tbuckley/cabot-search huggingface dataset:
Abstract 6229: MDM2 inhibitors sensitize testicular cancer models to mTORC1/2 inhibitors and cisplatin
Authors: Steven de Jong, Gerda de Vries, Gert Jan Meersma, Albert J.H. Suurmeijer, Marcel A.T.M. van Vugt, Jourik A Gietema
Journal: Cancer Research (2020)

Abstract Testicular cancer (TC) is one of the most common solid tumors in young men that can effectively be treated with cisplatin-based chemotherapy. However, 10% of those wild type p53 expressing TC patients will not survive their disease. The aim of this study was to identify effective combinations with MDM2 inhibitors in TC models. A panel of cisplatin sensitive and -resistant human TC cell lines and TC patient-derived xenograft (PDX) models have been treated with MDM2 inhibitors (Nutlin-3a, RG7388), cisplatin and AKT/mTORC1/2 inhibitors (MK2206, AZD8055 and INK128). Survival, apoptosis, and clonogenic assays were performed. Transcriptional activity of p53 was determined using chromatin immunoprecipitation (CHIP) followed by quantitative PCR of target promoters. Mechanisms of apoptosis induction were studied by measuring mitochondrial priming, siRNA approaches and BH3 mimetics. We found that MDM2 inhibitors sensitized TC cell lines to cisplatin and mTORC1/2 inhibition. Nutlin-3a in combination with cisplatin or AZD8055 treatment induced caspase 3 and PARP cleavage and reduced clonogenic outgrowth. Enriched p53 binding to the promoter regions of known activators of extrinsic and intrinsic apoptosis, FAS, PUMA and NOXA, was observed in response to Nutlin-3a or cisplatin. BH3 profiling of mitochondria and siRNA mediated silencing identified PUMA and NOXA as key pro-apoptotic proteins in TC cell lines. Interestingly, addition of the BH3 mimetics ABT-737 and A-1210477, mimicking PUMA and NOXA respectively, to combination treatments shifted the balance towards apoptosis as well. In vivo experiments showed reduced tumor growth especially in the wild type p53 PDX model TC1 treated with RG7388/cisplatin, which was reflected in p53 activation and increased caspase-3 activity. No potentiating effect of this combination was observed in the p53 wild type PDX model TC4. In conclusion, we have demonstrated that targeting of MDM2 in combination with chemotherapy can be very effective in TC models. Our results warrant further investigation of this drug combination in the treatment of TC. Supported by a grant from the Dutch Cancer Society (RUG 2014-6691) Citation Format: Steven de Jong, Gerda de Vries, Gert Jan Meersma, Albert J.H. Suurmeijer, Marcel A.T.M. van Vugt, Jourik A Gietema. MDM2 inhibitors sensitize testicular cancer models to mTORC1/2 inhibitors and cisplatin [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 6229.
Abstract 6016: The impact of cancer stem cell markers in the tissues of pancreatic ductal adenocarcinoma for prognosis after surgical resections
Authors: Yoshikuni Inokawa, Suguru Yamada, Masamichi Hayashi, Yuki Sunagawa, Fuminori Sonohara, Hideki Takami, Norifumi Hattori, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera
Journal: Cancer Research (2020)

