tbuckley/cabot-search huggingface dataset:
Abstract 1439: NUDT5 is a critical regulator of triple-negative breast cancer growth
Authors: Jing Qian, William Tahaney, Yanxia Ma, Lakshmi Bollu, Abhijit Mazumdar, Jamal Hill, Yun Zhang, Powel Brown
Journal: Cancer Research (2020)

Abstract Background: Triple-negative breast cancers (TNBC) represent 15% of all breast cancers, and are highly aggressive cancers with poor clinical outcome. We have previously conducted a whole phosphatase RNA microarray analysis of TNBCs compared to estrogen receptor (ER)-positive breast cancers. These studies identified phosphatases that were either over-expressed or under-expressed in TNBCs as compared to ER-positive breast cancers. One of the phosphatases highly expressed in TNBCs was NUDT5, which hydrolyzes 8-oxo-dGDP and ADP-ribose (ADPR). Recent studies have shown that NUDT5 regulates cell cycle progression, and increases cellular ATP in response to hormone stimulation in cancer cells. However, the biological function of NUDT5 in TNBCs is largely unknown. Hypothesis: We hypothesized that NUDT5 is a critical phosphatase over-expressed in TNBCs that regulates the growth of these breast cancer cells. Methods: We analyzed TNBC NUDT5 mRNA expression and clinical outcome using publicly available TCGA, METABRIC, and the CCLE datasets. Overall survival was evaluated using Kaplan-Meier curves and compared using log-rank analysis (* p&amp;lt;0.05). We next conducted siRNA knockdown studies using DharmaFECT transfection, and subsequently measured the effect on growth using automated cell counting. Results at day 7 were expressed as mean cell numbers +/- standard deviation, and analyzed using Student's t-tests. Results: Analysis of NUDT5 mRNA expression demonstrated that NUDT5 is overexpressed in triple-negative breast cancers, specifically in the basal-like subtype of TNBC. Analysis of publically available breast cancer datasets showed that high NUDT5 expression is associated with poor overall survival of breast cancer patients. Knockdown of NUDT5 decreased TNBC growth, but did not decrease the growth of non-TNBC cells. Conclusions: Our results demonstrate that NUDT5 is a critical regulator of TNBC growth, and raise the possibility of targeting this critical phosphatase for the treatment of TNBC tumors. Future studies will investigate the function of NUDT5 in regulating nucleotide pool metabolism in TNBCs. Understanding the role of NUDT5 in controlling TNBC growth will provide the basic science foundation for the future development of NUDT5 inhibitors for the treatment of women with these aggressive, potentially life-threatening cancers. This work was supported by Susan G Komen Promise Grant (PB), and the John Charles Cain Endowment (PB). Citation Format: Jing Qian, William Tahaney, Yanxia Ma, Lakshmi Bollu, Abhijit Mazumdar, Jamal Hill, Yun Zhang, Powel Brown. NUDT5 is a critical regulator of triple-negative breast cancer growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1439.
Comparative Trends in Percutaneous Coronary Intervention in Japan and the United States, 2013 to 2017
Authors: Taku Inohara, Shun Kohsaka, John A. Spertus, Frederick A. Masoudi, John S. Rumsfeld, Kevin F. Kennedy, Tracy Y. Wang, Kyohei Yamaji, Tetsuya Amano, Masato Nakamura
Journal: Journal of the American College of Cardiology (2020)
Abstract 1029: Epigenetic control of tumor-infiltrating lymphocyte metabolic-exhaustion
Authors: Brian Koss, Bradley D. Shields, Erin M. Taylor, Aaron J. Storey, Stephanie D. Byrum, Allen J. Gies, Charity L. Washam, Samrat Roy Choudhury, Jeong Hyun Ahn, Hidetaka Uryu, Kimberly J. Krager, Tung-Chin Chiang, Samuel G. Mackintosh, Rick D. Edmondson, Nukhet Aykin-Burns, Gang Greg Wang, Alan J. Tackett
Journal: Cancer Research (2020)

