tbuckley/cabot-search huggingface dataset:
Abstract LB261: Establishment and characterization of a paclitaxel-resistant human triple-negative breast cancer cell line
Authors: Ling-Huei Yih, Hsiao-Hui Kuo, Chieh-Ting Fang
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) is a lethal female cancer, of which paclitaxel resistance is a major factor limiting treatment outcomes, and continued unmet needs for more effective therapeutic strategies are arduous. The aim of this study is to establish a paclitaxel-resistant TNBC cell line and to characterize the underlying mechanism for potential strategies to overcome the resistance. The human TNBC cell line MDA-MB-231 was exposed to stepwise escalating paclitaxel concentration from 0.5 to 50 nM and a resistant cell line T50R was selected. The IC50 of paclitaxel was 2 and &amp;gt;100 nM in MDA-MB-231 and T50R cells respectively. However, T50R cells required 50 nM Taxol for proliferation. When cultured in the absence of paclitaxel, T50R cells arrested at mitotic stage with high levels of spindle abnormalities. Since induction of microtubule (MT) stabilization plays critical roles in paclitaxel’s potency, we thus measure cell MT polymerization and kinetochore-MT stability. The results showed that, compared to parental MDA-MB-231 cells, the interphase MTs were less polymerized and the kinetochore-MTs were less stable in T50R cells, indicating that the MT dynamic instability was significantly increased in T50R cells. Thus, the increased dynamic unstable MTs in T50R cells might contribute to drug requirement for cell growth and counteract with paclitaxel effects, and consequently lead to drug-resistant phenotype. Identification and interference of endogenous regulators involved in the increased MT instability in T50R cells might provide leads to overcome paclitaxel resistance. Citation Format: Ling-Huei Yih, Hsiao-Hui Kuo, Chieh-Ting Fang. Establishment and characterization of a paclitaxel-resistant human triple-negative breast cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB261.
Abstract LB364: Generation and Application of a Robust Humanized Mouse Tumor Model System for Evaluation of NK-Targeting Therapeutics
Authors: Feng Lu, Weiqun Ding, Guangliang Yang, Yaoqing Jia, Zhaoxiang Wang, Xusheng Yuan, Ming Yin, Zhijian Yang, WenQing Yang
Journal: Cancer Research (2024)

Abstract With the new waves of anti-tumor immunotherapy development, novel immunotherapies based on NK cells have emerged and advanced rapidly. Considering the inherent mechanisms of NK cells, various strategies are employed in tumor immunotherapy to maximize the efficacy of NK cells, including the following: 1) immune checkpoint inhibitors to relieve NK cell inhibition signals; 2) activation of NK cell activity; 3) targeted antibody therapy for tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC), and 4) cell therapy, such as CAR-NK. Although numerous NK-targeting immune therapeutics or various NK-modulating modalities have been developed or advanced toward clinical trials, there is a lack of clinically relevant preclinical animal models that can be widely accepted for the evaluation of NK-modulating agents, particularly for models that involve functional human NK cells in the test system. This study generated a humanized mouse tumor model system which involves specific reconstitution of functional and durable human NK cells in a murine system, providing a clinically relevant tumor microenvironment. We first engineered a stable monoclonal feeder cell line in vitro to expand NK cells isolated from human peripheral blood mononuclear cells (hPBMCs) using magnetic bead separation. Using this approach, the human primary NK cells were robustly and consistently amplified (up to hundreds of fold) while maintaining their purity and functionality. When compared with primary NK cells using in vitro immune assays including ADCC and FACs, the expanded NK cells showed comparable results as the parental cells. In vivo experimental results indicated that a durable and functional NK reconstitution can be established in tumor-bearing severely immune deficient mice expressing hIL-15. Furthermore, this NK-humanized tumor model system was proven to respond to standard of care (SOC) NK-targeting drugs. In summary, this novel NK humanized in vivo model may represent an effective preclinical tool for assessing NK-modulating drugs, with the hope of facilitating the development process of novel immune therapeutics employing both adaptive and innate immunity. Citation Format: Feng Lu, Weiqun Ding, Guangliang Yang, Yaoqing Jia, Zhaoxiang Wang, Xusheng Yuan, Ming Yin, Zhijian Yang, WenQing Yang. Generation and Application of a Robust Humanized Mouse Tumor Model System for Evaluation of NK-Targeting Therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB364.
