal a critical role of NINJ2 in tumorigenesis, inflammatory response, and metabolism via modulating pyroptosis. Citation Format: Jin Zhang, Weici Zhang, Xinbin Chen. The cell adhesion molecule ninjurin 2 modulates tumorigenesis, inflammatory response and metabolism via modulating and pyroptosis [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 6961.
Abstract 317: Using the Biomek NGeniuS Next Generation Library Prep System to automate the Illumina TruSight Oncology 500 assay
Authors: Zach Smith
Journal: Cancer Research (2024)

Abstract Cancer researchers using next generation sequencing (NGS) need reliable sample preparation methodologies that generate high-quality, sequence-ready libraries from often-challenging samples. This process can be aided using automated liquid handling systems. The Biomek NGeniuS Next Generation Library Prep System from Beckman Coulter Life Sciences is a reliable, easy-to-use, purpose-built liquid handler for NGS library preparation ideal for laboratories requiring more flexibility and less hands-on time. The user-friendly software requires no programming skills, making it easy to set up and run. Biomek NGeniuS Next Generation Library Prep System’s hardware features include an on-deck thermal cycler, gripper, temperature-controlled reagent storage, and high-density tip storage which reduces user interventions and enables more walkaway time. An extensive and growing library of complimentary demonstrated NGS sample prep protocols allows the user to select from a variety of applications for NGS workflows. One such workflow is Illumina TruSight Oncology 500 assay, which represents a comprehensive NGS assay targeting the full coding regions of 523 genes implicated in the pathogenesis of solid tumors. Using enrichment-based library preparation techniques for use with formalin-fixed, paraffin-embedded (FFPE) samples, the Illumina TruSight Oncology 500 assay, when running the DNA Only workflow, can detect single nucleotide variants (SNVs), indels, amplifications, and multinucleotide variants (MNVs) in a single sequencing run. The Illumina TruSight Oncology 500 assay also detects immunotherapy biomarkers for tumor mutational burden (TMB) and microsatellite instability (MSI) in DNA samples. The Illumina TruSight Oncology 500 assay also offers a combined RNA/DNA workflow that also allows for the assessment of fusion events. In this poster, we show the utility of the Biomek NGeniuS Next Generation Library Prep System to perform the Illumina TruSight Oncology 500 assay, which saves researchers valuable hands-on time and offers a highly streamlined setup process for users new to liquid handling automation. Confidential - Company Proprietary Citation Format: Zach Smith. Using the Biomek NGeniuS Next Generation Library Prep System to automate the Illumina TruSight Oncology 500 assay [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 317.
Abstract 1681: Characterizing signaling and localization of Daple-FLT3 gene fusion in leukemia cells
Authors: Michael Acquazzino, Jason Ear
Journal: Cancer Research (2024)

Abstract Receptor tyrosine kinases (RTKs) are cell surface receptors that regulate cell survival, cell proliferation, and cell migration upon ligand binding. Genetic mutations leading to hyperactivation of RTKs are often seen in cancer and allow signaling pathways to be constitutively active. In some hematological malignanices, the coiled-coil domain (CCD) of Daple, a cell signaling scaffold protein, has been found in gene fusions with the RTKs FLT3 and PDGFRB, and to the intracellular kinase JAK2. It is hypothesized that this gene fusion product causes the tyrosine kinase domain of FLT3 to become activated and mislocalizes in the cell, leading to rampant cell signaling of either the MAPK, AKT, and STAT5 signal transduction cascades. Using fluorescently tagged Daple-FLT3, it was shown that the gene fusion product is subcellularly localizes to the peri-centrosome space across all leukemia cell lines tested. Ectopic expression demonstrated activation of the kinase domain and subsequent increases in phosphorylation of STAT5α and AKT, but no significant increase in the phosphorylation of MAPK was observed. Further investigation is needed to identify direct substrates of the Daple-FLT3 gene fusion and transcriptional changes. Identifying the direct kinase substrates and insights gained through understanding the gene fusion localization, affects on cell signaling, and changes in gene expression, may unveil novel therapeutic strategies into targeting this protein in cancer. Citation Format: Michael Acquazzino, Jason Ear. Characterizing signaling and localization of Daple-FLT3 gene fusion in leukemia 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 1681.
Abstract 7293: Serum fusion gene transcripts to predict liver cancer
Authors: Jian-Hua Luo, Yan-Ping Yu, Silvia Liu, David Geller
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is the most common type of liver cancers and one of the most lethal malignancies for human. Early diagnosis of HCC is crucial in reducing the mortality of the disease. In this report, we analyzed a panel of 9 fusion transcripts in the serum samples from 136 individuals (61 HCC patients and 75 individuals without HCC) using TaqMan qRT-PCR. Our results showed that 7 fusion genes were frequently detected in the serum samples of HCC patients, including MAN2A1-FER (100%), SLC45A2-AMACR (62.3%), ZMPSTE24-ZMYM4 (62.3%), Pten-NOLC1 (57.4%), CCNH-C5orf30 (55.7%), STAMBPL1-FAS (26.2%) and PCMTD1-SNTG1 (16.4%). We then divided the samples into training and testing cohorts based on the sample collection time: 82 individuals with samples collected before 2016 as the training cohort while 54 individuals with sample collected after 2015 as the testing cohort. Machine learning models was constructed based on the combination of different fusion genes with various cutoffs to predict the occurrence of HCC in the training cohort using leave-one-out-cross-validation approach. One of the machine learning models called 4-fusion genes logistic regression model (MAN2A1-FER&amp;lt;40, CCNH-C5orf30&amp;lt;38, SLC45A2-AMACR&amp;lt;41, Pten-NOLC1&amp;lt;40) produced a 91.5% accuracy, with a sensitivity of 87.1% and specificity of 94.1% in the training cohort. The same model generated an accuracy of 83.3%, with a sensitivity of 73.3% and specificity of 95.8% in testing cohort. When the training and testing cohorts were combined, the model produced an accuracy of 86%. When serum α-fetal protein (AFP) level was incorporated into the machine learning model, we found a 2-fusion gene+AFP logistic regression model (MAN2A1-FER&amp;lt;40, CCNH-C5orf30&amp;lt;38, AFP) generated an accuracy of 94.8% in the training cohort with a sensitivity of 93.5% and specificity of 96.3%. The same model generated 95% accuracy in both the testing cohort and the combined cohorts in the validation. Cancer treatment reduced most of the serum fusion transcript levels, reflecting the reduction of the tumor load. As a result, serum fusion gene machine learning models may serve as important tools in screening HCC and monitoring the impact of HCC treatment. Citation Format: Jian-Hua Luo, Yan-Ping Yu, Silvia Liu, David Geller. Serum fusion gene transcripts to predict liver 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 7293.
Abstract 5991: Improved venetoclax therapy by a novel conjugate with artemisinin by NOXA-mediated reduction of Mcl-1 and cyclin D1 protein in myeloid leukemia cells
Authors: Jingyi Zhang, Zhenwei Zhang, Samuel Waxman, Linxiang Zhao, Yongkui Jing
Journal: Cancer Research (2024)

