tbuckley/cabot-search huggingface dataset:
Abstract 3: Amino acid profiles indicate dependence on different metabolic pathways between leukemia subtypes
Authors: Shannon R. Sweeney, Enrique Sentandreu, Stefano Tiziani
Journal: Cancer Research (2016)

Abstract Despite the growing body of evidence that the tumor microenvironment protects leukemia cells from chemotherapeutic stresses (1-3), the effect of many extracellular metabolites remains largely unknown. To explore the influence of extracellular metabolites on different leukemia subtypes, cells were treated for 24 hours in vitro with either a supplemental amino acid or amino acid derivative. From this initial screening, a subset of metabolites were chosen for metabolomics analysis. Mass spectrometry (UPLC-MS/MS) was performed on intracellular fractions to identify metabolic differences that resulted from supplementation. Metabolite profiles were also compared between leukemia cell types, namely AML, pre-B cell ALL, and T cell ALL. Of the metabolites tested, lysine and 4-hydroxyphenylpyruvate, an intermediate of tyrosine and phenylalanine metabolism, had the greatest impact on global amino acid profiles. In AML and T cell ALL cell lines, intracellular glutamate, glutamine, proline, and aspartate were increased relative to their respective controls. These amino acids can enter the tricarboxylic acid (TCA) cycle as either α-ketoglutarate or oxaloacetate, suggesting a central role of the TCA cycle in both AML and T cell ALL metabolism. Interestingly, these metabolites were not significantly increased in pre-B cell ALL, signifying the inverse it true for pre-B cells. This observation provides metabolomics evidence that is consistent with a previous study that reported downregulated expression of TCA cycle related genes in pre-B cell ALL (4). Our findings indicate that uptake and metabolism of amino acids and their derivatives is distinct for different leukemia types. Moreover, supplementation with a single metabolite can result in global changes in intracellular metabolite profiles, suggesting an influence not only as an energy substrate, but on overall metabolic pathway activity. Specifically, we conclude that the TCA cycle is more active in AML and T cell ALL and can be modulated by changing the extracellular environment, while pre-B cells are less sensitive to amino acid modulation. (1) Meads MB, et al. Clin Cancer Res 2008;14(9):2519-2526. (2) Ayala F, et al. Leukemia 2009;23:2233-2241. (3) Konopleva M, et al. Drug Resist Updat 2009;12:103-113. (4) Boag JM, et al. Leukemia 2006;20:1731-1737. Citation Format: Shannon R. Sweeney, Enrique Sentandreu, Stefano Tiziani. Amino acid profiles indicate dependence on different metabolic pathways between leukemia subtypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3.
Abstract LB-130: STAT3/PIAS3 as “early signature” gene pathways in the development of ovarian high grade serous carcinoma from the fallopian tube
Authors: Uksha Saini, John Wallbillich, Maria Riley Riley, John M. Fowler, Ross Wanner, Jenny Lester, Beth Karlan, Paul Goodfellow, Adrian Suarez, David Cohn, Karuppaiyah Selvendiran
Journal: Cancer Research (2016)

Abstract Objectives: Our recent studies in human samples have demonstrated constitutive activation of STAT3 Tyr705 and loss of protein inhibitor of activated STAT3 (PIAS3) in STICs in the fallopian tubes and advanced HGSC tissues. The goal of this current study is to identify and elucidate the molecular mechanisms leading to the initiation and development of HGSC through STAT3 activation and low levels or absence of PIAS3 in the fallopian tube (FT). Methods: Human tissues–benign normal FTs, STICs (without ovarian cancer) and HGSC—were evaluated for expression of STAT3/PIAS3 (as compared with their known TP53 signature) and their target proliferation genes. Isolated primary fallopian tubal serous epithelial carcinoma (FTSEC) cells from FT and immortalized FT cells were also utilized and were evaluated with real time PCR, IHC, ICC, western blots, cloning and orthotopic mouse models. Results: We observed high-level expression of pSTAT3 Tyr705, and decreased levels of PIAS3, in dysplastic areas of FT obtained from patients with and without cancer and advanced stage HGSC (as compared to high PIAS3 low pSTAT3 expression in normal benign FT). In addition, FT cells transfected with a STAT3 overexpression construct showed translocation of pSTAT3 and c-Myc into the nucleus. Further, the in vivo experiments demonstrated that the overexpression of STAT3 in FTSECs promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. In contrast, STAT3 knockdown in ovarian cancer cells was associated with reduced tumor growth and metastasis in vivo. Conclusions: The STAT3 pathway may play a critical role in the development of STIC lesions and their progression to HGSC. We will further screen more FT samples and number of human tissues from various stages of HGSC along with an in vivo mouse model of HGSC in order to establish the oncogenic role of STAT3 and expression levels of PIAS3 in ovarian HGSC. Our current and future findings offer an opportunity to address the clinically important questions that are critical for cancer prevention and early detection in deadly HGSC. Citation Format: Uksha Saini, John Wallbillich, Maria Riley Riley, John M. Fowler, Ross Wanner, Jenny Lester, Beth Karlan, Paul Goodfellow, Adrian Suarez, David Cohn, Karuppaiyah Selvendiran. STAT3/PIAS3 as “early signature” gene pathways in the development of ovarian high grade serous carcinoma from the fallopian tube. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-130.