Abstract LB370: Exploring SLC35B family genes in colorectal carcinoma: Bioinformatics and functional insights into prognosis and therapy
Authors: Yu-Jia Chang, Chang-Chun Yang, Cheng-Chin Lee, Chien-Yu Huang
Journal: Cancer Research (2024)

Abstract Colorectal carcinoma (CRC) poses a significant health challenge, with recent therapeutic advances yet to substantially improve long-term patient survival. Central to this study is the SLC35B gene family (SLC35B1-4), which encodes nucleotide sugar transporters essential to cellular membranes. Emerging research highlights a link between these transporters' dysfunction and the development and progression of tumors, yet the specific role of the SLC35B family in CRC remains unclear. Our investigation delves into the function of SLC35B genes in CRC, utilizing an integrated bioinformatics approach with databases like GENT2, TCGA, UALCAN, cBioportal, TIMER, and Kaplan-Meier plotter. Our analysis reveals a notable upregulation of SLC35B1/2/4 mRNA in CRC tissues compared to adjacent non-tumor tissues, with a concurrent downregulation of SLC35B3. Promoter methylation analysis shows increased methylation for SLC35B1/3/4, while SLC35B2 demonstrates decreased methylation. According to GEO and TCGA data, CRC patients exhibiting high SLC35B4 expression face lower survival rates. Multivariate Cox regression analysis confirms high SLC35B4 expression as an independent risk factor. Further, SLC35B4 expression correlates with increased infiltration of immune cells, particularly macrophages, and aligns positively with immune checkpoints such as CD274 and HAVCR2. In vitro assays link SLC35B4 to enhanced cancer cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT). In vivo, SLC35B4 knockdown leads to reduced tumor growth in mouse xenograft models. RNA sequencing identifies 241 genes differentially expressed in SLC35B4 knockdown compared to control cells, with Gene Set Enrichment Analysis (GSEA) associating SLC35B4 with the PI3K-Akt signaling pathway. In summary, our research sheds light on the SLC35B gene family's role in CRC, especially SLC35B4, highlighting its potential as both a prognostic marker and a therapeutic target in CRC, particularly through its involvement in the PI3K-Akt signaling pathway. Citation Format: Yu-Jia Chang, Chang-Chun Yang, Cheng-Chin Lee, Chien-Yu Huang. Exploring SLC35B family genes in colorectal carcinoma: Bioinformatics and functional insights into prognosis and therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB370.
