tbuckley/cabot-search huggingface dataset:
Abstract 3423: Elucidation of the role of miR-575 on tumorigenesis in glioblastoma
Authors: Ashley N. Gray, Tiantian Cui, Marjolein Geurts, Pierre Robe, Joseph McElroy, Erica Hlavin Bell, Arnab Chakravarti
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival rate less than 15 months, with only 3-5% of patients survive more than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. MiRNAs are small regulatory molecules that play a crucial role in carcinogenesis via repression of oncogenes and tumor-suppressor genes either transcriptionally or post-transcriptionally. Our clinical data (n=268) shows that miR-575 is one of the top miRNAs associated with GBM overall survival (FDR: 0.0036, p-value: 5.77E-05) by univariate analysis (NanoString Technologies; Seattle, WA). This study was designed to investigate the expression and function of miR-575 in GBM. Basal expression of miR-575 was first detected in GBM cell lines prior to functional experimentation. Cell proliferation, colony formation, migration and invasion assays were performed to understand the role of miR-575 in GBM. We found that overexpression of miR-575 significantly increased cell proliferation and cell motility in LN229 and U251 cell lines. Additionally, BLID, a tumor-suppressor gene, was negatively regulated by miR-575 at the transcriptional level by qRT-PCR, which will be further investigated at the post-transcriptional level by western blot. Up-regulation of miR-575 in GBM cell lines suggests that it could be acting as an oncogene by degrading the mRNA of BLID. Luciferase assays also showed negative regulation of BLID expression by miR-575, supporting our hypothesis and findings in other cancers. In conclusion, miR-575 might act as an oncogene in GBM, and BLID may be a putative target gene of miR-575. This mechanism could potentially be useful as a novel prognostic biomarker for GBM patients after further in vitro and in vivo validation. Funding: 1R01CA169368 (PI: Houghton; Co-I:Chakravarti); 1R01CA11522358 Multiple-PI R01: Chakravarti (PI); Xia (PI); 1R01CA1145128 Baroukhim (PI); Chakravarti (Co-PI) 7/2015-6/2020; R01CA108633 (PI:Chakravarti); 1RC2CA148190 (Scientific PI: Chakravarti). Citation Format: Ashley N. Gray, Tiantian Cui, Marjolein Geurts, Pierre Robe, Joseph McElroy, Erica Hlavin Bell, Arnab Chakravarti. Elucidation of the role of miR-575 on tumorigenesis in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3423. doi:10.1158/1538-7445.AM2017-3423
Abstract 1470: Fine-tuning the expression of heterogeneous network of genes involved in androgen signaling, aerobic glycolysis, apoptosis and epithelial-mesenchymal transition by microRNA-644a in prostate cancer potentiation of AR signaling therapy by miR-644a: Selective manipulation of the prostate cancer transcriptome by miR-644a
Authors: Jey Sabith Ebron, Jagjit Singh, Eswar Shankar, Crystal Weyman, Sanjay Gupta, Daniel J. Lindner, Girish C. Shukla
Journal: Cancer Research (2017)

Abstract Intratumoral Prostate cancer (PCa) heterogeneity is characterized by multiple intrinsic mechanisms including Androgen signaling, aerobic glycolysis, aberrant transcriptional activation of c-Myc and dysregulation of miRNAs. The ability of prostate cancer cells to alter growth and metabolism in a manner distinct from benign cells is a major concern in the treatment of castration-resistant prostate cancer. Therefore, targeting the diverse oncogenesis promoting pathways involved in PCa progression and resistance at the posttranscriptional level using micro RNAs (miRNAs) offers a novel therapeutic option. Using a miRNA mimic screen, we identified a human-specific miRNA miR-644a, which modulates expression of a diverse set of oncogenic pathways in PCa including androgen signaling, AKT/IGF-1R signaling, c-myc mediated signaling and EMT pathways. We have also demonstrated a potent tumor suppressive function of miR-644a in mouse prostate cancer xenograft model. miR-644a also sensitizes the PCa tumors to current therapeutic options including AR antagonist Enzalutamide by regulating the key modulators in development of drug resistance. In conclusion, our study demonstrates that miR-644a is a novel tumor suppressor miRNA regulating key prostate carcinogenesis promoting pathways. Citation Format: Jey Sabith Ebron, Jagjit Singh, Eswar Shankar, Crystal Weyman, Sanjay Gupta, Daniel J. Lindner, Girish C. Shukla. Fine-tuning the expression of heterogeneous network of genes involved in androgen signaling, aerobic glycolysis, apoptosis and epithelial-mesenchymal transition by microRNA-644a in prostate cancer potentiation of AR signaling therapy by miR-644a: Selective manipulation of the prostate cancer transcriptome by miR-644a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1470. doi:10.1158/1538-7445.AM2017-1470
Abstract 3632: BiTE® antibody constructs for the treatment of SCLC
Authors: Michael J. Giffin, Ed K. Lobenhofer, Keegan Cooke, Tobias Raum, Jennitte Stevens, Pedro J. Beltran, Angela Coxon, Paul E. Hughes
Journal: Cancer Research (2017)

