tbuckley/cabot-search huggingface dataset:
Abstract 1688: Nuclear receptor coactivator SRC-1 promotes colorectal cancer immune escape by enhancing PD-L1 transcription and protein stability
Authors: Yilin Hong, Qiang Chen, Zinan Wang, Yong Zhang, Bei Li, Xu Kong, Pingli Mo, Nengming Xiao, Jianming Xu, Yunbin Ye, Chundong Yu
Journal: Cancer Research (2024)

Abstract Programmed death-ligand 1 (PD-L1), one of the immunosuppressive molecules, overexpresses in multiple cancers and is critical for their immune escape. We previously showed that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability; however, the role of SRC-1 in CRC immune escape is unclear. Here, we demonstrated that SRC-1 was positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibited PD-L1 expression in both human and murine CRC cells and retarded murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration and antitumor activity of effector CD8+ T cells. Genetic ablation of SRC-1 in mice also decreased PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models. Taken together, our findings highlight a crucial role of SRC-1 in facilitating CRC immune escape and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment. Citation Format: Yilin Hong, Qiang Chen, Zinan Wang, Yong Zhang, Bei Li, Xu Kong, Pingli Mo, Nengming Xiao, Jianming Xu, Yunbin Ye, Chundong Yu. Nuclear receptor coactivator SRC-1 promotes colorectal cancer immune escape by enhancing PD-L1 transcription and protein stability [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 1688.
Abstract 1554: <i>LIM Domain 7</i> (<i>LMO7</i>) splice variant influences prostate cancer biology
Authors: Muthana Al Abo, Daniel J. George, Zefeng Wang, Steven R. Patierno, Jennifer A. Freedman, Alice Jiang
Journal: Cancer Research (2024)

Abstract LIM Domain 7 (LMO7) has been shown to participate in cell-cell junction formation through interaction with afadin and α-actinin. It has also been reported to collaborate with Rho kinase to regulate actin filament formation and to activate the Rho-myocardin-related transcription factor serum response factor pathway. Additionally, LMO7 itself may function as a transcription factor, regulating the expression of genes involved in Epithelial Mesenchymal Transition (EMT). Alternative splicing of LMO7 has the potential to modulate its function. Previously, we reported LMO7 as a target that is alternatively spliced in prostate cancer (PCa) between self-reported Black and White patients. In addition, by analyzing expression of LMO7 splice variants in The Cancer Genome Atlas (TCGA) data, we previously reported increased expression of a LMO7 splice variant skipping exon 12 in breast, lung and liver cancer compared with paired normal tissues. In the present study, we found that LMO7 is downregulated in metastatic PCa specimens within the Stand Up To Cancer cohort. To investigate the functional impact of expression of the LMO7 splice variant skipping exon 12 in PCa, we utilized CRISPR-Cas9 methodology to delete LMO7 exon 12 in PCa cells and assessed resulting alterations in PCa cell biology. The LMO7 exon 12 deleted PC3 PCa cells exhibited enhanced migratory potential compared with parental PCa cells. An Immunofluorescence (IF) assay showed weak staining of cell-cell junctions in LMO7 exon 12 deleted PCa cells compared with parental PCa cells. Moreover, IF staining showed retardation in f-actin in LMO7 exon 12 deleted PCa cells compared with parental PCa cells. As E-Cadherin is often inhibited during EMT, we assessed the level of E-Cadherin by western blot and real-time polymerase chain reaction (PCR). These analyses revealed that E-Cadherin protein as well as messenger RNA is suppressed in LMO7 exon 12 deleted PCa cells compared with parental PCa cells. These findings suggest a role for skipping of LMO7 exon 12 in disrupting PCa cell-cell junctions, down-regulating E-Cadherin in PCa and enhancing PCa cell migratory potential, consistent with EMT. Citation Format: Muthana Al Abo, Daniel J. George, Zefeng Wang, Steven R. Patierno, Jennifer A. Freedman, Alice Jiang. LIM Domain 7 (LMO7) splice variant influences prostate cancer biology [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 1554.
Abstract 1559: IKZF1 plays a crucial role in the spread of melanoma
Authors: Jongwook Oh, Dong Ki Lee, Soyeon Lee, Hyun Woo Park, Heon Yung Gee
Journal: Cancer Research (2024)