Abstract 588: Inhibition of liver inflammation and tumorigenesis by blocking Ccl2-Ccr2 axis in a mouse model
Authors: Kun-Yu Teng.
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC), the second cancer-related deadly disease, commonly arises in the setting of chronic liver inflammation. CC chemokine ligand 2 (CCL2), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in HCC patients. Here, we examined the therapeutic efficacy of inhibitors of the Ccl2-Ccr2 axis against hepatitis and HCC in the miR-122 knockout (aka KO) mouse model, in which upregulation of Ccl2 promotes liver inflammation that progresses to HCC with age. To determine whether blocking the Ccl2-Ccr2 axis has any therapeutic potential, we treated KO mice with Ccl2 neutralizing antibody (nab) or a small molecule inhibitor of Ccr2 and monitored liver pathology. Both agents were able to reduce the bridging inflammation in these mice by reducing the population of CD11highGr1+ cells, and expression of IL-6 and TNF-alpha in KO livers. Furthermore, treatment of tumor-bearing KO mice with Ccl2 nab for 8 weeks significantly reduced the recruitment of CD11bhighGr1+ monocytes, IL-6 and TNF-alpha production, and HCC incidence as well as tumor burden. The down-regulation of pStat3 and c-Myc (IL-6 downstream) as well as NF-kappaB (TNF-alpha downstream) upon targeting Ccl2 positively correlated with tumor growth suppression. In addition, inhibition of tumorigenesis by Ccl2 nab also correlated with enhanced cytotoxicity and IFN-gamma expression of NK cells isolated from the tumor microenvironment. Collectively, our results demonstrate that blocking the Ccl2-Ccr2 axis can be an effective therapeutic approach against both hepatitis and HCC. Citation Format: Kun-Yu Teng. Inhibition of liver inflammation and tumorigenesis by blocking Ccl2-Ccr2 axis in a mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 588.
Human and Mouse Brown Adipose Tissue Mitochondria Have Comparable UCP1 Function
Authors: Craig Porter, David N. Herndon, Maria Chondronikola, Tony Chao, Palam Annamalai, Nisha Bhattarai, Manish K. Saraf, Karel D. Capek, Paul T. Reidy, Alexes C. Daquinag, Mikhail G. Kolonin, Blake B. Rasmussen, Elisabet Borsheim, Tracy Toliver-Kinsky, Labros S. Sidossis
Journal: Cell Metabolism (2016)
Ultrasound-guided therapeutic modulation of hepatocellular carcinoma using complementary microRNAs
Authors: Sayan Mullick Chowdhury, Tzu-Yin Wang, Sunitha Bachawal, Rammohan Devulapally, Jung Woo Choe, Lotfi Abou Elkacem, Butrus Khuri Yakub, David S. Wang, Lu Tian, Ramasamy Paulmurugan, Jürgen K. Willmann
Journal: Journal of Controlled Release (2016)
A randomized Phase 3 study comparing first-line pemetrexed plus cisplatin followed by gefitinib maintenance (PC/G) with gefitinib monotherapy (G) in East Asian patients (pts) with locally advanced or metastatic nonsquamous non-small cell lung cancer (nSqNSCLC): Final survival results.