Abstract Evasion of apoptosis is crucial for the growth, survival and chemoresistance of myeloid leukemia. The Bcl-2 selective inhibitor venetoclax is the only apoptosis inducer approved for clinical use. Venetoclax in combination with hypomethylating agents or low-dose cytarabine has now become the standard care for elderly AML patients. However, a sizeable fraction of patients are either refractory to venetoclax combination therapy or ultimately relapse. High or induced expression of Mcl-1 and Bcl-xL mediates venetoclax resistance. Previously we reported that artemisinin enhances venetoclax apoptosis induction by degrading Mcl-1 through NOXA induction. We designed a novel conjugate A1 of venetoclax with dihydroartemisinin. A1 shows dual functions of inhibiting Bcl-2 and inducing NOXA. A1 treatment releases Bim from both Bcl-2 and Mcl-1, further degrades Mcl-1 protein, and presents ten-fold stronger apoptotic induction ability in venetoclax insensitive cells. Acquired increase of Mcl-1 protein was observed in venetoclax resistant MOLM-13/VEN cells, which are sensitive to A1-induced apoptosis. In Bcl-xL expressing venetoclax refractory leukemia cells A1 obtains a new mechanism of inhibiting cell cycling by downregulating cyclin D1 through a new NOXA/cyclin D1 cascade, mediated through the endoperoxide moiety of artemisinin and intracellular iron, independent of Bcl-2 inhibition. We reveal a new compound A1 overcoming venetoclax resistance by NOXA-mediated degradation of Mcl-1 and cyclin D1 protein. Citation Format: Jingyi Zhang, Zhenwei Zhang, Samuel Waxman, Linxiang Zhao, Yongkui Jing. Improved venetoclax therapy by a novel conjugate with artemisinin by NOXA-mediated reduction of Mcl-1 and cyclin D1 protein in myeloid leukemia 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 5991.
Abstract 3470: Evaluation of the association between sickle cell disease and breast cancer using the <i>All of Us</i> Research Program dataset
Authors: Ivan T. Jubilee, Lauren K. Evans, KiTani Parker Lemieux
Journal: Cancer Research (2024)

Abstract Background: The All of Us Research Program (AoURP) dataset was used to evaluate pharmacological treatment modalities in patients with both breast cancer (BC) and sickle cell disease (SCD). This study aims to identify treatment strategies for sickle cell patients with BC that may inform improved treatment options for patients living with either or both conditions, as there is an imminent need in this patient population. Methods: We investigated the relationship between SCD and BC using the AoURP dataset. Criteria were female patients with a confirmed diagnosis of concomitant SCD and BC were selected. Hematologic, antineoplastics, and immunomodulating agents prescribed to patients were identified. Analysis was conducted in a Jupyter Notebook environment by way of R. Using FDA-approved and off-label indications, medication use patterns were used to reverse-engineer patient information and identify trends between SCD and BC. Results: Nine female patients had concomitant diagnoses of SCD and BC, which aligned with the inclusion criteria. African Americans were significantly represented in this cohort, making up sixty-seven of patients. Twenty-two percent of patients did not indicate race, while eleven percent of patients identified as Caucasian. All patients included in the study were prescribed anemic therapy. Eleven percent of patients were prescribed an FDA-approved medication for SCD. Seventy-eight percent of patients were prescribed hormone-targeted BC medications. Thirty-three percent of patients were prescribed the immunotherapy regimen, Dinutuximab with adjunctive interferon-alpha. Eleven percent of patients were prescribed cytotoxic therapy. Conclusion: Further investigation is warranted for dinutuximab use in BC treatment, specifically the triple negative subtype, as currently no targeted therapeutic options exist, and prognosis is poor. The data suggests dinutuximab with adjunctive interferon-alpha may be promising for triple-negative BC patients with SCD. Citation Format: Ivan T. Jubilee, Lauren K. Evans, KiTani Parker Lemieux. Evaluation of the association between sickle cell disease and breast cancer using the All of Us Research Program dataset [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 3470.