Abstract Introductions: The prognosis after resection of pancreatic ductal adenocarcinoma (PDAC) is still limited though the survival benefit is recently reported by neo-adjuvant chemotherapy (NAC). The existence of cancer stem cells (CSCs) is known as one of the important mechanisms for cancer cells to survive against chemotherapy. We hypothesized that the population of CSCs among cancer cells after chemotherapy could contribute recurrence after surgical resections, and could be detected by some CSC markers. Methods: We checked elevation of CSC markers in resected cases after pre-operative therapy (NAC with gemcitabine plus nab-paclitaxel, n=3; NAC with FOLFIRINOX, n=3; and neo-adjuvant chemo-radiotherapy (NACRT) with S1+Radiation, n=3) compared to surgery alone (n=3) with RT2 Profiler PCR Array. As CSC models, we performed sphere formation assay with PDAC cell lines (Panc1 and BXPC3) and evaluated the expression of CSC markers with qRT-PCR. Then, we performed qRT-PCR with 48 PDAC resected cases including 26 cases with pre-operative therapy (54%). Results: RT2 Profiler PCR Array showed higher expression of some CSC markers with pre-operative treatment (n=9) than without them (n=3). Spheroid assay showed elevation of CSC markers in spheroid compared to parental cells (Panc1: 10 among 16 markers, BXPC3 14 among 16 markers). In the cohort of 48 resected PDAC patients, ALDH1, Nanog, SOX2, MYC CXCR4 and DCLK1 showed significantly higher expression in pre-operative therapy than in surgery alone (P&amp;lt;0.05). About prognosis, higher expression of YAP1 in tumor tissues showed worse outcomes of recurrence free survival (RFS) (P=0.06), and higher CXCR4 in adjacent parenchyma of pancreas showed worse RFS among patients with NAC and NACRT (P=0.08). Conclusions: Our findings indicated that CSCs are more in resected tissues after NAC and NACRT than in without pre-operative therapy. YAP1 expression in tumors or CXCR4 in adjacent parenchyma of pancreas can be prognosis markers after surgical resection for PDAC. Citation Format: Yoshikuni Inokawa, Suguru Yamada, Masamichi Hayashi, Yuki Sunagawa, Fuminori Sonohara, Hideki Takami, Norifumi Hattori, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera. The impact of cancer stem cell markers in the tissues of pancreatic ductal adenocarcinoma for prognosis after surgical resections [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 6016.
Abstract 1796: Requirement for LIM kinases in acute myeloid leukemia
Authors: Patrizia Jensen, Michela Carlet, Jana Kress, Andrea Weber, Ines Brunner, Mikolaj Slabicki, Gregor Grill, Simon Weisemann, Ya-Yun Cheng, Irmela Jeremias, Claudia Scholl, Stefan Fröhling
Journal: Cancer Research (2020)

Abstract Acute myeloid leukemia (AML) is a highly aggressive disease which, in spite of extensive research in the last decades, is still treated with conventional chemotherapeutic regimens in most cases. Recent approvals of FLT3 and IDH1/2 inhibitors have highlighted the promise of targeted approaches for personalized AML therapy. However, the majority of AML driver mutations currently remain “undruggable”, making the search for additional molecular targets imperative. LIM kinases 1 and 2 (LIMK1/LIMK2), which are primarily known for regulating actin dynamics via phosphorylation of the actin-depolymerizing factor cofilin, have previously been implicated in progression and metastasis formation of several epithelial tumors. However, their function in leukemia, and AML in particular, has not been addressed in detail. Using high-throughput RNA interference (RNAi) screens in AML cell lines, we identified LIMK1 as a potential novel molecular target for AML treatment. High LIMK1 expression was significantly correlated with shorter survival of AML patients, and was associated with NPM1 and DNMT3A mutations, MLL rearrangements, and elevated HOX gene expression. RNAi- and CRISPR/Cas9-mediated suppression, as well as pharmacologic inhibition of LIMK1 and its close homolog LIMK2, reduced colony formation and decreased proliferation due to slowed cell cycle progression of MLL-rearranged AML cell lines and patient-derived xenograft samples. This was accompanied by morphologic changes indicative of myeloid differentiation. Transcriptome analysis showed upregulation of several tumor suppressors as well as downregulation of HOXA9 targets and mitosis-associated genes in response to LIMK1 suppression, providing a potential mechanistic explanation for the anti-leukemic phenotype. Finally, we observed a mutual regulation between LIMK1 and CDK6, a kinase known to be involved in the differentiation block of MLL-rearranged AML, and addition of the CDK6 inhibitor palbociclib further enhanced the anti-proliferative effect of LIMK1 depletion. Our data therefore suggest that LIM kinases are promising targets for AML therapy. Citation Format: Patrizia Jensen, Michela Carlet, Jana Kress, Andrea Weber, Ines Brunner, Mikolaj Slabicki, Gregor Grill, Simon Weisemann, Ya-Yun Cheng, Irmela Jeremias, Claudia Scholl, Stefan Fröhling. Requirement for LIM kinases in acute myeloid leukemia [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 1796.
Abstract 15532: Telemedicine to Guide AMI Management - Introducing a New Metric for Evaluating Efficiency
Authors: Sameer Mehta, Roberto Botelho, Jamil Cade, Marco Perin, Mauricio Prudente, Ricardo Cavalcanti, Rodolfo Cardoso, Freddy Bojanini, Nabil Hamdan, Cesar Dusilek, Marco Alcocer, Juan Carlos Perez Alva, Alfredo Estrada, Manuel Odin De Los Rios, Alejandra Frauenfelder, Daniel Vieira, Mariana Ceschim, Gladys Pinto, Samantha Quintero, Francisco Nola, Maria I Acosta, Claudia Lopez, Seyna Krisciunas, Jose S Aguilar, Lilly Prieto, Akhil Vaid
Journal: Circulation (2019)

