tbuckley/cabot-search huggingface dataset:
Abstract 1102: Amentoflavone enhances regorafenib-induced apoptosis and -inhibited invasion via inactivating STAT3/NF-ΚB signaling pathway in Hepatocellular carcinoma
Authors: Yan ting Tsai, Ying-Tzu Chen, Fei-Ting Hsu, Jai-Jen Tsai, Yu-Chiang Liu
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is an aggressive tumor and ranks as the third leading cause of cancer-related deaths worldwide. Amentoflavone, a biflavonoid compound, possesses antiviral, angiogenesis-inhibitory, and anticancer properties. Prior studies have illustrated that amentoflavone effectively restrains tumor growth and promotes apoptosis in various cancers, including brain cancer and osteosarcoma. Regorafenib, a small molecule inhibitor of multi-kinases, can inhibit angiogenesis, tumor growth, and anti-tumor metastasis. While regorafenib is a targeted drug approved for the treatment of metastatic colorectal cancer and has also been approved for use in HCC, its effectiveness in HCC is limited. Consequently, our goal is to investigate whether amentoflavone may enhance the sensitivity of regorafenib in treating HCC and explore the underlying mechanisms. In our study, through the combined treatment and combination index analysis, we proved that the combination of regorafenib and amentoflavone may induce cytotoxicity more effectively compared to monotherapy, as assessed by the MTT assay in Huh7 and HepG2 cells. The invasion and migration assays also demonstrated a superior inhibitory effect in the combination group. Additionally, apoptosis markers such as "cleaved caspase-3, -8, -9, Fas and FasL" assayed by flow cytometry, confirm that the combination treatment may induce the extrinsic/intrinsic apoptosis pathway in HCC. In our Western blotting analysis, we observed that the phosphorylation of STAT3 and NF-κB proteins was effectively suppressed by the combination of regorafenib and amentoflavone in Huh7 and HepG2 cells, respectively. Furthermore, our in vivo study confirmed a superior tumor inhibition rate and control rate with the combination of regorafenib and amentoflavone. Importantly, no signs of general toxicity were observed in any of the treatment groups, as evidenced by body weight monitoring and Hematoxylin and Eosin stain (H&amp;E) pathology evaluation. We believe that the combined treatment of these two drugs effectively triggers cell death and suppresses metastatic patterns through the inactivation of the STAT3/NF-κB signaling pathway. These results suggest that amentoflavone has the potential to serve as an adjuvant that sensitizes regorafenib for the treatment of HCC without causing any side effects. Citation Format: Yan ting Tsai, Ying-Tzu Chen, Fei-Ting Hsu, Jai-Jen Tsai, Yu-Chiang Liu. Amentoflavone enhances regorafenib-induced apoptosis and -inhibited invasion via inactivating STAT3/NF-ΚB signaling pathway in Hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1102.
Abstract 7619: Tissue-derived peripheral biomarkers that reflect activity of T-cells, macrophages, and neutrophils in patients with solid tumors
Authors: Nicholas Willumsen, Neel I. Nissen, Morten A. Karsdal
Journal: Cancer Research (2024)

Abstract Background: A toolbox of tissue-derived peripheral biomarkers that reflect the activity of T-cells, macrophages and neutrophils is a medical need for immuno-oncology drug development allowing non-invasive quantification of immune cell activity before - and during - treatment, both for predictive and pharmacodynamic purposes. By identifying and quantifying specific extracellular matrix fragments with neo-epitopes that are generated by proteases specific for T-cells, macrophages, and neutrophils, respectively, it is possible to develop peripheral biomarkers that reflect the activity of these immune cells. Such biomarkers have previously shown associations with outcome of patients treated with immune checkpoint inhibitors. Here we investigated the distribution of 3 such biomarkers in different cancer indications. Moreover, these data were compared to data from melanoma patients showing associations with response to cancer immunotherapy. Methods: Tissue-derived biomarkers related to activity of T-cells (C4G: Collagen-4 degraded by Granzyme B), Neutrophils (CPA9-HNE: Calprotectin degraded by neutrophil elastase), Macrophages (VICM: citrullinated and MMP-degraded vimentin) were measured by validated ELISA/ECLIA in serum from patients with various solid tumor types (bladder-, breast- colorectal-, head and neck-, kidney-, lung-, ovarian-, pancreatic, stomach-, prostate- cancer, and melanoma, n=220) and compared to age-matched healthy controls (n=33) by ANOVA. The biomarker levels were compared to historical data. Results: Median biomarker levels of CPA9HNE (neutrophil activity/NETosis) and VICM (macrophage activity) were significantly increased in all solid tumor types (p&amp;lt;0.001), respectively and with a ~5-fold inter-patient variation as well. Median C4G levels was only slightly elevated in a few indications (p&amp;lt;0.05) and with a 5-10-fold inter-patient variation across tumor types. All biomarker levels were independent of disease stage. Similar biomarkers levels were seen to those found to be associated with objective response rate and overall survival of melanoma patients treated with cancer immunotherapy. Conclusion: Tissue-derived peripheral biomarkers that reflect the activity of T-cells (C4G), macrophages (VICM) and neutrophils (CPA9HNE) has biomarker potential in solid tumors and may serve as prognostic, predictive and pharmacodynamic biomarkers in clinical trials investigating cancer immunotherapy. Citation Format: Nicholas Willumsen, Neel I. Nissen, Morten A. Karsdal. Tissue-derived peripheral biomarkers that reflect activity of T-cells, macrophages, and neutrophils in patients with solid tumors [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 7619.