Abstract LB262: Reprogramming the tumor microenvironment by targeting IGF2-IGF1R signaling, enhancing viro-immunotherapy
Authors: Min Hye Noh, Alexandra Miller, Grace Nguyen, Hiroshi Nakashima, E. Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo
Journal: Cancer Research (2024)

Abstract While an FDA-approved oncolytic herpes simplex-1 virus (oHSV) has shown therapeutic promise with superior safety, accumulating clinical data revealed that its therapeutic efficacy is observed in a small subset of patients. Here, we show that NFκB-mediated Insulin-like Growth Factor 2 (IGF2)/Insulin-like Growth Factor-1 Receptor (IGF1R) signaling pathway as a key modulator for oHSV therapy-mediated tumor resistance. RNA sequencing on the oHSV-infected primary glioblastoma (GBM) and breast cancer (BC) cells identified IGF2 as one of the top 10 upregulated secretomes. Transcriptomic analysis also revealed significant upregulation/enrichment of genes related to IGF2-IGF1R-MAPK pathway in oHSV-treated tumor cells. Infection with oHSV in GBM and BC cells up-regulated IGF2 transcription via direct binding of NFκB in the IGF2 promoter 3. Compromising the IGF2-IGF1R signaling pathway using IGF2 neutralizing antibody significantlDB7 BC tumors in vivo. To circumvent this and promptly translate our findings in clinical settings, we have developed a novel oHSV, oHSV-D11mt, by incorporating modified IGF2R domain 11 into the parental oHSV genome to function as IGF2 decoy receptor as a single-agent modality. oHSV-D11mt specifically bind to IGF2 not IGF1, blocks oHSV-induced IGF2-IGF1R signaling, increases tumor cell killing, decreases oHSV-induced neutrophils/PMN-MDSCs infiltration, immune suppressive/proangiogenic cytokine secretion, and increases CD8+ cytotoxic T lymphocytes (CTLs) activation, resulting in increased virus propagation and mice survival. These findings suggest that IGF2-IGF1R signaling is a novel target to overcome oHSV therapy resistance and oHSV-D11mt could be used for improved viro-immunotherapy. Citation Format: Min Hye Noh, Alexandra Miller, Grace Nguyen, Hiroshi Nakashima, E. Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo. Reprogramming the tumor microenvironment by targeting IGF2-IGF1R signaling, enhancing viro-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB262.
Abstract LB185: High resolution telomere measurements in human cancer and aging using long-read nanopore sequencing
Authors: Santiago Sanchez, Jessica Gu, Anudeep Golla, William Shomali, Annika Martin, Dirk Hockemeyer, Sharon Savage, Steven Artandi
Journal: Cancer Research (2024)

Abstract Telomere length is an important biomarker of cellular replicative potential and aging, but existing measurement methods are limited in resolution and accuracy. During human carcinogenesis, telomeres shorten profoundly in the earliest stages that precede tumor invasion. Telomere shortening can either halt cancer progression by inducing senescence and cell death or can promote cancer development by destabilizing chromosomes and generating chromosomal rearrangements. Stabilization of telomeres, typically by the upregulation of telomerase, is required for progression of nearly all human cancers. Here, we deploy digital telomere measurement by nanopore sequencing to understand how distributions of human telomere length change during aging and following carcinogenesis. We measure telomere attrition and de novo elongation with unprecedented resolution in genetically defined populations of human stem cells, in cells from the peripheral blood of healthy individuals and patients with genetic defects in telomere maintenance, cancer patients, and cancer cell lines. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres in white blood cells. In patients with inherited defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. Next, we investigated the telomere lengths of a cohort of twenty colorectal tumors with patient-matched healthy colonic epithelia and found that two-thirds of colorectal tumors have telomere length distributions significantly shorter than the surrounding normal tissue. Finally, we explore the utility of telomere length distributions in cancer cell lines as clinically actionable disease biomarkers. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease. Citation Format: Santiago Sanchez, Jessica Gu, Anudeep Golla, William Shomali, Annika Martin, Dirk Hockemeyer, Sharon Savage, Steven Artandi. High resolution telomere measurements in human cancer and aging using long-read nanopore sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB185.