Abstract Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with a poor prognosis and limited therapeutic options. Most patients present with extensive stage disease, where recent advances in immunotherapies, including bi-specific T cell engager (BiTE®) antibody constructs, represent a promising new therapeutic approach. BiTE® molecules have demonstrated durable complete responses in the clinic in hematological malignancies. Similar to hematological malignancies, SCLC is also a widely-disseminated malignancy that shows very high response rate to first line therapies with high rates of disease recurrence, features which may support efficacy of the BiTE® modality. Next generation sequencing (NGS) identified Delta-like Ligand 3 (DLL3) as a highly specific tumor associated antigen for SCLC, with consistent expression in tumors and very low expression in normal tissues. Tumor expression of DLL3 protein was confirmed by IHC, with 30 of 35 SCLC tumors staining positive for DLL3. DLL3 BiTE® antibody constructs showed low pM potency in vitro and also demonstrated significant inhibition of tumor growth in vivo in an orthotopic model of SCLC. A half-life extended (HLE) BiTE® targeting DLL3 demonstrated antibody-like pharmacokinetic properties in single-dose studies in non-human primates (NHP), with a half-life of 11 days. This is predicted to support every other week dosing in humans. The combination of high potency and excellent PK properties suggests that HLE BiTE® molecules may provide a useful tool for targeting residual disease in SCLC patients whose tumors express DLL3. Citation Format: Michael J. Giffin, Ed K. Lobenhofer, Keegan Cooke, Tobias Raum, Jennitte Stevens, Pedro J. Beltran, Angela Coxon, Paul E. Hughes. BiTE® antibody constructs for the treatment of SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3632. doi:10.1158/1538-7445.AM2017-3632
Abstract 1787: miR-150 as a predictor of hematopoietic reconstitution after myeloablation
Authors: Marshleen Yadav, Arnab Chakravarti, Naduparambil K. Jacob
Journal: Cancer Research (2017)

Abstract The identification of biomarkers that allow evaluation of myeloablation and hematopoietic reconstitution time frame is important for tailoring the radiation or chemo therapy in cancer patients. The fate of hematopoietic cells is regulated at multiple stages by various genes and regulatory microRNAs. In this context, miR-150 has been demonstrated as a major regulator of lymphoid lineage differentiation and development. Our mouse model studies shows a novel role of miR-150 in imparting radiation resistance. We observed a prolonged survival benefit in mice where both the copies of miR-150 genes are deleted in comparison to that of wildtype mice in the same C57BL/6 background (p&amp;lt;0.05). The survival benefit after total body irradiation was found to be associated with lower apoptosis and early reconstitution in hematopoietic stem cells (lin-ckit+sca1+/-) in bone marrow. Furthermore, the recovery kinetics at sub lethal dose (6Gy) showed that HSCs in miR-150-/- mice recovers faster. Myeloid (Mac1+Gr1+) and lymphoid (CD45+CD19+) lineage cells reconstitutes within 14 days after radiation in KO mice compared to 21 days or more in WT mice. We observed a statistically significant upregulation in myeloid cells in KO mice which implicates an early recovery from radiation induced neutropenia and hence more survivability. In addition, the enhanced bone marrow reconstitution was reflected in peripheral blood counts where a noticeable difference (p&amp;lt;0.05) in blood RBCs lymphocytes, monocytes, neutrophils, and basophiles were noted when compared sub lethally irradiated KO with WT mice. Altogether we demonstrate that the level of miR-150 regulates the bone marrow cells distribution and hence could be targeted for achieving accelerated hematopoietic recovery after myeloablation. These findings may be translated to human cancer patients for therapy guiding based on miR-150 expression level. Besides its use in prediction of reconstitution, miR-150 in the circulating system could provide a direct readout of functional marrow and hence hematological acute radiation syndrome (H-ARS). Citation Format: Marshleen Yadav, Arnab Chakravarti, Naduparambil K. Jacob. miR-150 as a predictor of hematopoietic reconstitution after myeloablation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1787. doi:10.1158/1538-7445.AM2017-1787
Abstract 4932: Oxygen sensing by T cells establishes an immunologically favorable metastatic niche
Authors: David Clever, Nicholas Restifo
Journal: Cancer Research (2017)