Abstract 1031: Targeting genomic biomarker in voided urine for prostate cancer detection
Authors: Mathew L. Thakur, Vivek S. Tomar, Emma Dale, Leonard G. Gomella, Hector T. Navarro, Oleksandr Kolesnikov, Joon Yau Leong, Olivia Dahlgren, Edouard J. Trabulsi
Journal: Cancer Research (2024)

Abstract Introduction: Prostatic cancer (PCa) is the second most prevalent disease in men globally. In 2020 it lead to &amp;gt;14 million new cases and &amp;gt;375,000 deaths worldwide. Despite numerous detection methods, detecting PCa reliably and non-invasively continues to be challenging. PCa malignant cells (MC) express VPAC (combined for Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Peptide) in high density. A VPAC specific PACAP analogues (Kd=3.1 × 10−8M) developed in our laboratory was conjugated with a fluorophore and named TP4303. The goal was to assess if TP4303 will image PCa-MC shed in voided urine and present severity of PCa as grade group (GG). Method: Consenting PCa patients (N=110) scheduled for radical prostatectomy provided voided urine. Urine was cyto-centrifuged. Cells on glass slide were fixed, incubated with TP4303, washed, treated with DAPI (4,6-diamidodino-2-phenylindole), cover slip placed and analyzed with Zeiss Axio Observer microscope, coupled with ZENN Microscopy software. The software determined percentage of PCa MC shed by each patient. The results were corroborated as per GG, determined by post-surgical histopathology and analyzed statistically. Results:TP4303 imaged PCa in all subjects. The percent MC shed in urine increased from 13.1±14.4% for GG1 to 25.3±21.07% for GG3 (p=0.05) to 50.5±26.7% for GG5 (p=0.002). Similarly, the fluorescence intensity increased from 43.8±2.2 for GG1 to 48.8±7.0 for GG3 (p=0.01) to 51.5±14.4 for GG5 (p=0.15). Conclusions: The data strongly suggests that TP4303 may not only detect PCa reliably and noninvasively, but may also predict the severity of PCa. Supported by NIH: NC5R01CA249921 Citation Format: Mathew L. Thakur, Vivek S. Tomar, Emma Dale, Leonard G. Gomella, Hector T. Navarro, Oleksandr Kolesnikov, Joon Yau Leong, Olivia Dahlgren, Edouard J. Trabulsi. Targeting genomic biomarker in voided urine for prostate cancer detection [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 1031.