Authors: James Chih-Hsin Yang, Vichien Srimuninnimit, Myung-Ju Ahn, Chia-Chi Lin, Sang-We Kim, Chun-Ming Tsai, Tony Mok, Mauro Orlando, Tarun Puri, Xin Wang, Keunchil Park
Journal: Journal of Clinical Oncology (2015)

8041 Background: The primary analysis of this open-label, randomized, multicenter study found no significant difference in progression-free survival (PFS) between PC/G and G in pts with nSqNSCLC and unknown epidermal growth factor receptor (EGFR) mutation status, although the unadjusted hazard ratio (HR, PC/G vs G) favored PC/G (0.85, 95% CI: 0.63–1.13). Final overall survival (OS) data are reported here. Methods: Eligible pts were chemonaïve, East Asian light ex-smokers/never-smokers aged ≥18 years with advanced nSqNSCLC, ECOG PS 0/1 and unknown EGFR mutation status. Pts (N = 236) were randomized (1:1) to PC/G (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2for six 21-day cycles then gefitinib 250 mg/day) or G (gefitinib 250 mg/day). EGFR mutation status was determined for 76 pts; 52 (68.4%) had mutations. OS was analyzed (intent-to-treat population) by unadjusted Cox regression analysis. Results: Baseline characteristics were similar between groups (both N = 118). Median OS was similar in the PC/G and G groups in the overall population, but longer in the G group in the subgroups with EGFR mutations (EGFR-mutated, Ex19del, L858R; Table). Postdiscontinuation therapy (PC/G: 60.2%; G: 72.0%) included chemotherapy (PC/G: 34.7%; G: 61.9%) and rechallenge with an EGFR tyrosine kinase inhibitor (PC/G: 22.9%; G: 7.6%). Conclusions: There was no significant difference in OS between PC/G and G in the overall population. As reported for PFS, there appeared to be better outcomes with G in the EGFR mutation subgroups (especially Ex19del) and with PC/G in the EGFR wild-type subgroup. Clinical trial information: NCT01017874. OS (mo) Median (95% CI) Population (n) PC/G G PC/G vs G HR (95% CI; P value) Overall (236) 26.87 (20.76–35.12) 27.86 (21.26–32.36) 0.94 (0.68–1.31; 0.717) EGFR wild-type (24) 28.35 (11.27–50.63) 8.94 (0.69–NE) 0.62 (0.22–1.72; 0.356) EGFR-mutated (52) 32.39 (19.29–NE) 45.70 (25.76–NE) 1.57 (0.72–3.39; 0.255) Ex19del (26) 32.39 (15.15–NE) 45.70 (18.66–NE) 2.36 (0.70–7.92; 0.166) L858R (24) 35.65 (1.25–NE) 41.26 (13.60–NE) 1.23 (0.41–3.67; 0.709) NE: not estimable.
Abstract 4857: Design and biological evaluation of substituted pyrrolo[3,2-d]pyrimidines as dual acting RTK and microtubule targeting agents
Authors: Aleem Gangjee, Khushbu Shah, Nicholas Dybdal-Hargreaves, Susan Mooberry, Anja Bastian, Michael Ihnat
Journal: Cancer Research (2016)

Abstract Combination chemotherapy with antiangiogenic (cytostatic) and microtubule targeting (cytotoxic) agents (MTA) have shown significant promise and several studies with such combinations have progressed to the clinic. Single agents with both antiangiogenic activities as well as cytotoxicity would circumvent pharmacokinetic problems of multiple agents, might be effective at lower doses to alleviate toxicity, and delay or prevent tumor cell resistance. We have designed, synthesized and evaluated single agents that are novel pyrrolo[3,2-d]pyrimidine MTAs that also inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor â (PDGFRâ). Sixteen pyrrolo[3,2-d]pyrimidine analogs were synthesized with variations on the C-2 and the 4-anilino position. The importance of various substituents was evaluated based on their abilities to cause cellular microtubule depolymerization and inhibit proliferation of MDA-MB-435 cancer cells. Compounds with N5-Me were more potent than the N5-H analogs indicating that a conformational restriction induced by N5-Me could mimic the bioactive conformation. In addition, all C2-Cl compounds afforded 2 to 10-fold more potentIC50 values than their C2-Me counterparts as illustrated by C2-Cl analog AG336 (IC50 = 18.3 ± 5.0 nM) compared to its C2-Me analog AG85 (IC50 = 193 ± 39 nM). The most active antitubulin agents were evaluated against RTKs and demonstrated good inhibition for EGFR (IC50 = 29.5 - 91.5 nM), VEGFR-2 (182.3 - 543.6 nM) and PDGFRâ (IC50 = 204.4 - 450.2 nM), thus demonstrating dual-targeting ability. Preclinical assessment of AG165 at 75 mg/kg in mice in the NCI/ADR resistant tumor model demonstrated significant reduction of tumor volume compared to paclitaxel (10 mg/kg) treated mice [p = 0.0333], indicating antitumor activity in a multidrug resistant tumor model, in addition to excellent antitumor activity in MDA-MB-435 and MDA-MB-231 xenograft models. These results demonstrate the viability of these multitargeted single agents as potential clinically active antitumor agents. Citation Format: Aleem Gangjee, Khushbu Shah, Nicholas Dybdal-Hargreaves, Susan Mooberry, Anja Bastian, Michael Ihnat. Design and biological evaluation of substituted pyrrolo[3,2-d]pyrimidines as dual acting RTK and microtubule targeting agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4857.