Abstract Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T-cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4(+)-regulatory T (Treg) cell induction, and restrain CD8(+) T cell effector function. Tumor colonization is accompanied by PHD-protein-dependent induction of pulmonary Treg cells and suppression of IFN-γ-dependent tumor clearance. T-cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. Note: This abstract was not presented at the meeting. Citation Format: David Clever, Nicholas Restifo. Oxygen sensing by T cells establishes an immunologically favorable metastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4932. doi:10.1158/1538-7445.AM2017-4932
Abstract 2386: HDAC6 regulates ERK1’s kinase activity via deacetylation
Authors: Jheng-Yu Wu, Xiaohong Zhang
Journal: Cancer Research (2017)

Abstract Extracellular signal-regulated kinases 1/2 (ERK1/2) are important kinases regulating cell proliferation and cell migration, and have been established as therapeutic targets for cancer treatment. Previously, we found that ERK1 phosphorylates histone deacetylase 6 (HDAC6), a class IIb HDAC, to regulate its enzymatic activity. HDAC6 plays an important role in several types of cancers. HDAC6 governs cancer cells’ migration by cooperating with cytoskeleton proteins and their associated proteins, and HDAC6 is arising as a determinant for cisplatin-resistance in non-small cell lung cancer (NSCLC) and ovarian cancer. Here, we have shown that HDAC6 manipulates ERK1’s kinase activity via deacetylation. We demonstrated that both ERK1 and ERK2 interact with HDAC6 physically via GST pull-down assays. To examine whether ERK1/2 are acetylated, we transfected GST-ERK1 or GST-ERK2 into HEK293T cells, and treated the cells with a pan-HDAC inhibitor, Trichostatin A. We showed that the level of acetylated GST-ERK1/2 increased in a dose- and time-dependent manner. Furthermore, when GST-ERK1 or GST-ERK2-expressed cells were treated with an HDAC6-specific inhibitor, ACY-1215, the level of acetylated GST-ERK1/2 increased. These results suggest that HDAC6 is a deacetylase for ERK1/2. In addition, we determined that acetyltransferases CBP and p300 acetylate ERK1/2. We found a novel acetylation site located in ERK1 N-terminus by mass-spectrometry analysis. We then mutated this lysine (K) site with either Glutamic acid (Q) or Arginine (R) to mimic the acetylation or deacetylation status, and performed kinase assays using ELK1 as a substrate. The acetylation mimicking mutant exhibits a decreased kinase activity toward ELK1, while the deacetylation mimicking mutant exhibits a similar level of kinase activity as the wild-type ERK1 does, suggesting that acetylation/deacetylation alters ERK1 enzymatic activities. Therefore, HDAC6 may regulate ERK1’s kinase activity via deacetylation of this site. Furthermore, we have shown that HDAC6 is overexpressed in lung cancer tissue samples and plays an important role in chemo-sensitivity in lung cancer. We predict that inhibition of the HDAC6-ERK1 pathway may provide clinical benefit for lung cancer patients. Citation Format: Jheng-Yu Wu, Xiaohong Zhang. HDAC6 regulates ERK1’s kinase activity via deacetylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2386. doi:10.1158/1538-7445.AM2017-2386
Excess economic burden of comorbidities in COPD: a 15-year population-based study
Authors: Wenjia Chen, J. Mark FitzGerald, Don D. Sin, Mohsen Sadatsafavi
Journal: European Respiratory Journal (2017)