Introduction: Telemedicine protocols can guide population-based AMI by teleconsulting the entire STEMI process and procedure. We have previously reported on the application of telemedicine to reduc...
Lactate Induces Production of the tRNAHis Half to Promote B-lymphoblastic Cell Proliferation
Authors: Xiaohui Mo, Shujuan Du, Xiaoting Chen, Yuyan Wang, Xiaoqing Liu, Chongqi Zhang, Caixia Zhu, Ling Ding, Ying Li, Yin Tong, Qiang Ju, Di Qu, Fei Tan, Fang Wei, Qiliang Cai
Journal: Molecular Therapy (2020)

High plasma lactate is emerging as a critical regulator in development and progression of many human malignancies. Small RNAs derived from cleavage of mature tRNAs have been implicated in many cellular stresses, but the detailed mechanisms that respond to lactic acid (LA; acidic lactate) are not well defined. Here, using an Epstein-Barr virus (EBV)-immortalized B lymphoblastic cell line (LCL) as a model, we report that LA induces cleavage of mature tRNA at the anticodon loop, particularly production of three 5′-tRNA halves (5′-HisGUG, 5′-ValAAC, and 5′-GlyGCC), along with increased expression of RNA polymerase III and angiogenin (ANG). Of these, only the 5′-HisGUG half binds to the chromatin regulator argonaute-2 (AGO2) instead of the AGO1 protein for stability. Notably, the levels of ANG and 5′-HisGUG half expression in peripheral blood mononuclear cells from B cell lymphoma patients are tightly correlated with lactate dehydrogenase (LDH; a lactate indicator) in plasma. Silencing production of the 5′-HisGUG half by small interfering RNA or inhibition of ANG significantly reduces colony formation and growth of LA-induced tumor cells in vitro and in vivo using a murine xenograft model. Overall, our findings identify a novel molecular therapeutic target for the diagnosis and treatment of B cell lymphoma. High plasma lactate is emerging as a critical regulator in development and progression of many human malignancies. Small RNAs derived from cleavage of mature tRNAs have been implicated in many cellular stresses, but the detailed mechanisms that respond to lactic acid (LA; acidic lactate) are not well defined. Here, using an Epstein-Barr virus (EBV)-immortalized B lymphoblastic cell line (LCL) as a model, we report that LA induces cleavage of mature tRNA at the anticodon loop, particularly production of three 5′-tRNA halves (5′-HisGUG, 5′-ValAAC, and 5′-GlyGCC), along with increased expression of RNA polymerase III and angiogenin (ANG). Of these, only the 5′-HisGUG half binds to the chromatin regulator argonaute-2 (AGO2) instead of the AGO1 protein for stability. Notably, the levels of ANG and 5′-HisGUG half expression in peripheral blood mononuclear cells from B cell lymphoma patients are tightly correlated with lactate dehydrogenase (LDH; a lactate indicator) in plasma. Silencing production of the 5′-HisGUG half by small interfering RNA or inhibition of ANG significantly reduces colony formation and growth of LA-induced tumor cells in vitro and in vivo using a murine xenograft model. Overall, our findings identify a novel molecular therapeutic target for the diagnosis and treatment of B cell lymphoma.
Abstract 2895: Characterization of payload release from a novel camptothecin drug-linker
Authors: Julia H. Cochran, Lauren Farr, Ryan Lyski, Peter D. Senter, Scott C. Jeffrey, Shawna M. Hengel, Nicole M. Okeley
Journal: Cancer Research (2020)