Abstract 3784: The role of the taurine transporter SLC6A6 in promoting prosurvival activity and multidrug resistance of colorectal cancer
Authors: Masahiro Yasunaga, Yasuhiro Matsumura
Journal: Cancer Research (2016)

Abstract The identification of a novel therapeutic target is desired to improve the treatment of colorectal cancer (CRC). In a comprehensive gene expression analysis, we found that the taurine transporter SLC6A6 was highly expressed in CRC. In the functional analysis, SLC6A6-knocked down (KD) CRC cells showed attenuated cell-survival activity accompanying enhanced sensitivity of the drugs (5-FU, DOX and SN-38). Moreover, the number of side population (SP) cells and their cancer stem cell (CSC)-like properties such as tumor-initiation were abrogated by SLC6A6-KD. Conversely, increased the cell-survival activity, the fraction of SP cells and enhancement of multidrug resistance (MDR) were observed in SLC6A6-overexpressed cells. Furthermore, SLC6A6-siRNA treatment enhanced the cytotoxic effect of all 3 drugs as distinct from ABCG2-siRNA treatment, the efficacy of which was limited to its 2 substrate-drug, DOX and SN-38. Finally, we clarified the prosurvival and anti-apoptotic effects of the taurine transporter SLC6A6 in CRC cells. Moreover, we found that SLC6A6 plays an important role in the maintenance of CSC characteristics promoting cell survival signal and MDR. Our findings indicate that the SLC6A6 may be a novel therapeutic target for refractory CRC. Citation Format: Masahiro Yasunaga, Yasuhiro Matsumura. The role of the taurine transporter SLC6A6 in promoting prosurvival activity and multidrug resistance of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3784.
JAK1/2 Inhibition Suppresses T Cell Proliferation and Inflammatory Cytokine Production In An Allogeneic Setting and Ameliorates Graft-Versus-Host Disease (GvHD) In a Murine GvHD Model
Authors: Silvia Spoerl, Sophia Chen, Michael Bscheider, Nimitha Mathew, Martina Schmickl, Tony Mueller, Annette Schmitt-Graeff, Christian Peschel, Justus Duyster, Hendrik Poeck, Robert Zeiser, Nikolas von Bubnoff
Journal: Blood (2013)
Abstract 4759: Identification of ALK, ROS1, FGFR2 and NRG1 fusions and validation with targeted inhibitors in lung and ovarian PDX models
Authors: Xuzhen Tang, Hua Dong, Yibo Gao, Zhixiang Zhang, Xiangnan Qiang, Baoyuan Zhang, Yuxin Qin, Shuqun Yang, Yunbiao Yan, Qingyang Gu, Norman Zhang, Jie He, Qunsheng Ji
Journal: Cancer Research (2016)

Abstract Chromosomal rearrangement mediated gene fusions and activation of oncogenic signaling pathways have become druggable targets for therapeutic intervention, with successful development of Imatinib as an inhibitor of Bcr-Abl in treatment of Philadelphia chromosome positive chronic myelogenous leukemia. A recent study by Stransky et. al. reported systemic analysis of the transcriptome of nearly 7000 human tumor samples from the Cancer Genome Atlas and revealed the landscape of near twenty kinase fusions across twenty solid tumor types. Identification of corresponding PDX models that carry given kinase fusions would be of paramount interest for preclinical validation of candidate inhibitors. We have established about 1000 PDX models across 20 tumor types. Here we report the identification of ALK, ROS1, FGFR2 fusions in lung cancer PDX models and a NRG1 fusion in the ovarian cancer models by RNA using Sequencing data combined with the Chimerascan and Star-Fusion software for fusion calling.. The gene fusions, as validated by PCR and Sanger Sequencing, led to over-expression of the affected kinases, supporting the notion that kinase activation may be the oncogenic driver in the corresponding tumors. We