Abstract 3230: Discovery of selective BRM (SMARCA2) ATPase inhibitors for the treatment of BRG1 (SMARCA4) mutant cancers
Authors: Janice Y. Lee, Nathan Brooks, Brandon Antonakos, Bryan Perria, Candace Langan, Bonita D. Jones, Robert Stephen Flack, Zhifang Li, David Terry, Ross Wallace, Robert Bondi, Gereint Sis, Ronee Baracani, Maralee McVean, Gabrielle Kolakowski, Dayo Osimboni, Kevin Wilson
Journal: Cancer Research (2024)

Abstract BRM (SMARCA2) and BRG1 (SMARCA4) are highly homologous ATPases that are members of the BAF (also known as the mSWI/SNF) chromatin remodeling complex. BRM and BRG1 are mutually exclusive enzymatic subunits of BAF complexes, and functional genomic screens have shown a synthetic lethal relationship between the two genes. BRG1 is frequently mutated in cancer, including in approximately 10% of non-small cell lung carcinomas. Selective inhibition of BRM is a mechanism by which BRG1-mutated cancer cell growth would be affected by losing BRM function, while normal tissues should be spared as they still express functional BRG1. Given that the ATPase domains of BRM and BRG1 are 92% identical, the identification of selective enzymatic inhibitors of BRM has been challenging. Here, we report the discovery of novel, highly potent compounds that selectively inhibit BRM over BRG1 as seen in cell-based transcription and proliferation assays, that also possess excellent oral pharmacokinetics. Our lead compounds inhibit BRM in a cell-based reporter assay with an unbound IC50 of 1 nM and are greater than 20-fold selective over BRG1. They are also selective against other helicases and do not show any significant activity in off-target screening panels. Dosing of mice carrying BRG1-mutant xenografts causes target gene modulation that is correlated with compound exposure. Treatment of A549 and RERF-LC-AI xenografts with lead compounds led to tumor growth inhibition of 87% and 96%, respectively, at well-tolerated doses, and significant tumor growth inhibition was also achieved in multiple other BRG1-mutant models. The results suggest that our compounds have first-in-class potential as potent and selective BRM ATPase inhibitors for the treatment of BRG1-mutated cancers, and we are planning to file an IND in 2024. Citation Format: Janice Y. Lee, Nathan Brooks, Brandon Antonakos, Bryan Perria, Candace Langan, Bonita D. Jones, Robert Stephen Flack, Zhifang Li, David Terry, Ross Wallace, Robert Bondi, Gereint Sis, Ronee Baracani, Maralee McVean, Gabrielle Kolakowski, Dayo Osimboni, Kevin Wilson. Discovery of selective BRM (SMARCA2) ATPase inhibitors for the treatment of BRG1 (SMARCA4) mutant 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 3230.
Abstract 3232: LSD1 inhibition transcriptionally reprograms neuroendocrine prostate cancer exposing unique therapeutic vulnerabilities
Authors: Sumer M. Jasmine, Adel Mandl, Susan L. Dalrymple, Sunghyun Kim, Jennifer Dias, Maria Kleppe, Cassandra Celatka, Amy Tapper, Ilsa Coleman, Peter Nelson, Hugh Rienhoff, Samuel R. Denmeade, W. Nathaniel Brennen
Journal: Cancer Research (2024)

Abstract Therapeutics have been developed to target castration-resistant prostate cancer (CRPC) classified as adenocarcinoma (CRPC-Adeno). However, an increasing frequency of CRPC-Adeno tumors progress to the highly aggressive and lethal neuroendocrine prostate cancer (NEPC) by acquiring a neuroendocrine (NE) phenotype as a mechanism of therapeutic resistance. This transformation from CRPC-Adeno to NEPC requires distinct epigenetic reprogramming by lysine-specific demethylase 1 (LSD1), which can be exploited for development of novel therapies to target NEPC. LSD1 is upregulated in NEPC and promotes a stem-like transition state through lineage plasticity which enables the cancer cell to undergo NE differentiation. We have shown that LSD1 inhibition reduces the NE program, driving NEPC towards a non-neuroendocrine state through ASCL1 suppression and YAP1 re-expression. This less aggressive non-neuroendocrine state exposes unique vulnerabilities for the development of novel combination therapies to treat this lethal disease. Citation Format: Sumer M. Jasmine, Adel Mandl, Susan L. Dalrymple, Sunghyun Kim, Jennifer Dias, Maria Kleppe, Cassandra Celatka, Amy Tapper, Ilsa Coleman, Peter Nelson, Hugh Rienhoff, Samuel R. Denmeade, W. Nathaniel Brennen. LSD1 inhibition transcriptionally reprograms neuroendocrine prostate cancer exposing unique therapeutic vulnerabilities [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 3232.