Abstract Melanoma is one of the most fatal type of skin cancer. If melanoma has spread to distant sites, it is refractory to existing therapies with the 5-year survival rate declining to 17%. Metastasis remains as the main barrier to successful therapy, persisting as the main cause of cancer-related death. Thus, understanding metastasis mechanism is vital. First, we confirmed that IKZF1 gene was more increased in circulating tumor cells than primary tumor cells. Using GFP+ B16F10, we generated an orthotopic melanoma mouse model and isolated GFP+ tumor cells of primary footpad, blood, and lung. In single cell RNA sequencing, IKZF1, IRF8, NFE2 genes were more upregulated in circulating tumor cells than primary tumor cells. We also found these correlations in human melanoma cell line orthotopic mouse model and Braf/Pten mouse model. Next, we conduct intervention study to find causality in IKZF1 and metastasis. IKZF1 KO led to fewer CTCs and IKZF1 inhibitor, lenalidomide, reduced metastasis in mice. Collectively, we demonstrate that IKZF1 could contribute the formation of CTC and IKZF1 could be a target for metastasis treatment. Citation Format: Jongwook Oh, Dong Ki Lee, Soyeon Lee, Hyun Woo Park, Heon Yung Gee. IKZF1 plays a crucial role in the spread of melanoma [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 1559.
Abstract 7373: Generative Bayesian networks for augmentation of molecular data from commercial genetics panels
Authors: Dillon H. Tracy, Jeff Sherman, Maayan Baron
Journal: Cancer Research (2024)

Abstract Background: Computational models in medical research which use molecular features to predict patient sensitivities or outcomes are traditionally limited to producing a scalar output for a given disease phenotype, e.g. progression-free survival or drug response. Even for relatively intelligible models, it is generally difficult to place confidence limits on the prediction or develop an intuition for how a prediction varies with respect to “what-if” changes in those features or how sensitive a prediction is to changes in input variables. Moreover, while essential for understanding and modeling tumor behavior, molecular features from patient tumors in real-world settings are typically limited to profiles of hundreds of genes, while the biologically relevant inputs to the patient’s condition can be much larger. Approach: To generate data required to enhance the interpretation of predictive models and extend the utility of real-world patient oncology datasets, a distribution of conditions consistent with the observed features and their incidence across cancer patient cohorts is required. We hypothesized we could synthesize patient samples drawn from the joint probability distribution of a broader universe of features when a subset of them is held fixed at the observed values. We model this joint distribution by learning a Bayesian network over a broad feature set for which some training data is available and generate feature profiles by applying Gibbs sampling to the learned network. Results: We assessed the potential clinical utility of using these generated feature profiles in predicting drug response and enhancing biological interpretation of different model outputs. We found generative somatic mutations were useful for predicting cancer patient outcomes, including drug response predictions in breast cancer tumors from AACR Project GENIE. Synthesized patient feature profiles enhanced biological interpretability of nominal panel data (100-200 genes), providing a means to assign probabilities to outcomes and uncovering previously described mechanisms of drug response in real-world patient data. Conclusion: We introduce an approach that leverages Bayesian networks to synthesize richly annotated patient feature profiles from limited molecular data routinely collected in real-world settings. This approach addresses challenges associated with limited molecular data, biological interpretability and evaluation of predictive models and enhances the utility of real-world datasets for cancer research. Citation Format: Dillon H. Tracy, Jeff Sherman, Maayan Baron. Generative Bayesian networks for augmentation of molecular data from commercial genetics panels [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 7373.
Abstract 2085: Targeting the translation initiation complex component eIF4G1 in melanoma
Authors: Yongmei Feng, Mariia Radaeva, Hyungsoo Kim, Anagha Deshpande, Ani Deshpande, Predrag Jovanovic, Rabi Murad, Ivan Topisirovic, Steven Olson, Artem Cherkasov, Ze'ev Ronai
Journal: Cancer Research (2024)