further validated that ALK inhibitors Crizotinib, AP26113 and LDK378 exhibited robust antitumor activities in the ALK fusion model. Current works on validation of ROS1, FGFR2 and NRG1 inhibitors in the pertinent fusion models are under progression. These models should provide means for pre-clinical validation of novel kinase inhibitors and for experimenting novel combinatorial therapeutic strategies. Citation Format: Xuzhen Tang, Hua Dong, Yibo Gao, Zhixiang Zhang, Xiangnan Qiang, Baoyuan Zhang, Yuxin Qin, Shuqun Yang, Yunbiao Yan, Qingyang Gu, Norman Zhang, Jie He, Qunsheng Ji. Identification of ALK, ROS1, FGFR2 and NRG1 fusions and validation with targeted inhibitors in lung and ovarian PDX models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4759.
Abstract LB-366: miRNA as markers of CIN risk and persistence for optimization of HPV-based cervical cancer screening
Authors: Alessio Naccarati, Daniela De Maria, Francesca Cordero, Barbara Pardini, Stavrula Gouzounis, Maddalena Arigoni, Raffaella Rizzolo, Laura De Marco, Anna Gillio-Tos, Paolo Vineis, Guglielmo Ronco
Journal: Cancer Research (2016)

Abstract Cervical cancer (CC) is caused by oncogenic human papillomaviruses (HR-HPVs) infection and exhibits well-defined clinical stages associated with different steps of tumorigenesis. Screening for CC based on HPV is more effective than cytology, but it may increase costs and over treatment of spontaneously regressive high-grade lesions (hgCIN). Thus triage of HPV positive women is needed. Several microRNAs (miRNAs) are dysregulated in CC and hgCIN. However, the studies so far are based on miRNA candidate genes or array approach, mainly in tumor/healthy tissues. The aim of this study is to investigate, for the first time, miRNA profiles by next-generation sequencing in exfoliated cervical cells of HPV-positive women in relation to the presence of hgCIN lesions or as predictors of persistence/progression of CIN lesions. The study is nested in a large Italian multi-centre randomised controlled trial recruiting women in population-based screening programs that actively invite women aged 25-64 years. The study population includes HPV-positive women with CIN2 and CIN3 or without hgCIN lesion. For the discovery phase libraries of 100 samples of exfoliated cervical cells have been set up for miRNA sequencing. For the validation an additional set of 250 samples has already been selected. Preliminary results shows that, after correction for multiple testing, 44 miRNAs resulted dysregulated in women with vs. those without prevalent hgCIN. This set includes some miRNAs previously reported in the literature, such as miR-100 and miR-126, and other additional miRNAs not included in arrays before. The association of miRNAs with occurrence of hgCIN and clearance of infection during follow up reveals other significantly differentially expressed miRNAs under investigation for their biological roles. The high stability of miRNAs, in contrast to the fast degradation of mRNA and proteins, allows their accurate determination also in samples of exfoliated cervical collected during screening. Validation of the results, associations with other investigated markers and with HPV genotypes will be performed. Study supported by Italian Association on Cancer Research (AIRC, IG2013 N.14119). Citation Format: Alessio Naccarati, Daniela De Maria, Francesca Cordero, Barbara Pardini, Stavrula Gouzounis, Maddalena Arigoni, Raffaella Rizzolo, Laura De Marco, Anna Gillio-Tos, Paolo Vineis, Guglielmo Ronco. miRNA as markers of CIN risk and persistence for optimization of HPV-based cervical cancer screening. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-366.