tbuckley/cabot-search huggingface dataset:
Abstract 4482: Development of small molecule inhibitors of lipocalin 2 for the treatment of aggressive cancers
Authors: Marienid Flores-Colón, Cristal A. Peña-Vázquez, Eliud Hernández-O'Farril, Luis E. Vázquez-Quiñones, Pablo E. Vivas-Mejía
Journal: Cancer Research (2024)

Abstract Lipocalin-2 (LCN2), a secreted protein pivotal in iron homeostasis, immune responses, siderophore transport, and epithelial cell differentiation. LCN2 is highly abundant in aggressive forms of many cancers including breast, pancreatic, ovarian, and esophageal cancer. Elevated LCN2 levels in aggressive tumors correlate with heightened cancer cell motility, proliferation, angiogenesis, invasion, and metastasis. After the protein folds it makes a barrel structure which encloses a three-calyx pocket that can bind and transport molecules. A first generation of small molecule inhibitors (SMIs) targeting LCN2 demonstrated efficacy in attenuating the proliferative capacity of Inflammatory breast cancer (IBC) cells. IBC stands as a rare and highly aggressive variant, accounting for 1 to 5% of all BC cases, with 20-30% presenting as de novo metastatic disease. In the previous studies the concentration of LCN2 inhibitors to reduce cell proliferation in 50% was around 10 µM. In pursuit of better LCN2 SMIs, we conducted in-silico analysis using a library of 369,000 ligands. Through the High-Performance Computer Facility at UPR Río Piedras, we employed AutoDock Vina for virtual screening, targeting the LCN2-calyx with Lys134 as the central coordinate. Docking protocols, predicting binding affinities, identified 8,162 out of 327,638 ligands that have been docked already with values below -9.6 kcal/mol for further consideration. The next phase involves subjecting these potential inhibitors to the SwissADME tool for a comprehensive evaluation of absorption, distribution, metabolism, and excretion parameters, as well as pharmacokinetics, drug-likeness, and medicinal chemistry considerations. The parameters to be evaluated are the Lipinski rules, which states that an orally active drug may have a maximum of one violation and the pann-assay interference compounds (PAINS) alerts tool, a source of false positives for biologically active compounds. The top candidates, exhibit binding affinities within the range of -11.5 to -12.2. After SwissADME filtering, we will re-rank the ligand list, identifying 30 commercially available candidates for subsequent cell viability assays in SUM149 (TNBC) and SUM190 (HER2+) cell lines. This multifaceted approach integrates computational methodologies with rigorous experimental validation, paving the way for potential therapeutic interventions in IBC treatment. Citation Format: Marienid Flores-Colón, Cristal A. Peña-Vázquez, Eliud Hernández-O'Farril, Luis E. Vázquez-Quiñones, Pablo E. Vivas-Mejía. Development of small molecule inhibitors of lipocalin 2 for the treatment of aggressive cancers [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 4482.
Abstract 5357: The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC
Authors: Yifei Guo, Jennifer M. Finan, Alexandra Q. Bartlett, Jonathan R. Brody, Robert Eil
Journal: Cancer Research (2024)