Abstract Direct competition between tumor-infiltrating lymphocytes and cancer cells for metabolic resources often renders T cells dysfunctional. It is becoming clearer that T cell metabolic changes can precede functional exhaustion. In the case of solid tumors, the driving force of this dysfunction is thought to be a result of inhibitory metabolism (e.g. glucose deprivation and mitochondrial dysfunction). The mechanisms connecting inhibitory metabolism and T cell metabolic exhaustion are largely unknown. Interestingly, T cells undergo a loss of the histone methyltransferase EZH2 (H3K27me3) during tumor infiltration. Methyltransferases, like EZH2, depend on mitochondria to supply S-Adenosyl-L-Methionine (SAM), the primary methyl donor. We sought to determine if there was a link between EZH2 and mitochondrial function. In this work, we utilized highly specific EZH2 inhibitors to model acute inhibition of EZH2 in CD8+ and CD4+ T cells. Taking an unbiased, multi-omics approach (proteomics, RNAseq, ChIPseq) we fully interrogate the downstream consequences of EZH2 inhibition in T cells. The loss of H3K27me3 does indeed lead to an induction of mitochondrial dysfunction, which in turn, drives a dependency on glycolytic metabolism and sensitivity to glucose withdrawal. The metabolic shift phenotype was confirmed using extracellular metabolic flux analysis. In T cells, we found the loss of H3K27me3 repression of the Cdkn2aArf locus to be a major contributor to mitochondrial dysfunction, independent of the canonical role to stabilize p53. Furthermore, we show Arf-/- mice are resistant to EZH2-inhibition induced mitochondrial dysfunction. Reprogramming tumor-specific T cells to exogenously express a gain-of-function EZH2 mutant (Y641F) resulted in an enhanced ability of T cells to inhibit solid tumor growth. This work demonstrates the potential for manipulation of EZH2 in cellular therapies for solid tumors with harsh metabolic conditions and sheds light on the dynamic interplay of epigenetics and metabolic sufficiency. Citation Format: Brian Koss, Bradley D. Shields, Erin M. Taylor, Aaron J. Storey, Stephanie D. Byrum, Allen J. Gies, Charity L. Washam, Samrat Roy Choudhury, Jeong Hyun Ahn, Hidetaka Uryu, Kimberly J. Krager, Tung-Chin Chiang, Samuel G. Mackintosh, Rick D. Edmondson, Nukhet Aykin-Burns, Gang Greg Wang, Alan J. Tackett. Epigenetic control of tumor-infiltrating lymphocyte metabolic-exhaustion [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1029.
Abstract 2145: <i>Ex vivo</i> phenotyping and potency monitoring of CD19 CAR T cells with a combined flow cytometry and impedance-based real time cell analysis workflow
Authors: Li Zhao, Ming Lei, Peifang Ye, Yan Lu, Xiaoping Ji, Yu Yan, Lauren Jachimowicz, Garret Guenther, Nancy Li
Journal: Cancer Research (2020)

Abstract Immunotherapy harnesses the immune system to attack cancer cells. While immunotherapy holds tremendous promise for cancer treatment, significant challenges remain in clinical translation. Further development is still required to expand treatment to more cancers and minimize adverse effects. T-cell differentiation and exhaustion influence the establishment and persistence of CAR-expressing T cells. Evaluation of the potency of CAR T cells is essential for effective immunotherapies. Here, we study the potency of CAR-T cells using a combined impendence-based Real-Time Cell Analysis (RTCA) and flow cytometry cell analysis workflow for ex vivo cytolytic potency monitoring of CD19 CAR T cells (CART19). CART19 cell killing of CD19 expressing HEK-293 cells with different E:T (Effector to Target) ratio was monitored by the xCELLigience RTCA system. Concurrently, T cell cytokine production was measured on the NovoCyte Quanteon. This workflow provides a thorough examination of CART cell function, RTCA data demonstrates that CART19 killing is highly potent as well as being antigen-specific and dose-dependent. In conjunction, more cytokine was produced with higher numbers of effector CART19 cells. It was also observed that CART19 cells express stem memory cell (TSCM) markers, expressing activation and exhaustion markers after expansion. Co-culture with HEK-293-CD19 also results in increased expression of CD25, decreased expression of CD127 and upregulation of exhaustion markers, PD-1, TIM-3, and LAG-3. In summary, this study demonstrates the combination of RTCA and flow cytometry cell analysis is a powerful workflow for immunotherapy research and can be employed for QC in CAR T cell manufacturing. Citation Format: Li Zhao, Ming Lei, Peifang Ye, Yan Lu, Xiaoping Ji, Yu Yan, Lauren Jachimowicz, Garret Guenther, Nancy Li. Ex vivo phenotyping and potency monitoring of CD19 CAR T cells with a combined flow cytometry and impedance-based real time cell analysis workflow [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2145.
Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial
Authors: Robert J. Motzer, Paul B. Robbins, Thomas Powles, Laurence Albiges, John B. Haanen, James Larkin, Xinmeng Jasmine Mu, Keith A. Ching, Motohide Uemura, Sumanta K. Pal, Boris Alekseev, Gwenaelle Gravis, Matthew T. Campbell, Konstantin Penkov, Jae Lyun Lee, Subramanian Hariharan, Xiao Wang, Weidong Zhang, Jing Wang, Aleksander Chudnovsky, Alessandra di Pietro, Amber C. Donahue, Toni K. Choueiri
Journal: Nature Medicine (2020)
Abstract 6139: Sex-dependent development of anal squamous cell carcinoma in <i>Kras</i>-mutant mice
Authors: Morgan Walcheck, Jessica Noel, Manabu Nukaya, Kristina Matkowskyj, Sean Ronnekleiv-Kelly
Journal: Cancer Research (2020)

Abstract A historical over-reliance on male animals in research studies has clouded sex differences in pathologic diseases. This led to a mandate from the NIH requiring the use of both male and female animals in preclinical studies. Our study began with the aim to evaluate both sexes of KC mice (LSL-KrasG12D/+; Pdx1-Cre), a standard pre-clinical model for pancreatic ductal adenocarcinoma (PDAC). This was because previous characterization of this model to advanced age (9-12 months) only included males, and evaluating both sexes was an essential foundation for subsequent studies of PDAC progression. Twenty-eight KC mice have been evaluated, comprised of 15 males and 13 females. KC mice developed the expected pancreatic cancer pre-cursor lesions called PanINs (100% PanIN1, 7% PanIN 2 and 7% PanIN 3) and PDAC (14%) at an established time point (age 9 months). Surprisingly, female KC mice developed anal lesions, a finding that has not previously been described. Histopathologic analysis demonstrated anal squamous cell carcinoma (SCC), with all 13 KC females developing anal SCC compared to 0/15 in KC males and 0/83 control mice (Table 1). Genotyping for activated Kras mutation confirmed the presence of KrasG12D, indicating Pdx1 expression (Pdx1-Cre) in the anal tumor tissue. To understand the distinct sex differences and connection to sex-dependent steroids (estrogen and testosterone), female mice were ovariectomized (n = 5) and males castrated (n = 6). Remarkably, while 5/5 females developed anal SCC (i.e. unchanged phenotype), 6/6 males developed anal SCC, a stark contrast to the absence of tumor development in non-castrated KC males. This suggests a novel mechanism in which Kras driven anal SCC tumor development is suppressed through testosterone / dihydrotestosterone (DHT) exposure. Follow-up studies will focus on the mechanism by which testosterone or DHT suppresses Kras-driven anal SCC formation. These findings may ultimately have therapeutic implications for the subset of patients with Kras-mutant anal SCC. Table 1:Characterization and Incidence of Anal SCC TumorsGroupMouseAnal SCC IncidenceControlC57Bl6 Male (n=12)0/12 (0%)ControlC57Bl6 female (n=11)0/11 (0%)ControlKrasG12D/+ Female (n=9)0/9 (0%)ControlKrasG12D/+ Male (n=18)0/18 (0%)ControlPDX1-Cre male (n=10)0/10 (0%)ControlPDX1-Cre Female (n=23)0/23 (0%)KC MiceKC Male (n=15)0/15 (0%)KC MiceKC Female (n=13)13/13 (100%)Study KC MiceCastrated KC Male (n=6)6/6 (100%)Study KC MiceOvariectomized KC Female (n=5)5/5 (100%) Citation Format: Morgan Walcheck, Jessica Noel, Manabu Nukaya, Kristina Matkowskyj, Sean Ronnekleiv-Kelly. Sex-dependent development of anal squamous cell carcinoma in Kras-mutant mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6139.