Abstract The translation initiation factor 4F (eIF4F) complex assembly is a rate-limiting step in mRNA translation. eIF4F subunits including eIF4A, eIF4E, and eIF4G, are often upregulated in cancer and neurodegeneration diseases. Elevated eIF4F level/activity has been correlated with poor prognosis and drug resistance. Leveraging our findings with the small molecule SBI-756, which interacts with eIF4G1 and impairs eIF4F complex assembly, we set to map domains that are required for SBI-756 activity. A CRISPR screen using sgRNAs that target different sequences on eIF4G1 led to the identification of the MA3 domain, as a putative binding site for SBI-756. Deletion/mutation of the eIF4G1 MA3 domain attenuated melanoma cells and spheroids growth. Polysome profiling assays confirmed attenuated translation activity, which resembled those seen with SBI-756. In silico virtual screen identified 64 small molecules (out of &amp;gt;10 million) that interact with the MA3 domain. Of these, we have selected four that effectively attenuated melanoma growth in culture. Analogs developed for these four compounds were more potent in impairing the assembly of the eIF4F complex, inhibition of protein translation and the 2D and 3D growth of melanoma cells. RNA-sequencing analysis highlighted altered expression of genes implicated in apoptosis, UPR, cell cycle, and ROS pathways, leading us to test possible combination with pathways that may complement the above. Among those, autophagy inhibitors synergized with our lead compound, M19-6, resulting in efficient melanoma cell death, using notably lower concentrations of these inhibitors. Our findings identify the eIF4G1 MA3 domain as an important player in eIF4F assembly and a potential target for cancer therapy. Citation Format: Yongmei Feng, Mariia Radaeva, Hyungsoo Kim, Anagha Deshpande, Ani Deshpande, Predrag Jovanovic, Rabi Murad, Ivan Topisirovic, Steven Olson, Artem Cherkasov, Ze'ev Ronai. Targeting the translation initiation complex component eIF4G1 in melanoma [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 2085.
Abstract 6239: Human computer interface guided approach to accelerate anticancer drug discovery: Application to human estrogen receptor interactome
Authors: Rajendram V. Rajnarayanan, Aya Alsabagh
Journal: Cancer Research (2024)

Abstract Structure-based drug discovery of target specific drugs greatly rely on the existence of high resolution X-ray crystal structure of the target proteins. Flexible and dynamic regions including hinges and loops which constitute major protein-protein interaction sites as well as allosteric sites are often beyond the scope of current tools and techniques available for protein folding and modeling. Human ability in recognizing patterns and to solve complex puzzles are far superior to any existing computer program at folding these atypical regions of proteins. We have utilized an unconventional combination of using dynamic three-dimensional protein models as physical human computer interface (HCI) devices and integrated proteomics data to predict flexible and dynamic protein-protein interfaces and allosteric pockets of key regulatory proteins to accelerate compound discovery. To this end, we have successfully utilized 1) Flexible HCI devices to generate an ensemble of dynamic three dimensional structures which includes a subset of biologically active conformations among others (thereby exploring the viable chemical space) and 2) Structure refinement and efficient filtering of biologically active conformations can be accomplished by integrating protein-protein interface and fold proteomics data. Here we present AI ready, HCI guided exploration of human estrogen receptor interactome and early in vitro confirmatory analyses. AI approachs to predict 3D protein structures from amino acid sequences like AlphaFold are often on par with experimentally generated structures and AI-guided structure prediction or docking approaches have been reported to significantly reduce computer time utilization. Streamlining of HCIguided tools to enable access to dynamic druggable pockets in protein targets will accelerate drug discovery. Citation Format: Rajendram V. Rajnarayanan, Aya Alsabagh. Human computer interface guided approach to accelerate anticancer drug discovery: Application to human estrogen receptor interactome [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 6239.
Abstract 6153: Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma
Authors: Jingjing Zhu, Ke Wu, Shuai Liu, Alexandra Masca, Hua Zhong, Tai Yang, Dalia H. Ghoneim, Praveen Surendran, Tanxin Liu, Qizhi Yao, Tao Liu, Sarah Fahle, Adam Butterworth, Md A. Alam, Jaydutt V. Vadgama, Youping Deng, Hong-Wen Deng, Chong Wu, Yong Wu, Lang Wu
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on two selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC. Our dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions. Citation Format: Jingjing Zhu, Ke Wu, Shuai Liu, Alexandra Masca, Hua Zhong, Tai Yang, Dalia H. Ghoneim, Praveen Surendran, Tanxin Liu, Qizhi Yao, Tao Liu, Sarah Fahle, Adam Butterworth, Md A. Alam, Jaydutt V. Vadgama, Youping Deng, Hong-Wen Deng, Chong Wu, Yong Wu, Lang Wu. Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal 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 6153.
Abstract 7368: Sentinel omics signatures: Comparative clinical and blood sample analysis from canine mammary tumor patients and their human guardian
Authors: Keun Hong Son, A-Reum Nam, Hyoung-Min Park, HuiSu Kim, Jeong-Woon Lee, Je-Yoel Cho
Journal: Cancer Research (2024)