Abstract Immunotherapies have shown limited effectiveness in pancreatic ductal adenocarcinoma (PDAC), despite having success in other cancers. The RNA-binding protein HuR is known to play a critical role in the oncogenesis of PDAC by regulating key mRNA transcripts. Our lab has shown that tumor-intrinsic HuR is overexpressed in PDAC and regulates the tumor microenvironment composition, altering multiple tumor cytokines to release. Thus, we hypothesized that HuR plays a role in immune evasion of PDAC. We disrupted the locus encoding HuR (Elavl1) using CRISPR Cas9 in Kras-p53 mutant-driven (KPC) murine PDAC to assess its function in tumor immune evasion. Here, we report that HuR, a known pro-survival factor for PDAC, has a role in tumor immune evasion by suppressing T cell infiltration and T cell activation. Specifically, HuR-knockout (KO) KPC tumors grew slower compared to KPC wildtype (WT) tumors in an orthotopically implanted model (p-value &amp;lt; 0.0001), even though human PDAC cell lines with HuR-WT and HuR-KO grew at the same rate in NRG mice (in an immune-compromised environment). Accordingly, HuR-KO tumors had more T cell infiltration and activated T cells compared to HuR-WT tumors (p-value = 0.0047). Importantly, T cell depletion (both CD4+ and CD8+) partially rescued the size of HuR-KO tumors. Next, we rescued the expression of HuR in the HuR-KO cell line, and the re-expression partially rescued the tumor size in vivo. This observation validates a HuR-mediated dependent mechanism. Collectively, these data support the hypothesis that HuR suppresses T cell activation and prevents T cells from infiltrating into the PDAC microenvironment, leading to PDAC immune evasion. Ongoing experiments will transduce KPC cell lines with ovalbumin (OVA) antigen, which will selectively activate CD8+ OT-I T cells through their transgenic TCR, to measure the ability of KPC HuR-WT or HuR-KO OVA cells in directly activating CD8+ OT-I T cells. We will also investigate HuR's impact on immune cells' cytokine release and how that will impact the cytotoxicity of T cells. These findings support the ongoing concept that HuR plays an important pro-survival role in PDAC in vivo, and targeting strategies against HuR being developed (e.g., siHuR nano-therapies and small molecule inhibitors) could potentially enhance PDAC sensitivity to immune-based anti-cancer therapies, such as checkpoint blockade and T cell transfer. Citation Format: Yifei Guo, Jennifer M. Finan, Alexandra Q. Bartlett, Jonathan R. Brody, Robert Eil. The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC [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 5357.
Abstract 2550: Investigating glutathione peroxidases as potential prognostic factors in uterine corpus endometrial cancer
Authors: Alexis Dukesherer, Calli A. Davison-Versagli
Journal: Cancer Research (2024)

Abstract Introduction: Uterine corpus endometrial cancer (UCEC) is one of the deadliest women’s reproductive cancers in the United States, and mortality rates have not improved in the last 30 years due to poor prognostic methodologies. Altered expression patterns of Glutathione Peroxidases (GPX1-8) have been connected to the outcome of many cancers. Still, GPX expression patterns and their use as prognostic biomarkers in UCEC have yet to be explored. This project aimed to evaluate the potential utility of GPX1-8 as prognostic biomarkers for UCEC. Methods: To identify GPX1-8 expression alterations in UCEC tumors, the UCEC tissue samples (n=543) from the Cancer Genome Atlas Database (TCGA) dataset were analyzed using the University of Alabama at Birmingham Cancer Data Analysis portal (UALCAN) software to statistically compare mRNA levels between UCEC tumor samples and non-tumorigenic uterine tissue. To determine the impacts of GPX1-8 expression on overall survival (OS) and relapse-free survival (RFS), the UCEC TCGA dataset was analyzed using the pan-cancer RNA seq platform using Kaplan-Meier Plotter (KM plotter). The patient cohort was split into groups according to high GPX expression status and low GPX expression status using the trichotomization function in KM plotter. Hazard ratio (HR), 95% confidence interval (95% CI), and log-rank P value were calculated using the KM plotter platform. Results: GPX1, GPX2, GPX4, GPX7, and GPX8 were differentially expressed in UCEC tumor tissue compared to non-cancerous uterine tissue. However, unfavorable OS in patients associated with low GPX4 expression in UCEC tumor samples (P=0.0043, HR=0.39, 95% CI=0.2-0.76) only. Unfavorable RFS in UCEC patients only correlated with low GPX1 expression (P=0.019, HR=0.43, 95% CI=0.21-0.89) or high GPX6 expression (P=0.0032, HR=2.37, 95% CI=1.31-4.27) in UCEC tumor samples. Conclusion: Low GPX1 and GPX4 expression and high GPX6 expression may be novel unfavorable UCEC prognostic markers. Citation Format: Alexis Dukesherer, Calli A. Davison-Versagli. Investigating glutathione peroxidases as potential prognostic factors in uterine corpus endometrial 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 2550.
Abstract 4850: Sex differences in cancer incidence: Prospective analyses in the UK Biobank
Authors: Maira Khan, Keren Papier, Kirstin Pirie, Joshua Atkins, Tim Key, Ruth Travis
Journal: Cancer Research (2024)