Abstract 3798: Advancements in multiplexed spatial phenotyping
Authors: Leticia Montoya, Scott Clarke, Austin Harvey, Jen Serafin, Mae Voeun
Journal: Cancer Research (2024)

Abstract Spatial omics is an expanding research area focused on integrating spatial knowledge of tissue with transcriptomics (RNA) and proteomics (protein). Understanding the complexity of the biological structure(s) is an important biological process in cancer immunotherapy research which requires accurate target classification. Translational profiling of 4+ targets on a single sample at one time can be difficult in many ways, such as, panel design, staining protocols, and data analysis. Furthermore, to design a reliable multi-target biomarker panel, there are many parts to overcome, such as protein abundance and localization, fluorophore compatibility, varying tissue types, and data characterization, to name a few. To address the needs of high target multiplex ability, labeling methods have advanced in cyclic detection enabling iterative labeling and detection using automated fluidics, however these approaches suffer from low simultaneous target throughput. Thermo Fisher Scientific can now provide a streamline process for tissue labelling; a process that enables sufficient labelling of high multiplexed panels completed within a couple of hours. We show successful detection of a wide range of various protein markers across numerous tissue organs used in various biological research applications with our uniform technique of labelling. Citation Format: Leticia Montoya, Scott Clarke, Austin Harvey, Jen Serafin, Mae Voeun. Advancements in multiplexed spatial phenotyping [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 3798.
Abstract 5212: Prognostic biomarkers for breast cancer: Metabolic and inflammatory pathways
Authors: Alexandra N. McMahon, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, Eunkyung Lee, George Yang, Jennifer J. Hu
Journal: Cancer Research (2024)

Abstract Objective: To assess the prognostic significance of molecular biomarkers, particularly metabolic and Inflammatory pathways using samples from a prospective study of breast cancer patients undergoing adjuvant radiotherapy (RT). Methods: We used ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) for measuring urine metabolites. Following normalization to osmolality, log transformation, and imputation of missing values, we used Welch’s two-sample t-test to identify biochemicals that differed significantly by progression status. We measured pre- and post-RT plasma high-sensitivity C-reactive protein (hsCRP) levels. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of disease progression or last follow-up. Univariable and multivariable Cox proportional hazards regression models assessed the associations between hsCRP and PFS. Results: In 120 breast cancer patients, carbohydrate metabolism, branch-chain amino acid (BCAA) metabolism, phosphatidylcholine metabolism, arginine metabolism, oxidative stress-related metabolites, androgenic steroids, and nucleotide metabolism had the most notable differences in patients with progression versus progression-free cases. In 488 breast cancer patients, RT significantly increased plasma hsCRP levels, and post-RT hsCRP levels were significantly higher in deceased vs. alive patients (p=0.031). In multivariable models, hsCRP had a prognostic value for all-stage and stage 0-II patients. Conclusions: In our study of breast cancer patients receiving adjuvant RT, multiple metabolite biomarkers and post-RT plasma CRP levels were associated with a worse prognosis. BCAAs and fatty acids regulate cell metabolism by affecting mitochondrial function and inflammation signals. Thus, our findings suggest a potential role of metabolic and inflammatory pathways in breast cancer prognosis. These molecules may have potential utility as prognostic biomarkers for breast cancer patients undergoing adjuvant RT and targets for intervention. Keywords: breast cancer, metabolomics, inflammation, prognosis Citation Format: Alexandra N. McMahon, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, Eunkyung Lee, George Yang, Jennifer J. Hu. Prognostic biomarkers for breast cancer: Metabolic and inflammatory pathways [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 5212.