Abstract 4822: The 3'UTR of <i>CAPZA1</i> functions separately and oppositely to its host gene in ESCC
Authors: Dan Li, Nan Kang, Zhangfu Li, Qimin Zhan
Journal: Cancer Research (2020)

Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and highly prevalent in China. According to our previous study on whole-genome sequencing (WGS) and whole-exome sequencing (WES) of ESCC, we identified that CAPZA1 displayed copy number losses in the ESCC sequencing cohort. CAPZA1, which modulates the dynamic assembly of actin filament and cell motility, has been reported dysregulated expression in neuroblastoma, gastric cancer, liver cancer and breast cancer. However, the functional role and the underlying mechanism of CAPZA1 in ESCC have not been elucidated. Here, we identify the expression of CAPZA1 significantly decreased in cancer tissues than in normal tissues by immunohistochemical assay. Through gain and loss of function approaches, we found that CAPZA1 suppressed the proliferation, migration and invasion of ESCC cells in vivo and in vitro. Moreover, we found that CAPZA1 promoted the expression of E-cadherin, while decreased the expression of Vimentin and Twist. Intriguingly, we demonstrated that the 3'UTR of CAPZA1 could function as an independent RNA molecule separately with a full length of 1487nt by RACE and Northern-blot assays. Furthermore, the RNA in situ hybridization assay was employed to validate that 3'UTR expression levels were significantly higher in cancer tissues than in normal tissues. Additionally, the 3'UTR promoted cell migratory and invasive capabilities, which is oppositely to its host gene CAPZA1. The 3'UTR performed oncogenic role by enhancing the combination of IGF2BPs proteins to c-myc mRNA and promoted the translation of c-myc. These findings offer a new dimension to the crosstalk between 3'UTR and its host gene, which may open new ways towards additional therapeutic strategies in the treatment of ESCC. Citation Format: Dan Li, Nan Kang, Zhangfu Li, Qimin Zhan. The 3'UTR of CAPZA1 functions separately and oppositely to its host gene in ESCC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4822.
Abstract 985: SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of early-stage myeloid-derived suppressor cells via the miR-155/C/EBPβ/Wnt axis
Authors: Wenwen Zhang, Mengmeng Jiang, Rui Zhang, Pengpeng Liu, Yingnan Ye, Xiubao Ren, Wenwen Yu, Jinpu Yu
Journal: Cancer Research (2020)

Abstract Early-stage myeloid-derived suppressor cells (eMDSCs) are a newly defined subset of myeloid-derived suppressor cells (MDSCs) that accumulate densely in tumors and potently promote tumor growth and metastasis by suppressing antitumor immune responses in vitro and in vivo. We previously identified a subset of eMDSCs in human breast cancer with a characteristic phenotype of Lin-HLA-DR-CD33+. We also found that SOCS3 deficiency and sustained activation of the JAK/STAT signaling pathway are critical molecular events coordinating the differentiation of eMDSCs, although the distinct molecular regulation has not been fully elucidated. Herein, we genetically constructed conditional SOCS3 knockout mice with SOCS3 deficiency specifically in the myeloid linage (SOCS3MyeKO). We delineated that the number of eMDSCs in SOCS3MyeKO mice (eMDSCsSOCS3KO) with the murine GMP phenotype increased significantly, and these cells suffered from a differentiation block in the myeloid lineage. To explore which pathways participated in dysfunctional eMDSC differentiation, we performed whole-genome RNA sequencing and miRNA microarray on CD11b+Gr-1+ cells, eMDSCsfl/fl and eMDSCsSOCS3KO to screen the potential regulatory ceRNA network in eMDSCsSOCS3KO. CD11b+Gr-1+ cells isolated from SOCS3fl/fl mouse spleens were used as mature myeloid cell controls. The transcriptome results and corresponding intervention experiment revealed that the differentiation block in eMDSCsSOCS3KO was caused by SOCS3 deficiency-mediated limited autophagy activation in an AMPK-independent manner. The results of miRNA microarray and RNA sequencing demonstrated that miR-155 overexpression and Wnt/β-catenin pathway activation were involved in the SOCS3 knockout-mediated myeloid differentiation block and autophagy repression. Further experiments revealed that miR-155 was induced by activation of the STAT3/NK-κB pathway upon SOCS3 deficiency, which consequently activated the Wnt/β-catenin pathway via targeting C/EBPβ. Furthermore, applying a specific miR-155 antagonist or the autophagy agonist rapamycin efficiently suppressed tumor growth and eMDSC infiltration in vivo. Overall, these findings indicated that SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of e-MDSCs via the miR-155/C/EBPβ/Wnt axis, and thus targeted therapy against this pathway could be a potential therapeutic target in breast cancer. Citation Format: Wenwen Zhang, Mengmeng Jiang, Rui Zhang, Pengpeng Liu, Yingnan Ye, Xiubao Ren, Wenwen Yu, Jinpu Yu. SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of early-stage myeloid-derived suppressor cells via the miR-155/C/EBPβ/Wnt axis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 985.