A better understanding of the true burden of chronic obstructive pulmonary disease (COPD) needs to consider the implications of comorbidities. This study comprehensively examined the impact of comorbidities on excess direct medical costs in COPD patients. From health administrative data in British Columbia, Canada (1996–2012), we created a propensity-score-matched cohort of incident COPD patients and individuals without COPD. Health services use records were compiled into 16 major disease categories based on International Classification of Diseases codes. Excess costs (in 2015 Canadian dollars and converted to 2015 Euros; CAD1.000=EUR 0.706) were estimated as the adjusted difference in direct medical costs between the two groups. The sample included 128 424 subjects in each group. COPD patients generated excess costs of CAD5196/EUR3668 per person-year (95% CI CAD3540–8529), of which 26% was attributable to COPD itself and 51% was attributable to comorbidities (the remaining 23% could not be attributed to any specific condition). The major cost driver was excess hospitalisation costs. The largest components of comorbidity costs were circulatory diseases, other respiratory disorders, digestive disorders and psychological disorders (CAD696/EUR491, CAD312/EUR220, CAD274/EUR193 and CAD249/EUR176 per person-year, respectively). These findings suggest that the prevention and appropriate management of comorbidities in COPD patients may effectively reduce the overall burden of COPD.
Abstract 3837: Primary tumor cell lines derived from gastric PDX tumors displays differences in chemosensitivity
Authors: Xiaomei Ge, Fulin Qiang, Yixin Zhang, Jibing Liu, Lei Yang, Yingying Qu, Fubo Xie, Xueting Li, Ying Gu, He Zhou
Journal: Cancer Research (2017)

Abstract Gastric cancer is a multifactorial and fatal disease with limited effective therapeutic options. Its overall mortality ranked third among cancer-related deaths worldwide. Patient-derived-xenograft (PDX) models have been widely used in the biomedical research. They recapitulate the genomic diversity/heterogeneity of patient tumors, maintain a lot of the characteristics of the original tumors and showed much better correlation with clinical outcome comparing to traditional cell line derived xenograft models. However, the relatively low throughput and time-consuming nature of PDX studies prevent them from being used in large scale screening or mechanistic studies. To facilitate drug development in gastric cancer, different cancer cell lines have been developed in our laboratory from gastric PDX tumors. We performed STR analyses to validate their identity and RNAseq data also showed high similarities to their parental PDX tumors. These primary gastric tumor cell lines displayed differences from each other in their chemo-sensitivities in vitro and in vivo. They also differ in their protein expression such as the HER-2 expression level. Pharmacology studies using different compounds showed similar drug responses of these cell lines in tissue culture, xenografts using these cell lines and the original PDX models. Our data demonstrated the high fidelity of these cell lines to their parental PDX tumors and serve as a bridge between the high-throughput drug screening and highly clinical relevant PDX models and will greatly facilitate the drug development in gastric cancer. Citation Format: Xiaomei Ge, Fulin Qiang, Yixin Zhang, Jibing Liu, Lei Yang, Yingying Qu, Fubo Xie, Xueting Li, Ying Gu, He Zhou. Primary tumor cell lines derived from gastric PDX tumors displays differences in chemosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3837. doi:10.1158/1538-7445.AM2017-3837
Abstract LB-311: Characterization of the antizyme/antizyme inhibitor protein-protein interaction using a novel FRET sensor
Authors: James M. Rice, Michael S. Rogers, Bruce R. Zetter
Journal: Cancer Research (2017)