Abstract 5331: Spatial resolution of immune cell lineages in the tumor microenvironment of plasma cell dyscrasias
Authors: Medbh A. Dillon, Lisa Arvidson, Cole G. Phalen, Julian R. Ishibashi, John B. Johanneson, Zachary J. Thomson, Peiyao A. Zhao, Jocelin Malone, Mackenzie S. Kopp, Matthew Norton, Gabriella Spang, Susan A. Ludmann, Adam K. Savage, Claire E. Gustafson, Marla Glass, Emma L. Kuan, Tao Peng, Lucas T. Graybuck, Xiao-jun Li, Troy R. Torgerson, Peter J. Skene, Ananda W. Goldrath, Samuel Jensen, Stephanie Anover-Sombke, Melinda L. Angus-Hill
Journal: Cancer Research (2024)

Abstract Plasma cell dyscrasias (PCDs) are diseases of the hematologic system, with Multiple Myeloma as the most common disease. Less common PCDs include primary and secondary extramedullary plasmacytomas (EMP), which occur in soft tissues. EMPs are typically solitary and infrequent, often localized in the upper aerodigestive and gastrointestinal tracts, lung, and lymph nodes among other organs, and can convert to Multiple Myeloma. Secondary extramedullary plasmacytomas are often noted in advanced disease following multiple rounds of therapy and are commonly associated with poor prognosis. Studies aimed at gaining a better understanding of soft tissue EMPs, whether solitary plasmacytomas with undiagnosed multiple myeloma or in the context of recurrent or metastatic EMP disease, are limited. In this study, we employ a comprehensive approach using multiple modalities, including dissociated CITE-seq, spatial transcriptomics, and multiplexed spatial immuno-fluorescence imaging to interrogate the tumor and immune landscape in EMP disease. Importantly, the use of the same biomarker antibodies across these modalities provides a cross-data-framework for a deep contextual understanding of the immune and tumor cell organization and cell-to-cell signaling in EMP. Ultimately, this study provides new insights into patient-to-patient and tumor location variability, tumor and immune cell microenvironment heterogeneity, and possible future therapeutic strategies for EMP. Citation Format: Medbh A. Dillon, Lisa Arvidson, Cole G. Phalen, Julian R. Ishibashi, John B. Johanneson, Zachary J. Thomson, Peiyao A. Zhao, Jocelin Malone, Mackenzie S. Kopp, Matthew Norton, Gabriella Spang, Susan A. Ludmann, Adam K. Savage, Claire E. Gustafson, Marla Glass, Emma L. Kuan, Tao Peng, Lucas T. Graybuck, Xiao-jun Li, Troy R. Torgerson, Peter J. Skene, Ananda W. Goldrath, Samuel Jensen, Stephanie Anover-Sombke, Melinda L. Angus-Hill. Spatial resolution of immune cell lineages in the tumor microenvironment of plasma cell dyscrasias [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 5331.
Abstract 5242: In vitro cytotoxicity assays to support CAR T cell evaluation against solid tumors
Authors: Carla N. Castro, Veronica Bergo, Holger Weber, Philipp Metzger
Journal: Cancer Research (2024)

Abstract CAR T cells are donor/patient-derived T cells genetically engineered to express a chimeric receptor against a specific tumor antigen (TA), which allows an MHC-independent recognition and targeting of tumor cells. While CART cell therapies have been tremendously successful against hematological cancers, with 6 T cell products being approved up to date from the FDA (Sengsayadeth S etal, EJHaem. 2022), the activity on solid tumors is more difficult. Solid tumors remain a unique challenge in part due to trafficking problems of CAR T cells, a hostile TME and heterogenous antigen expression, which limits CART cell capacity to find their target. Several strategies are being developed at the moment with the aim to overcome these hurdles, such as multispecific CART cells, co-therapy with checkpoint inhibitors, or inhibition of DNA methylation enzymes to prevent exhaustion. To offer an in vitro platform to assess the effectiveness of upcoming cellular therapies we developed several pipelines to allow the investigation of cytotoxic potential in 2D and 3D formats. We show here our results using a CART cell product expressing a coreceptor to enhance its activation potential upon recognition of the target. We next tested the capacity of these cells to kill solid tumor in vitro by coculturing with potential target cells cultured in a monolayer (2D). By measuring the luciferase expression of the target cells, we could track the cytotoxicity exerted by the effector cells. In vitro, the CART cells were able to kill in a dose dependent manner different solid tumor cell lines expressing the cognate antigen for the co-receptor. At Reaction Biology we have developed spheroid-based 3D killing assays in which target cells from solid tumor entities are pre-cultured to form spheroids prior to their coculture with effector cells. Using this technique, we challenged the capacity of these CART cells to recognize their antigen in a 3D format. This 3D assay system can be used as well in combination with co therapies such as PD1 inhibitors, in a sensitive and high throughput manner. Finally, we evaluated the therapeutic capacity of these CART cells in vivo in a subcutaneous THP-1 tumor model. Mice treated with these CART cells showed a marked reduction of tumor volume. In summary we show here a pipeline to characterize in vitro the effectivity of new T cell products, in particular those designed to overcome some of the hurdles against solid tumors. Citation Format: Carla N. Castro, Veronica Bergo, Holger Weber, Philipp Metzger. In vitro cytotoxicity assays to support CAR T cell evaluation against solid tumors [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 5242.