tbuckley/cabot-search huggingface dataset:
Abstract 3034: Krüppel-like factors in regulation of gastric cancer progression
Authors: Sooraj Kakkat, Prabhat Suman, Sandeep Goswami, Sujit Basu, Martin J. Heslin, Elba A. Turbat-Herrera, Veronica Ramirez Alcantara, Chandrani Sarkar, Debanjan Chakroborty
Journal: Cancer Research (2024)

Abstract Introduction: Gastric cancer (GC) is the third leading cause of cancer-associated mortality and the fifth most frequently diagnosed cancer worldwide. The development and progression of GC is a complicated multistage process subjected to dynamic changes in gene regulation. Investigating the effects of these changes is therefore critical for improving our knowledge about GC initiation and progression. Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with altered expressions and diverse regulatory functions in GC. We previously reported that there is loss of KLF4 in GC. Here we report that KLF4 is a crucial regulator of KLF5 expression and vice versa and together they regulate GC cell behavior. Methods: The Cancer Genome Atlas (TCGA) and pan cancer data of differential expressions of KLFs in GC was analyzed. TCGA RNAseq and clinical data for the differential expression status of KLF genes in normal and cancerous tissues and the clinicopathological association was accessed from the UALCAN web portal. The expressions of KLF4 and KLF5 in human normal stomach and GC and orthotopic xenografts were detected by immunohistochemistry (IHC). KLF4, KLF5 cross regulation was evaluated by gene manipulation of each gene individually and checking the expression of the other factor in GC cells. The effect of KLFs on GC cell proliferation, migration, and invasion was determined by Ki67 staining of tissues, PrestoBlue cell viability assay, scratch wound and transwell cell invasion assays. Results and Conclusion: Our results indicated that not only KLF4 and KLF5 have contrasting expressions and effects in GC but also these two factors cross regulate each other. While lower expressions of KLF4 was found in human GC and orthotopic xenografts, increased expression of KLF5 was found in both human GC tissue and orthotopic xenografts. KLF4 silencing and CRISPR/Cas9 knockdown in human GC cells resulted in increased expression of KLF5 which was associated with increased GC cell proliferation and invasiveness. Interestingly, KLF5 knockdown by CRISPR/Cas9 in human GC cells on the other hand resulted in increased expression of KLF4, which was associated with decreased GC cell growth. Our data therefore suggests that the differential expressions of KLF4 and KLF5 might serve as valuable prognostic markers in GC. Citation Format: Sooraj Kakkat, Prabhat Suman, Sandeep Goswami, Sujit Basu, Martin J. Heslin, Elba A. Turbat-Herrera, Veronica Ramirez Alcantara, Chandrani Sarkar, Debanjan Chakroborty. Krüppel-like factors in regulation of gastric cancer progression [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 3034.
Abstract 180: <i>LINC00261</i> is functionally linked to tumor DNA mutational burden and tumor immune microenvironment composition in lung adenocarcinoma
Authors: Jonathan Castillo, Tianchun Xue, Mayela Norwood, Samantha Joseph, Alan L. Epstein, William D. Wallace, Anthony W. Kim, Crystal N. Marconett
Journal: Cancer Research (2024)