Abstract Background: Exploring the underlying sex differences in cancer incidence and the potential reasons for the differences may provide insights into cancer aetiology. We aimed to examine the differences in incidence of cancer between men and women in the UK Biobank and to assess the extent to which any disparities persisted after accounting of established risk factors for those cancers. Methods: Prospective analyses were performed in the UK Biobank to examine associations between sex and risk of 15 cancers (and 13 subtypes) common to both sexes using minimal and multivariable-adjusted Cox proportional hazards regression models. Results: Over an average of 10.5 (SD 2.2) years of follow-up, 46,081 incident cancers were identified in 470,771 individuals (aged 37 to 73 years at recruitment); 24,634 cancers (53.5%) diagnosed in women and 21,447 (46.5%) in men. While some differences in cancer risk between the sexes were attenuated in the comprehensively multivariable-adjusted models, men compared to women remained at greater risk of cancers at eight sites. Compared to women, men had higher risks of oesophageal adenocarcinoma (hazard ratio 5.45; 95% confidence interval, 4.17-7.12), gastric cardia (3.65; 2.48-5.38), bladder (3.47; 2.85-4.24), oral (2.06; 1.69-2.51), liver (1.91; 1.48-2.47), kidney (1.77; 1.51-2.09), rectum (1.7; 1.47-1.96), and leukaemia (1.43; 1.21-1.69); while women had higher risks of cancers of the breast, thyroid (0.36; 0.26-0.49), anus (0.41; 0.26-0.64), gallbladder (0.56; 0.31-0.99), and lung adenocarcinoma (0.72; 0.62-0.84). Conclusion: Further studies of unexplained sex differences may provide insights into cancer aetiology. Citation Format: Maira Khan, Keren Papier, Kirstin Pirie, Joshua Atkins, Tim Key, Ruth Travis. Sex differences in cancer incidence: Prospective analyses in the UK Biobank [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 4850.
Abstract 5723: Selectivity profiling of small molecule kinesin inhibitors using microplate-based ATPase activity assay
Authors: Brenna P. Lee, Sung Won Oh, Kurumi Y. Horiuchi, Safnas F. AbdulSalam
Journal: Cancer Research (2024)

Abstract Kinesin superfamily proteins (KIFs) are a large family of molecular motor proteins, that share a highly conserved motor domain. KIFs play an important role in cell division and transport of vesicles and organelles within cells. Mitotic kinesins hydrolyze ATP through its ATPase activity to move along the spindle microtubules and carry out several functions during mitosis to facilitate precise chromosome segregation. Altered expressions of several kinesins are shown in various cancers, fueling the aggressive nature of cancers leading to genomic instability. KIF11/Eg5 overexpression is shown in various cancers including hepatic carcinoma, lung, prostate, colorectal, gastric, and pancreatic cancers. Small molecule inhibitors of KIF11/Eg5 and CENP-E are shown to result in mitotic arrest leading to apoptosis in tumor cell lines. Despite the poor clinical outcome of several Eg5 and CENP-E inhibitors entered in clinical trials, targeting kinesins remains an attractive anti-cancer therapeutic approach. Recently, an inhibitor of KIF18A has entered clinical trial for treatment of solid tumors with high chromosomal instability. Here we show development of a microplate based biochemical screening assays for a panel of kinesin motor domain proteins. We summarize kinetic characterization of kinesin proteins and study the selectivity of various previously reported KIF18A, Eg5, CENP-E inhibitors across a kinesin selectivity panel. Citation Format: Brenna P. Lee, Sung Won Oh, Kurumi Y. Horiuchi, Safnas F. AbdulSalam. Selectivity profiling of small molecule kinesin inhibitors using microplate-based ATPase activity 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 5723.
Abstract 3717: Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing
Authors: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Zgheib, Isabelle Cousineau, Veronique Lullier, Richard Beliveau, Christian Marsolais, Borhane Annabi
Journal: Cancer Research (2024)