Abstract The protein-protein interaction (PPI) between the tumor suppressor antizyme (AZ) and its endogenous regulator antizyme inhibitor (AZIN) has recently been demonstrated to be important in several human cancers. AZIN siRNA treatment reduces AZIN expression and slows prostate cancer cell growth in vitro and in vivo but is not currently a viable therapeutic strategy. To further probe the AZ/AZIN PPI and to screen for potential small molecule inhibitors, we have developed a FRET assay (Z score &amp;gt;0.7) utilizing the Clover (donor) and mRuby2 (acceptor) fluorescent proteins linked to AZIN and AZ, respectively. An alanine mutant screen of 43 amino acid positions in the AZIN protein revealed 2 hotspots that dramatically affect the affinity for the AZ protein, thereby identifying key regions for disruption by potential therapeutics. Furthermore, mutating the N327 and Y331 positions in ornithine decarboxylase (ODC) to equivalent residues in the homologous AZIN protein, increased the affinity of ODC for AZ, providing evidence for key residues that contribute to AZ/AZIN PPI. In addition, the S367G AZIN mutation, which is associated with an mRNA editing event in hepatocellular carcinoma, further increases the affinity of AZIN for AZ and supports a mechanism of AZ sequestration as an important driver in cancer cell growth. Taken together, this data expands our current understanding of the contribution of different amino acid residues to the AZ/AZIN binding interaction. The development of small molecule inhibitors to target these regions of the AZIN protein would rescue the tumor suppressive activity of AZ and present a novel therapeutic opportunity for the treatment of prostate cancer and hepatocellular carcinoma. Note: This abstract was not presented at the meeting. Citation Format: James M. Rice, Michael S. Rogers, Bruce R. Zetter. Characterization of the antizyme/antizyme inhibitor protein-protein interaction using a novel FRET sensor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-311. doi:10.1158/1538-7445.AM2017-LB-311
Abstract 2051: LSTRA cell line as a model for large granular lymphocytic leukemia in drug screening
Authors: Fu-Shin Chueh, Fu-Yu Chueh, Chao-Lan Yu
Journal: Cancer Research (2017)

Abstract Large granular lymphocytic (LGL) leukemia is a rare form of leukemia that is caused by the increase in cytotoxic T-lymphocytes or natural killer (NK) cells. A subcategory of T-LGL leukemia that co-expresses T and NK cell surface markers is very aggressive and has a very poor prognosis. Current treatment of aggressive T-LGL is based on non-specific immunosuppressive therapy. Lack of model cell lines contributes to slow progress in designing targeted therapy and clinical trials. Our recent studies demonstrate that the mouse T-leukemic cell line LSTRA reproduces some important characteristics of aggressive T-LGL leukemia. This is the first report of a cell line model mimicking the deadly human leukemia and has great potentials for drug screening in treating T-LGL leukemia. Bortezomib is one of the drugs that show promising results in treating LGL leukemia patients in clinical trials. Bortezomib is the first FDA-approved reversible proteasome inhibitor in treating multiple myeloma and mantle cell lymphoma patients. One of the major concerns in using single-agent bortezomib is that patients develop resistance during the course of treatment and cancers relapse. Therefore, it is important to develop novel strategies in overcoming LGL leukemic cells’ resistance to bortezomib and its derivatives. In our current study, we showed that bortezomib inhibited cell proliferation and induced apoptosis in LSTRA leukemic cells. Partial reversion after 48-72 hr of bortezomib treatment suggested development of resistance to bortezomib. We further established bortezomib-resistant LSTRA cells that tolerated significantly higher levels of bortezomib. Both carfilzomib (FDA-approved second generation irreversible proteasome inhibitor) and MLN 4924 (proteasome pathway upstream inhibitor) failed to overcome bortezomib resistance. Only luteolin, a common flavonoid found in plants, can effectively overcome bortezomib resistance. Metabolic reprogramming has been linked to drug resistance in cancer cells. Indeed, We found that bortezomib-resistant LSTRA cells had smaller cell size as well as reduced rate of glucose uptake, lactate secretion, and mitochondrial respiration. These results suggest that reduced mitochondrial activity may be an important molecular marker for LSTRA cell’s resistance to bortezomib. All together, we identified luteolin as a potential small molecule in overcoming LGL leukemia’s resistance to proteasome inhibitor therapy. Altered mitochondrial activity and cell metabolism in bortezomib-resistant cells provide additional targets in developing novel combined chemotherapy for cancer patients. Citation Format: Fu-Shin Chueh, Fu-Yu Chueh, Chao-Lan Yu. LSTRA cell line as a model for large granular lymphocytic leukemia in drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2051. doi:10.1158/1538-7445.AM2017-2051