Abstract Immunotherapy has emerged as a breakthrough in the improvement of survival outcomes for lung adenocarcinoma (LUAD), however effective response requires the combination of blocking inhibitory signals on the tumor surface and antigen presentation to the tumor surface for proper immune recognition. Several commercially available and robust methods exist for identification of tumors displaying immune-inhibitory surface receptors, such as PD-L1, however it is currently difficult to predict effectiveness of antigen presentation on the cell surface. To address this, we utilized clinical and next-generation sequencing data from The Cancer Genome Atlas (TCGA) to identify gene signatures that are correlated to tumor mutational burden (TMB) within cancers of epithelial origins as a surrogate for neoantigen signatures. We identified LINC00261 as a top gene correlated to TMB, whose expression activates DNA damage response pathways in vitro along with resistance to cisplatin. LINC00261 expression was also significantly correlated to MHC class I and II genes involved in endogenous neoantigen presentation expression within the TCGA-LUAD cohort. This relationship was confirmed in vitro through ectopic reintroduction of LINC00261 for key MHC class II presentation genes. Interferon gamma-induced MHC gene activation in vitro was also able to induce endogenous expression of LINC00261. Staining of primary human lung cancer sections suggested that loss of LINC00261 is associated with an immunosuppressive tumor microenvironment. Taken together, our results suggest there is a mechanistic relationship in the silencing of LINC00261 in LUAD and compromised DNA repair, accumulation of mutations, and reduced antitumor immune response. Citation Format: Jonathan Castillo, Tianchun Xue, Mayela Norwood, Samantha Joseph, Alan L. Epstein, William D. Wallace, Anthony W. Kim, Crystal N. Marconett. LINC00261 is functionally linked to tumor DNA mutational burden and tumor immune microenvironment composition in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 180.
Abstract 7155: Dichloroacetate reverses cisplatin resistance in ovarian cancer through promoting ROS production
Authors: Yen Thi Do, Seungmee Lee, Changmin Shin, Hyewon Chung, Jin Young Kim, Eunyoung Ha, Sojin Shin, Ji Hae Seo
Journal: Cancer Research (2024)

Abstract Chemotherapy resistance and the high rate of ovarian cancer relapse pose major challenges in the treatment of ovarian cancer. The development of chemoresistance contributes to poor overall prognosis associated with ovarian cancer and high cancer-related mortality in women worldwide. Herein, we found that Dichloroacetate (DCA), a pan-pyruvate dehydrogenase kinase (PDK) inhibitor, is a potent agent to overcome Cisplatin (CP) resistance in ovarian cancer treatment. Firstly, we elucidated that phosphorylation of pyruvate dehydrogenase (pPDH) was elevated in CP-resistant ovarian cancer cells. Then, blockage of pPDH by DCA treatment significantly inhibited cell migratory and invasive capacity in CP-resistant ovarian cancer cells through the transition of motile mesenchymal phenotypes into epithelial characteristics. DCA markedly decreased the number of sphere formations and attenuated the stem cell-like properties in CP-resistant ovarian cancer cells. In combination with CP treatment, DCA effectively inhibited cell proliferation in chemoresistant ovarian cancer cells by triggering apoptosis. Collectively, we suggested that DCA is a promising drug to reverse CP resistance for ovarian cancer treatment. We further tested the underlying mechanisms of DCA to restore CP sensitivity in ovarian cancer. We found that CP treatment promoted reactive oxygen species (ROS) production to induce cell death in CP-sensitive ovarian cancer. However, CP-resistant ovarian cancer cells exhibited higher basal levels of ROS compared with sensitive cancer cells, and CP treatment failed to generate ROS production. That means ovarian cancer cells steadily adapted to elevated ROS levels, then becoming ROS-adapted ovarian cancer cells to survive. Interestingly, DCA treatment results in the buildup of ROS production, causing cell death in CP-resistant ovarian cancer. Therefore, our study suggests that ROS production can be an attractive target in DCA treatment to restore CP sensitivity in ovarian cancer. Citation Format: Yen Thi Do, Seungmee Lee, Changmin Shin, Hyewon Chung, Jin Young Kim, Eunyoung Ha, Sojin Shin, Ji Hae Seo. Dichloroacetate reverses cisplatin resistance in ovarian cancer through promoting ROS production [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 7155.
Abstract 6747: Engineering M13 filamentous phages to target dendritic cells and elicit anti-tumor immunity
Authors: Yee Man Betty Au-Yeung, Zheng Zeng, Jiandong Huang
Journal: Cancer Research (2024)