Abstract 5751: Patient-reported toxicities in head and neck cancer patients treated with immunotherapy
Authors: Brian W. James, Aasha I. Hoogland, Nathaly Irizarry-Arroyo, Jameel Muzaffar, Kedar Kirtane, Julie A. Kish, Heather S. Jim, Christine H. Chung
Journal: Cancer Research (2020)

Abstract Background: Immune checkpoint inhibitors (ICIs) (i.e. nivolumab, pembrolizumab) are FDA-approved agents used in the treatment of various head and neck malignancies. While much is known about clinician-rated adverse clinical events of these immunotherapies from clinical trials, less is known about patient-reported toxicities. The goal of the current study was to describe patient-reported toxicities in patients receiving ICIs for head and neck cancer. Methods: Patients with head and neck cancer were recruited as part of a larger study on quality of life on ICIs. Prior to initiation of ICIs, participants completed a sociodemographic questionnaire and a measure of symptomatic toxicities of ICIs developed based on input form providers, patients, and caregivers. Patients completed follow-up symptom assessments every 6-8 weeks until cancer progression. Severity of each symptom over the past 7 days was rated on a 5-point scale (i.e., 0 = “not at all,” 4 = “very much”). A score of 3 or 4 was considered moderate to severe symptomatology. Results: There were 45 patients (22% female; M age = 62), who completed a least 2 symptom assessments before cancer progression. The five most common moderate to severe symptoms at baseline were fatigue (27%), changes in taste (18%), insomnia (16%), coughing (11%), and muscle aches (9%). At the assessment before cancer progression, the five most common moderate to severe symptoms were fatigue (38%), insomnia (24%), rash (13%), cough (13%), and numbness in hands and feet (13%). From the baseline assessment to the last symptom assessment preceding progression, most patients reported worsening skin dryness (49%), skin sensitivity (46%), weakness in arms of legs (46%), and itching (42%). Most patients also reported worsening fatigue (49%), although a large subset reported improvements in fatigue (36%). Conclusion: Results indicate that fatigue and insomnia are the most common and severe patient-reported toxicities of ICIs for head and neck cancer. These preliminary findings warrant larger future studies with longer follow-up to better understand changes in patient-reported toxicities in this population. Citation Format: Brian W. James, Aasha I. Hoogland, Nathaly Irizarry-Arroyo, Jameel Muzaffar, Kedar Kirtane, Julie A. Kish, Heather S. Jim, Christine H. Chung. Patient-reported toxicities in head and neck cancer patients treated with immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5751.
Abstract 1457: Akt phosphorylation of mitochondrial Lonp1 protease enables oxidative metabolism and advanced tumor traits
Authors: Jagadish C. ghosh, Jae Ho Seo, Ekta Agarwal, Yuan Wang, Andrew V. Kossenkov, Hsin-Yao Tang, David W. Speicher, Dario C. Altieri
Journal: Cancer Research (2020)

Abstract Introduction: The control of protein homeostasis, or proteostasis is essential for cellular adaptation to disparate environmental cues and relies on protein (re)folding or proteolytic removal of aggregated or misfolded proteins. Defective proteostasis can irreversibly impair organelle functions and activate cell death through an unfolded protein response. Tumor mitochondria have heightened protein folding quality control, but the regulators of this process and how they impact cancer traits are not completely understood. In this study, we investigated the mechanisms of stress-regulated LonP1 (ATP-dependent protease) in tumor mitochondria and their implications for advanced cancer traits. Experimental procedures: We monitored kinase activity in immunoprecipitation, protein expression by immunoblotting, mitochondrial ROS quantification in live cells, mitochondrial electron transport chain (ETC) activity, mitochondria time-lapse video microscopy, protein folding, proteomics analysis, mitochondrial bioenergetics, mitochondrial trafficking and tumor cell motility, and tumor growth and metastasis. A xenograft prostate cancer model was used to study antitumor activity in vivo. Results: We showed that the ATP-directed mitochondrial protease, LonP1 is upregulated by stress conditions, including hypoxia, in tumor, but not normal cells. In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. Interference with this pathway induces accumulation of misfolded subunits of electron transport chain complex II and complex V, resulting in impaired oxidative bioenergetics and heightened ROS production. Functionally, this suppresses mitochondrial trafficking to the cortical cytoskeleton, shuts off tumor cell migration and invasion, and inhibits primary and metastatic tumor growth, in vivo. Conclusion: These data identify LonP1 as a key effector of mitochondrial reprogramming in cancer and potential therapeutic target. Citation Format: Jagadish C. ghosh, Jae Ho Seo, Ekta Agarwal, Yuan Wang, Andrew V. Kossenkov, Hsin-Yao Tang, David W. Speicher, Dario C. Altieri. Akt phosphorylation of mitochondrial Lonp1 protease enables oxidative metabolism and advanced tumor traits [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1457.