Abstract Breast cancer remains a leading cause of morbidity and mortality worldwide, necessitating innovative approaches for early detection and intervention. This study leverages the comparative biology paradigm, exploring the shared oncological pathways between humans and canines through a unique multi-omics approach. We have gathered a diverse cohort comprising healthy dogs, canine mammary tumor patients, and their respective human guardians, collecting comprehensive clinical data alongside blood samples. Employing RNA-seq, MBD-seq, and LCMS, we aim to construct a detailed transcriptomic, methylomic, and proteomic landscape to elucidate potential sentinel biomarkers indicative of an oncogenic environment shared between species. While results are forthcoming, the premise of our research rests on the hypothesis that environmental factors contributing to mammary cancer may manifest systemically, potentially affecting both canines and humans. By delineating these interspecies molecular signatures, we hope to advance the field of precision medicine, offering insights into early detection and the systemic nature of cancer pathobiology. This abstract presents the foundation and direction of our ongoing investigation, with a commitment to providing a comprehensive update, inclusive of significant findings, at the conference. Citation Format: Keun Hong Son, A-Reum Nam, Hyoung-Min Park, HuiSu Kim, Jeong-Woon Lee, Je-Yoel Cho. Sentinel omics signatures: Comparative clinical and blood sample analysis from canine mammary tumor patients and their human guardian [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 7368.
Abstract 4610: Dual inhibition of CDK4/6 and IL-6 pathways as a novel therapeutic approach for triple-negative breast cancer cells
Authors: Kailey Caroland, Changyou Shi, Hui-Wen Lo, Jiayuh Lin
Journal: Cancer Research (2024)

Abstract Triplenegative breast cancer (TNBC) is highly aggressive and associated with poor clinical outcomes. TNBC stands as a major cause of death among breast cancer patients and offers only a few therapeutic options. Abemaciclib, a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, has received FDA approval for use in hormone receptor-positive, HER2-negative, and metastatic breast cancers. However, acquired resistance to CDK4/6 inhibitors in treating TNBC is becoming an increasing concern. Our recent results indicated that CDK4/6 inhibitors can induce IL-6 levels in TNBC cells as a potential resistance mechanism by augment IL-6 signaling axis, and that targeting IL-6 signaling can sensitize TNBC cells to CDK4/6 inhibitor therapy. In this study, combination of Abemaciclib with an IL-6/GP130 inhibitor (bazedoxifene) was tested in TNBC cells. We examined the effect of the combination on cell viability, cell migration, and invasion of human and mouse TNBC cell lines. Our data demonstrated that the bazedoxifene and abemaciclib combination treatment synergistically inhibited TNBC cell viability, cell migration, and invasion in vitro. These results support dual inhibition of CDK4/6 and IL-6 as a novel therapeutic approach for TNBC. Citation Format: Kailey Caroland, Changyou Shi, Hui-Wen Lo, Jiayuh Lin. Dual inhibition of CDK4/6 and IL-6 pathways as a novel therapeutic approach for triple-negative breast cancer 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 4610.
Abstract 673: Mechanisms of drugs in ovarian cancer and prevention of invasion and metastasis
Authors: Laura F. Mortan, Doris Benbrook
Journal: Cancer Research (2024)

Abstract Introduction: Ovarian cancer patients are typically diagnosed late stage after the cancer has left the primary site, this is the major factor contributing to the 70% 5-year mortality rate. Standard of care is Platinum therapies or debulking surgery followed by maintenance therapies to keep cancer from coming back. The limitation to these therapies is overall toxicity to the patient forcing them to stop treatments or eventual resistance to the therapy. The objective of this study is to evaluate the mechanisms in which the novel drug, SHetA2, alone compares to the competitor, Olaparib. Additionally, discover the genetic differences between attached tumor and floating tumor in ascites.Objective: Our objective was to evaluate the mechanisms in which the novel drug, SHetA2, alone compares to the front-line competitor, Olaparib, in affecting Filamin A and cyclin d1 levels in ovarian cancer. Methods: Individual and combination drug treatments were preformed on two ovarian cancer cell lines and patient samples for cell viability assays. Immunocytochemistry was performed to visualize colocalization of proteins. RNA isolation was performed for Nanostring analysis. Results: Ovarian cancer cells treated with SHetA2 or olaparib demonstrate a decrease of cyclin D1 on the membrane colocalized with filamin A, a structural protein that facilitates movement by acting as a signaling molecule for downstream effects. Nanostring analysis of attached tumor and spheroids form ascites shows significant differential gene expression in tumor versus ascites. Conclusions: These results suggest the decrease of cyclin D1 with filamin A upon treatment with SHetA2 or olaparib could be one of the primary factors leading to each drug’s efficacy and additivity with each other. The differential gene expression of tumor versus ascites begins to elucidate the fundamental differences between attached and floating tumors and spheroids. Citation Format: Laura F. Mortan, Doris Benbrook. Mechanisms of drugs in ovarian cancer and prevention of invasion and metastasis [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 673.