Abstract Filamentous phage is a safe and effective vaccine vector that can elicit robust immune responses by activating Toll-like receptor pathways. However, engineering neoantigen-displaying phages for cancer vaccines using phage display technology has been challenging and yielded inconsistent results. We developed a dendritic cell (DC)-targeting cancer vaccine platform with M13 filamentous phages using the phage display technology. The engineered phages express DC-targeting peptides (SLS) on p3 sites and spy-catcher proteins on p8 positions, allowing neoantigens and proteins of interest to be linked to the phage vector. We named our platform SCP (SLS-spy catcher phage). Imaging and western blot showed that spy-tagged proteins can be easily attached to SCP by simple mixing. Further studies demonstrated that targeting DCs can enhance antigen presentation and anti-cancer immunity. We tested SCP in MB49 and B16 mouse models and the serum, spleen and tumor tissues were isolated for further investigation of immune response upon treatment. We found that SCP effectively suppressed tumor growth by inducing systemic anti-tumor humoral and cell-mediated immunity. SCP also showed efficacy in late-stage tumor models. SCP treatment triggered particularly robust local anti-tumor response. Histological and flow cytometry analysis revealed increased infiltration of innate and adaptive immune cells, reduced PDL1 expression, and restricted neovascularization in the tumor microenvironment after intratumoral administration of SCP. Our study demonstrated that SCP can induce multifactorial modifications in the tumor microenvironment to impede tumor growth. SCP overcomes the limitations of traditional phage display technology, enabling a wide variety of peptides and proteins to be loaded onto the phage vectors. SCP is also cost-effective and scalable as phage production and purification processes are relatively mature. We propose that SCP can serve as a universal platform for cancer immunotherapy, and may offer novel treatment options for patients. Citation Format: Yee Man Betty Au-Yeung, Zheng Zeng, Jiandong Huang. Engineering M13 filamentous phages to target dendritic cells and elicit anti-tumor immunity [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 6747.
Abstract 2261: A scalable comparison of tumor immune atlases
Authors: Jing Yang, Qi Liu, Yu Shyr
Journal: Cancer Research (2024)

Abstract Large single-cell atlases can serve as references for the analysis of smaller-scale studies. However, there are strong biases among atlases due to their varying sample sources, conditions, cell type annotation strategies and resolutions. Selecting appropriate atlas for future or smaller-scale studies is complicated due to unclear understanding of atlases, that limits the future or smaller-scale studies take advantage of the wealth of data that such atlases provide. For example, the tumor-infiltrating immune cell atlases including pan-cancer and cancer type-specific atlases provide comprehensive profiling of immune cells, which desperately facilitates future single-cell studies. However, lack of a comprehensive assessment and comparison of tumor immune cell atlases with standardized benchmarks blocked the application of the most appropriate atlas for smaller-scale study. In this study, we compared pan-cancer immune cell atlases including TICA, pan-cancer T cells and pan-cancer blueprint atlases, and cancer-type specific immune cell atlases containing ABTC, HCC and STAD atlases. We quantified the correlations of cell types and observed similar heterogeneity among atlases and unique immune cell populations in TICA as well. Then, we assessed the performance of atlases on accurately annotating immune cell types in the widely studied PBMC datasets—in which cell types were well annotated. Comparative analysis revealed the complementarity within atlases on mapping success, accuracy, clustering, annotatability and stability by benchmarking reference-based populations to reference-free de novo clustering on real immunotherapy datasets. We identified potential indicators of immune response and found that reference-based populations outperformed reference-free clusters in recognizing immunotherapy-related cell states. Our study can be easily extended to future atlases. Citation Format: Jing Yang, Qi Liu, Yu Shyr. A scalable comparison of tumor immune atlases [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 2261.
Abstract 7142: Optimizing estradiol dimers through linker design: Enhancing anticancer efficacy by targeting microtubule dynamics
Authors: Petr Dzubak, Michal Jurášek, Jiří Řehulka, Soňa Gurská, Pavel Polishchuk, Pavel Dráber, Lukáš Huml, Pavel B. Drašar, Alexandra Ivanova, Olena Mokshyna, Lenka Hrubá, Marián Hajdúch
Journal: Cancer Research (2024)