Abstract The potential impact of the immune tumor microenvironment (iTME) was assessed with respect to the anticancer efficacy of sudocetaxel zendusortide (TH1902), a peptide-drug conjugate internalized through a sortilin (SORT1)-mediated endocytic pathway. In the triple-negative breast cancer (TNBC)-derived MDA-MB-231 immunocompromised xenograft tumor model, TH1902 induced complete tumor regression for more than 40 days after the last treatment. Surprisingly, immunohistochemistry analysis revealed higher staining of CD45 leukocytes and of STING, a master regulator in the cancer-immunity cycle, in comparison to docetaxel. Additionally, in a murine B16-F10 melanoma syngeneic tumor model, weekly administration of TH1902 as a single agent also demonstrated superior tumor growth inhibition than did docetaxel. Although B16-F10 is considered a non-immunogenic “cold” tumor model, we observed a net increase in CD45 leukocyte infiltration within TH1902-treated tumors, especially for tumor-infiltrating lymphocytes and tumor-associated macrophages. Moreover, in TH1902-treated tumors, increased staining of perforin, granzyme B, and caspase-3 was suggestive of elevated cytotoxic T and natural killer cell activities. Combined TH1902/anti-PD-L1 treatment led to increased tumor growth inhibition and median animal survival. Accordingly, TH1902 inhibited cell proliferation and triggered apoptosis and senescence in B16-F10 cells in vitro, while inducing several downstream effectors of the cGAS/STING pathway and the cell surface expression of MHC-I and PD-L1. This is the first evidence that TH1902 exerts its antitumor activity, in part, through modulation of the iTME and that the combination of TH1902 with checkpoint inhibitors (anti-PD-L1) could lead to improved clinical outcomes. Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Zgheib, Isabelle Cousineau, Veronique Lullier, Richard Beliveau, Christian Marsolais, Borhane Annabi. Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing [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 3717.
Abstract 6267: Evaluating estrogen receptor signaling modifications at bone marrow related stiffnesses in metastatic breast cancer
Authors: Logan Alexander Northcutt, Marjan Rafat, Julie Rhoades
Journal: Cancer Research (2024)

Abstract Bone metastasis is highly prevalent in breast cancer (BC) patients with metastatic disease and can increase the risk of hypercalcemia and pathological fractures. Several studies have evaluated the mechanisms of metastasized BC cells’ involvement in bone destruction, but how the bone marrow (BM) microenvironment contributes to this process remains ambiguous. Recent studies have shown that as BC cells experience increased stiffnesses outside of the primary microenvironment, there is higher expression of epithelial-to-mesenchymal transition (EMT) markers, increased expression of osteolytic proteins, and decreased drug responses. However, these changes have not been evaluated at stiffnesses relative to the BM. Estrogen receptor (ER) status also plays a pivotal role in BC patient survival. Clinical studies have indicated that the majority of ER+ patients with metastatic disease have more incidences of bone metastases compared to ER- patients. There is some evidence that suggests that the physical properties can also affect estrogen receptor signaling at the primary site, however, there is minimal work to establish how the physical factors of the BM can affect ER sensitivity after metastasis. We hypothesize that higher stiffness ranges of the BM can alter the estrogen receptor sensitivity of metastasized tumor cells and increase osteolysis. To analyze this question, we seeded ER+ BC cell lines (MCF7s and T47Ds) on CytoSoft® Rigidity Plates that mimicked the stiffness of the BM (0.5 - 32 kPa). After 2 days in culture, we probed the expression of downstream estrogen signaling factors, GREB1, PGR, and TIFF1, to evaluate estrogen activity using western blot. Our results show an increase in downstream estrogen signaling at higher stiffnesses (32 kPa) compared to lower stiffnesses (0.5 kPa) at the protein level but not at the transcriptional level. In the future, we will analyze factors associated with osteolysis (ITGB3, TGFB-RII, and PTHLH). Additionally, we plan to conduct RNA sequencing to analyze any larger transcriptional changes at different stiffnesses. Overall, this work gives insight into how estrogen signaling changes in the BM compared to the primary site. It will also give us insight into potential therapeutic targets for ER+ BC after metastasis to the bone. Citation Format: Logan Alexander Northcutt, Marjan Rafat, Julie Rhoades. Evaluating estrogen receptor signaling modifications at bone marrow related stiffnesses in metastatic 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 6267.
Abstract 852: Measuring the level of knowledge and awareness about radon in Northeast Tennessee
Authors: Kawther Al ksir, Stacy Stanifer, Megan Quinn, Hadii Mamudu, Deborah Slawson
Journal: Cancer Research (2024)