Abstract Camptothecins (CPT) are an important class of molecules that have been employed in cancer therapy for the past 20 years. These molecules interact with the DNA-topoisomerase I complex leading to double-strand breaks and cell death. While these molecules are important cancer therapies, they also induce toxicities including diarrhea and myelosuppression. Antibody-drug conjugates (ADCs) have emerged as a method to help mitigate small molecule toxicities by targeting them to tumors via conjugation to tumor-specific antibodies. Recently, encouraging clinical results have been observed with ADCs bearing CPT payloads, demonstrating a potential new utility for this class. The linker that is used to conjugate a payload to an ADC influences its activity, by controlling the identity of the molecular species that can be released, as well as efficiency of drug release. When employed as an ADC, maleimidopropionyl-PEG7-valine-lysine-glycine-7-aminomethyl-10,11-methylenedioxycamptothecin (VKG-AMDCPT), a novel, highly active and enzyme-cleavable tripeptide CPT drug-linker, releases two CPT payloads in cancer cells, as demonstrated both in vitro and in vivo. Using tandem mass spectrometry (LC-MS/MS), the two CPTs have been identified as 7-amino methyl 10,11-methylenedioxy CPT (AMDCPT) and the corresponding glycine adduct of AMDCPT (G-AMDCPT). We have characterized the efficiency of drug release and intracellular retention of the small molecules released from VKG-AMDCPT-conjugated ADCs. This was accomplished through quantification of each species released in vitro and in vivo using multiple cancer cell lines and xenografts. We report here characterization of the biochemical, cellular and bystander killing potencies of each released drug species to further understand their contributions to ADC activity. Citation Format: Julia H. Cochran, Lauren Farr, Ryan Lyski, Peter D. Senter, Scott C. Jeffrey, Shawna M. Hengel, Nicole M. Okeley. Characterization of payload release from a novel camptothecin drug-linker [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 2895.
Abstract 6154: H3K27M gliomas are characterized by a stall in the epithelial-mesenchymal transition
Authors: ALLISON R. CHENEY, Lauren M. Sanders, Lucas Seninge, Holly C. Beale, Ellen Towle Kephart, Jacob Pfeil, Katrina Learned, A. Geoffrey Lyle, Isabel Bjork, David Haussler, Sofie R. Salama, Olena M. Vaske
Journal: Cancer Research (2020)

Abstract Pediatric diffuse midline gliomas are lethal cancers, the majority of which harbor the H3 p.K27M mutations. Although it has potential implications on the treatment of diffuse midline glioma as a disease driver; the timing, cell type of origin, and effect of the H3 p.K27M mutation on early embryonic brain development is poorly understood. The purpose of our study is to elucidate the molecular mechanisms by which the histone H3 p.K27M mutation drives tumorigenesis of pediatric diffuse midline gliomas using the analysis of genomic datasets. Here, we performed differential RNA sequencing gene expression analysis of a cohort of H3K27M and H3 wild type (WT) pediatric diffuse midline gliomas, revealing that genes in the epithelial-mesenchymal transition (EMT) pathway were significantly differentially expressed between the mutant and WT tumors. Several EMTs are required for normal brain development. Overall, pre-EMT genes, including the master regulator of EMT SNAI1, were overexpressed in H3K27M tumors compared to the WT tumors, while post-EMT genes were underexpressed. We hypothesized that the H3 p.K27M mutation may lead to gliomagenesis by inducing a stall in the EMT in early brain development. To test this hypothesis, we examined published single-cell RNA sequencing data from pediatric diffuse midline gliomas alongside similar data from organoid models of neural development, collected from multiple developmental timepoints. This analysis revealed transcriptional similarities between H3K27M and pre-EMT neural stem cells. Currently, we are investigating the expression of EMT markers in H3K27M and WT pediatric glioma primary cell lines, using Western blotting, RT-PCR, and CRISPRi screening. In conclusion, we observed aberrant expression of genes involved in EMT in H3K27M pediatric gliomas. Our observations are consistent with a model in which the p.H3K27M mutation is associated with a pre-EMT cell phenotype, potentially due to an arrest in the EMT pathway or de-differentiation of mature astrocytes. Citation Format: ALLISON R. CHENEY, Lauren M. Sanders, Lucas Seninge, Holly C. Beale, Ellen Towle Kephart, Jacob Pfeil, Katrina Learned, A. Geoffrey Lyle, Isabel Bjork, David Haussler, Sofie R. Salama, Olena M. Vaske. H3K27M gliomas are characterized by a stall in the epithelial-mesenchymal transition [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 6154.
Abstract 510: Novel glutamine antagonist JHU-395 suppresses MYC-driven medulloblastoma growth and induces apoptosis
Authors: Khoa Pham, Micah Maxwell, Heather Sweeney, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2020)