Abstract We investigated the development and anticancer efficacy of novel estradiol dimers (ED), targeting the dynamics of microtubules—an essential factor in effective cancer therapy. Employing copper-catalyzed azide-alkyne cycloaddition (CuAAC), two distinct series of ED variants were synthesized. The initial series included thirteen dimers, derived from 17α-ethinyl estradiol, incorporating varied five-atom linkers with central carbon, nitrogen, or oxygen atoms, and, in some instances, modified with benzyl groups containing hydroxy or methoxy substituents. These dimers were evaluated for their cytotoxic properties and impact on the cell cycle, revealing certain structures with substantial efficacy, compared with the original ED. The subsequent series, encompassing twelve variants, concentrated on structural alterations within the aromatic bridges linking the estradiol units. In this series, linkers of simpler composition and fewer substituents demonstrated increased selectivity and potency against cancer cell lines, particularly ED3 and ED5, which exhibited cytotoxicity levels comparable to established tubulin inhibitors. Both dimers series showed the ability to disrupt microtubule assembly and mitotic processes, confirmed through cell-based evaluations and in vitro tubulin assembly assays. Complementing these results, in silico modelling and binding free energy calculations exhibited a strong correlation with the demonstrated biological activities, especially in terms of binding affinity to the colchicine site. Collectively, these findings highlight the promise of estradiol dimers as potential anticancer agents and emphasize the critical role of linker structures in enhancing their biological effectiveness. Work was supported by the Ministry of Education, Youth and Sports of the Czech Republic through infrastructural projects (CZ-OPENSCREEN - LM2018130; EATRIS-CZ - LM2018133) and National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU. Citation Format: Petr Dzubak, Michal Jurášek, Jiří Řehulka, Soňa Gurská, Pavel Polishchuk, Pavel Dráber, Lukáš Huml, Pavel B. Drašar, Alexandra Ivanova, Olena Mokshyna, Lenka Hrubá, Marián Hajdúch. Optimizing estradiol dimers through linker design: Enhancing anticancer efficacy by targeting microtubule dynamics [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 7142.
Abstract 7133: Phenomics-enabled discovery and optimization of small-molecule RBM39 degraders as an alternative to CDK12 targeting in high-grade serous ovarian cancer (HGSOC)
Authors: Chase Neumann, Harish Shankaran, Kiran Nadella, Kelly Biette, Shane Rowley, Ethan Gardner, Shadi Swaidani, Vamshi Manda, Lu Chen, Daria Beshnova, Ashraf Saeed, Christopher Bailey, Janet Paulsen, Paul Rearden, Carl Brooks, Ashish Bhandari, Chris Gibson, Laura Schaevitz, Imran Haque, Hayley Donnella, Michael Cuccarese, Marie Evangelista
Journal: Cancer Research (2024)

Abstract Phenomics-enabled drug discovery is a powerful approach to identify novel targets and relationships previously unappreciated in biology. We built a phenomics platform leveraging high content microscopy and generated unique phenoprints for &amp;gt;7,000 genes using CRISPR/Cas9 technology and a diverse chemical library of &amp;gt;1 million compounds. This phenomics dataset contains an unprecedented quantity of gene-gene, gene-compound, and compound-compound relationships. We applied our phenomics platform and an inference based target-agnostic drug discovery approach to discover novel genes and small molecules that mimic CDK12 inhibition, an important transcriptional regulator of DNA damage response, while avoiding inhibition of the paralog CDK13. We discovered a novel and unappreciated association between CDK12 and RBM39 as well as small molecule degraders of RBM39. We established structure activity relationships (SAR) solely leveraging our phenomics platform, to generate REC-1170204, an RBM39 degrader. Unlike inhibitors of CDK12, we show that REC-1170204 does not directly inhibit CDK12, CDK13 or other kinases. However, REC-1170204 demonstrates candidate quality properties with improved potency, selectivity, and drug-like characteristics. Finally we show that REC-1170204 shows efficacy in High Grade Serous Ovarian cancer (HGSOC) pre-clinical models and synergizes with PARP inhibition in a PARP-resistant patient-derived xenograft (PDX) model. Together, our data suggests that targeting RBM39 may provide an attractive and safer approach to targeting CDK12 in the clinic. Citation Format: Chase Neumann, Harish Shankaran, Kiran Nadella, Kelly Biette, Shane Rowley, Ethan Gardner, Shadi Swaidani, Vamshi Manda, Lu Chen, Daria Beshnova, Ashraf Saeed, Christopher Bailey, Janet Paulsen, Paul Rearden, Carl Brooks, Ashish Bhandari, Chris Gibson, Laura Schaevitz, Imran Haque, Hayley Donnella, Michael Cuccarese, Marie Evangelista. Phenomics-enabled discovery and optimization of small-molecule RBM39 degraders as an alternative to CDK12 targeting in high-grade serous ovarian cancer (HGSOC) [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 7133.
Abstract 1257: CHD5 suppresses glioblastoma by inhibiting MYC
Authors: Xueqin Sherine Sun, Alea Mills
Journal: Cancer Research (2024)