Abstract Introduction: Radon, a radioactive gas found in soil and rocks, is the second leading cause of lung cancer in the United States (1). Despite its significant health risks, radon awareness and knowledge remain low (2). In Tennessee, where geological factors contribute to elevated radon levels, understanding the levels of awareness and knowledge about radon is crucial (3). This study focuses on Northeast Tennessee, an area known for its high radon concentrations. Methods: This cross-sectional study, conducted from September to November 2023, aims to assess radon awareness and knowledge among participants from seven Northeast Tennessee health councils. These councils play a critical role in public health initiatives and provide access to individuals actively involved in health-related discussions. A convenience sample of 150 participants was chosen from an email listserv of 650 health council members. Participants, aged 18 or older, affiliated with the health councils in the study area, and physically present in the US, were eligible to participate. Demographic data, radon knowledge and awareness were assessed. Additional questions evaluated information sources, concern levels, and willingness to inform the community about radon. Conclusion: This research addresses a significant knowledge gap regarding radon awareness and knowledge in Northeast Tennessee, an area with unique geological factors that elevate radon exposure risks. The study's findings will contribute to the development of targeted educational campaigns and interventions, ultimately promoting awareness and proactive measures to mitigate radon exposure in the region. With the potential to inform policy and public health efforts, this study holds the promise of reducing the health risks associated with radon in Northeast Tennessee. Citation Format: Kawther Al ksir, Stacy Stanifer, Megan Quinn, Hadii Mamudu, Deborah Slawson. Measuring the level of knowledge and awareness about radon in Northeast Tennessee [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 852.
Abstract 6270: Anti-metastatic effects of estrogen receptor β in inflammatory breast cancer
Authors: Harika Nagandla, Spyros Tastsoglou, Kim Cuong Cap, Aireana Phillips, Wei Qian, Jianying Zhou, Jenny Chang, Savitri Krishnamurthy, Naoto Ueno, Artemis Hatzigeorgiou, Christoforos Thomas
Journal: Cancer Research (2024)

Abstract Inflammatory breast cancer (IBC) is a rare but highly aggressive form of breast cancer with a 5-year survival rate of less than 50%. Although 20-30% of women with IBC have distant metastasis at the time of diagnosis, the biology underlying the aggressive behavior of the disease is poorly understood and molecular markers that distinguish IBC from non-IBC have not yet been identified. In response to the urgent need of discovering new targeted therapies in IBC, we have studied the second estrogen receptor (ERβ) since prior work from our lab correlated higher tumor expression of ERβ in samples from IBC patients with longer metastasis free survival. We showed that ERβ exerted anti-metastatic activity in IBC by inhibiting actin-based cell migration through the suppression of RhoC GTPase signaling. However, since estrogen receptors elicit their effects by inducing global cellular alterations, we have now adopted an integrated genomic approach to fully understand the anti-metastatic effects of ERβ in IBC and delineate the underlying transcriptional regulatory circuits. We found ERβ binding sites in IBC cells and combined this information with gene expression data to identify downstream direct target genes and associated pathways. Our findings suggest the regulation of tumor micro-environment and metabolism as the primary targets of ERβ and we are currently working to pinpoint the crucial regulatory components in these functions. Our findings thus offer an opportunity to better understand the mechanism of ERβ action in aggressive breast cancer, serving as a critical step in validating its tumor repressive role. Citation Format: Harika Nagandla, Spyros Tastsoglou, Kim Cuong Cap, Aireana Phillips, Wei Qian, Jianying Zhou, Jenny Chang, Savitri Krishnamurthy, Naoto Ueno, Artemis Hatzigeorgiou, Christoforos Thomas. Anti-metastatic effects of estrogen receptor β in inflammatory 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 6270.