Abstract LB026: Exploring MCT4 inhibitor Ful-23 and cytarabine synergy in acute myeloid leukemia therapeutics
Authors: Yong Wu, Ke Wu, Jay Vadgama
Journal: Cancer Research (2024)

Abstract In the ongoing pursuit of addressing the formidable challenge presented by Acute Myeloid Leukemia (AML) treatment, this comprehensive study delves into the intricate antileukemic effects of Ful-23, our newly developed Monocarboxylate Transporter 4 (MCT4) inhibitor. Positioned as a promising candidate, Ful-23's unique mechanisms and potential synergies with established chemotherapeutic agents, such as Cytarabine, are elucidated in this research. Intracellular alkalinization stands as a crucial factor contributing to the evasion of chemotherapy by cancer cells. It serves as the primary determinant for the heightened resistance exhibited by cancer cells against chemotherapy interventions. The investigation reveals the multifaceted impact of Ful-23 on AML cells, showcasing its capacity to induce intracellular lactate accumulation and acidification. These metabolic alterations correlate with a substantial inhibition of proliferation, as evidenced by an IC50 of approximately 0.55 μM, and a marked induction of apoptosis, particularly notable in the MV411 AML cell line. These findings underscore Ful-23's potential as a potent antileukemic agent with distinct cellular effects. A collaborative approach involves the combination of low concentrations of Ful-23 (0.312 μM) with Cytarabine (0.312 μM), revealing a significant enhancement in cytarabine-induced proliferation inhibition and apoptosis when Ful-23 is introduced concurrently. Importantly, the translational impact of these findings extends to a zebrafish model, utilizing both MV411 cells and transplanted primary AML patient-derived bone marrow cells. In the zebrafish AML model, the combination treatment of Ful-23 and Cytarabine demonstrates a significant enhancement in their respective antitumor effects compared to monotherapy, indicating a pronounced synergistic effect. This additional validation strengthens the clinical relevance of the observed synergistic antileukemic interactions between Ful-23 and Cytarabine. Essentially, this investigation advances our understanding of AML treatment dynamics, emphasizing the crucial role of MCT4 inhibition and elucidating the mechanism by which it leads to intracellular acidification in synergistic therapeutic approaches for this intricate and formidable disease. Citation Format: Yong Wu, Ke Wu, Jay Vadgama. Exploring MCT4 inhibitor Ful-23 and cytarabine synergy in acute myeloid leukemia therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB026.
Abstract LB292: Glutathione supports lipid abundance in vivo
Authors: Gloria Asantewaa, Emily T. Tuttle, Nathan P. Ward, Yun P. Kang, Yumi Kim, Madeline Kavanagh, Aaron R. Huber, Joshua Munger, Benjamin Cravatt, Calvin L. Cole, Gina M. DeNicola, Isaac S. Harris
Journal: Cancer Research (2024)

Abstract Glutathione (GSH), the most abundant antioxidant, scavenges free radicals and prevents the detrimental effects of oxidative stress. As a result, GSH levels are associated with protection from stress-related conditions, such as aging and cancer. Given this rationale, antioxidants are routinely consumed by the public, mainly because they are viewed as “cure-alls” and almost uniformly beneficial to a range of diseases. This is an oversimplification, as the relationship between antioxidants and diseases is much more complex. Recent evidence has implicated GSH in protecting cancer cells from oxidative stress and promoting their survival. Therefore, understanding GSH metabolism in vivo and its intricate crosstalk with other cellular pathways is vital to improving the efficacy of therapies for diseases, including cancer. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance via the LXR/SREBP signaling pathway, as well as by repressing NRF2, a transcription factor induced by oxidative stress. Overall, these findings suggest an essential function for GSH in maintaining circulating lipids levels and lipid depots, possibly as a mechanism to prevent lipid peroxidation and redox imbalances. Notably, the accumulation of oxidized lipids propagates oxidative stress and associated cell death phenotypes (i.e., ferroptosis). This also highlights a potentially novel mechanism by which GSH regulates lipid production and suggests a possible link between oxidative stress (caused by GSH deficiency) and cachexia (commonly characterized by loss of fat and lean mass), a disorder linked to cancer but poorly understood. Consequently, by elucidating the contributions of GSH to lipid homeostasis, we can better understand the basic biology surrounding GSH and obtain critical insight into potentially improving the treatment of cancer-related cachexia. Citation Format: Gloria Asantewaa, Emily T. Tuttle, Nathan P. Ward, Yun P. Kang, Yumi Kim, Madeline Kavanagh, Aaron R. Huber, Joshua Munger, Benjamin Cravatt, Calvin L. Cole, Gina M. DeNicola, Isaac S. Harris. Glutathione supports lipid abundance in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB292.