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism, and medulloblastoma tumors with evidence of high glutamate have a poor prognosis. We modified the naturally occurring glutamine analog 6-diazo-5-oxo-l-norleucine (DON) to increase its lipophilicity and its stability in plasma, creating a prodrug termed JHU-395. We hypothesized that this prodrug would have enhanced cell penetration compared to DON and would kill MYC-expressing medulloblastoma. JHU-395 treatment caused decreased growth and increased apoptosis in human MYC-expressing medulloblastoma cell lines at lower concentrations than DON. In D283MED for example IC50 for DON is 20 uM while JHU 395 IC50 is 1 uM (p value &amp;lt; 0.05). Similar results were obtained with other high-MYC medulloblastoma cell lines, including D425MED and D341MED. JHU-395 induced apoptosis at low micromolar concentrations as measured by cleaved PARP Western blot and cleaved caspase 3 (CC3) immunofluorescence (60% CC3+ cells compared to 30% CC3+ in control p&amp;lt;0.05). Parenteral administration of JHU-395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain as measured by mass spectrometry. These data suggest that JHU-395 may have activity against high MYC medulloblastoma in vivo, and testing this prodrug against MYC-driven medulloblastoma orthotopic xenografts is currently underway. Citation Format: Khoa Pham, Micah Maxwell, Heather Sweeney, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe. Novel glutamine antagonist JHU-395 suppresses MYC-driven medulloblastoma growth and induces apoptosis [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 510.
Lactose-reduced infant formula with added corn syrup solids is associated with a distinct gut microbiota in Hispanic infants
Authors: Roshonda B. Jones, Paige K. Berger, Jasmine F. Plows, Tanya L. Alderete, Joshua Millstein, Jennifer Fogel, Stanislav N. Iablokov, Dmitry A. Rodionov, Andrei L. Osterman, Lars Bode, Michael I. Goran
Journal: Gut Microbes (2020)

Infant formula feeding, compared with human milk, has been associated with development of a distinct infant gut microbiome, but no previous study has examined effects of formula with added sugars. This work examined differences in gut microbiota among 91 Hispanic infants who consumed human milk [at breast (BB) vs. pumped in bottle (BP)] and 2 kinds of infant formula [(traditional lactose-based (TF) vs. lactose-reduced with added sugar (ASF)]. At 1 and 6 months, infant stool was collected to characterize gut microbiota. At 6 months, mothers completed 24-hour dietary recalls and questionnaires to determine infant consumption of human milk (BB vs. BP) or formula (TF vs. ASF). Linear regression models were used to determine associations of milk consumption type and microbial features at 6 months. Infants in the formula groups exhibited a significantly more 'mature' microbiome than infants in the human milk groups with the most pronounced differences observed between the ASF vs. BB groups. In the ASF group, we observed reduced log-normalized abundance of Bifidobacteriaceae (TF-BB Mean Difference = −0.71, ASF-BB Mean Difference = −1.10), and increased abundance of Lachnospiraceae (TF-BB Mean Difference = +0.89, ASF-BB Mean Difference = +1.20). We also observed a higher Community Phenotype Index of propionate, most likely produced by Lachnospiraceae, in the ASF group (TF-BB Mean Difference = +0.27, ASF-BB Mean Difference = +0.36). This study provides the first evidence that consumption of infant formula with added sugar may have a stronger association than birth delivery mode, infant caloric intake, and maternal BMI on the infant's microbiome at 6 months of age.