Abstract Fundamentally, cancer is a disease caused by genetic and epigenetic alterations that converge to reprogram gene expression networks, leading to unrestrained proliferation. Glioblastoma (GBM) is the most prevalent and aggressive primary brain cancer, median survival being approximately one year and the 5-year survival rate being only 5%. Despite decades of effort, this devastating picture has not appreciably improved and effective therapies have been elusive for GBM patients. A better understanding of GBM biology is essential for developing more effective therapies. Although several genetic alterations have been implicated in gliomagenesis, driving genetic factors responsible for GBM are still obscure, and the interplay between genetic alterations and epigenetic dysregulation is largely undocumented during the gliomagenic process. Here, we show that CHD5 — a gene mapping to the 1p36 chromosomal region that is notoriously deleted in many cancers, is recurrently deleted in over 20% of GBM cases and is further downregulated through epigenetic means. To delineate how CHD5 loss promotes gliomagenesis, we established a glioma-prone mouse model harboring conditional alleles of Pten, Trp53, and Chd5. We developed an engineered mouse neural stem cell (NSCs)-based strategy to elicit glioma formation, as NSCs are the major cell-of-origin for GBM. We show that Chd5 loss significantly impairs NSCs differentiation while promoting proliferation, transformation, and gliomagenesis in vivo. Mechanistically, Chd5 forms a Chd3-containing but Chd4-independent NuRD complex that directly binds the Myc promoter and super enhancers to govern Myc expression in normal NSCs, with the Snf2 domain of Chd5 playing the most critical chromatin regulating role in the context of GBM. Chd5 loss triggers the remodeling of chromatin, enhances accessibility, and augments Myc expression, leading to the formation of highly aggressive glioma. Furthermore, reactivating CHD5 in human GBM xenograft models significantly extends survival. This work demonstrates the tumor suppressive role of CHD5 in gliomagenesis, providing therapeutic insights for cancers with 1p36 deletions. In parallel, this work presents a powerful strategy for rapidly interrogating gene function during gliomagenesis using engineering NSCs, and the generation of novel mouse models with classic clinical features of GBM, offering new approaches for elucidating GBM biology that can inform on therapeutic opportunities for treating patients with GBM. Citation Format: Xueqin Sherine Sun, Alea Mills. CHD5 suppresses glioblastoma by inhibiting MYC [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 1257.
Abstract 1406: Plk1 attenuates colon inflammation and tumorigenesis
Authors: Xinyi Wang, Dang he, Fengyi Mao, Yifan Kong, Chaohao Li, Sai Wu, Jia Peng, Chi Wang, Zhiguo Li, Xiaoqi Liu
Journal: Cancer Research (2024)

Abstract Inflammation-associated colon cancer, linked with long-standing colon inflammation, is often seen in patients with inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis. Typically, these patients are diagnosed at a younger age compared to those with sporadic colon cancer. Despite some advancements, the detailed molecular mechanisms driving cancer development in IBD remain unclear. Polo-like kinase 1 (Plk1), a serine/threonine kinase and cell cycle regulator, is recognized as an oncogene in various cancers. Intriguingly, higher Plk1 expression correlates with better survival rates in colon cancer patients. Besides, Plk1 also elevates in IBD cases, suggesting its significant role in both colitis and colon cancer. Our study explores Plk1's role in IBD-associated colon cancer using the azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model, revealing Plk1's suppressive impact on both colitis and related colon cancer. Citation Format: Xinyi Wang, Dang he, Fengyi Mao, Yifan Kong, Chaohao Li, Sai Wu, Jia Peng, Chi Wang, Zhiguo Li, Xiaoqi Liu. Plk1 attenuates colon inflammation and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1406.