Abstract LB247: TCPAplus: An LLM-empowered chatbot for analyzing a large protein expression atlas of human cancers
Authors: Wei Liu, Jun Liu, Yitao Tang, Chaozhong Liu, Meiyi Song, Zhenlin Ju, Shweth V. Kumar, Yiling Lu, Rehan Akbani, Gordon Mills, Han Liang
Journal: Cancer Research (2024)

Abstract We present a comprehensive functional proteomics resource comprising nearly 9,000 samples from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, using ~500 high-quality antibodies through reverse phase protein arrays. To enhance its utility, we have developed an analytical chatbot harnessing advanced large language models. This intuitive platform empowers researchers to effortlessly query protein-centered cancer omics data, conduct related analyses, and visualize results using natural language, significantly easing the translation from intricate proteogenomic data to valuable biological insights. Citation Format: Wei Liu, Jun Liu, Yitao Tang, Chaozhong Liu, Meiyi Song, Zhenlin Ju, Shweth V. Kumar, Yiling Lu, Rehan Akbani, Gordon Mills, Han Liang. TCPAplus: An LLM-empowered chatbot for analyzing a large protein expression atlas of human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB247.
Abstract LB349: Cysteine restriction enhances antitumor immunity in colorectal cancer
Authors: Jichang Li, Kang Xia, Zeruo Yang, Xiaoxue Pan, Xiaojing Yang, Pengyuan Wang, Shanwen Chen
Journal: Cancer Research (2024)

Abstract Background: Colon cancer is the second leading cause of cancer mortality worldwide, however, there are still issues with multidrug resistance and severe adverse reactions. Previous studies have shown that sulfur-containing amino acids are involved in cancer development, drug resistance, and immune evasion. Here, Our experimental findings suggested that restricting the intake of sulfur-containing amino acids may present a novel strategy for treating colorectal cancer. Methods: We assessed the impact of sulfur-containing amino acid restriction (SAR) on distinct cellular subpopulations within the tumor microenvironment through single-cell sequencing on colon carcinogenesis induced by azoxymethane/dextran sodium sulfate (AOM/DSS). Employing our custom-produced neutralizing antibodies against SLC7A11 to restrict cysteine intake, we examined the therapeutic implications and underlying molecular mechanisms by RNA-seq, Multiplexed immunofluorescence staining and Western blotting. Results: In the AOM/DSS model, SAR led to a slight reduction in mouse body weight compared to the normal diet. However, this dietary restriction significantly enhanced the survival rate of mice and effectively suppressed tumor growth. The single-cell sequencing results indicated a significant increase in the proportion of T cells within the tumor microenvironment in response to SAR. This suggested that restricting the intake of sulfur-containing amino acids may be a promising anti-tumor strategy. Previous studies have indicated high expression of the SLC7A11, a cysteine transporter protein, in various cancers, including colorectal cancer. To further investigate the role of cysteine in colorectal cancer, we developed the neutralizing antibody 1A4 against SLC7A11. Our results indicated that 1A4 markedly inhibited colorectal cancer development in mice. As known, 85% of colorectal cancers are microsatellite stable, which hardly benefit from treatment with immune checkpoint inhibitors (ICIs). Compared to anti-PD-1 and anti-CTLA4, 1A4 significantly inhibited the growth of CT26 in vivo. Multiplexed immunofluorescence staining results demonstrated that 1A4 significantly increased the proportion of CD8+ T cells in colorectal cancer tissues. Conclusion: Limiting cysteine intake significantly inhibits the growth of colorectal cancer, increases the proportion of CD8+ T cells, and enhances anti-tumor immunity. Citation Format: Jichang Li, Kang Xia, Zeruo Yang, Xiaoxue Pan, Xiaojing Yang, Pengyuan Wang, Shanwen Chen. Cysteine restriction enhances antitumor immunity in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB349.