bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A113: Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures
Authors: Graham Nicholas , Minasyan Aspram , Christofk Heather , Mellinghoff Ingo , Graeber Thomas G. 
Published: August 2018

Abstract
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution.
Citation Format: Nicholas Graham, Aspram Minasyan, Heather Christofk, Ingo Mellinghoff, Thomas G. Graeber. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A113.
Abstract A121: Transient increase of tumor perfusion using hypertonic saline
Authors: Patiño Angelica M. , Junqueira Mara S. , Zhang Xiaomeng , Bailey Kate , Ibrahim-Hashim Arig , Gillies Robert J. , Chammas Roger 
Published: August 2018

Abstract
Intravenous administration of hypertonic saline solution (HSS) induces systemic circulatory changes including increases in systemic blood pressure and effective circulating volume, as well as local effects on microvasculature. We analyzed the effects produced by 7.5% HSS administration on tumor hemodynamics through functional imaging studies. Blood velocity assessed by color Doppler ultrasound was increased after HSS injection compared to PBS in B16F10 (p=0.019), SK-MEL-147 (p=0.028), and 4T1 (p=0.015). No statistical differences were observed on the segmental kidney arteries (p=0.476). Dynamic contrast-enhanced ultrasound (CEUS) was used to assess functional blood volume in B16F10, HCT-116, and MDA-MB-231 tumor xenografts, kidney and muscle tissues (n=3 per group). After HSS injection, relative blood volume was increased in B16F10 (p=0.022) and HCT-116 (p=0.039) but not on MDA-MB-231 (p=0.186). There was a mild change that was not statistically significant on the normal tissues (kidney p=0.957; muscle p=0.104). Finally, dynamic contrast-enhanced MRI (DCE-MRI) was performed in B16F10 tumors (n=4) and showed that contrast distribution increases in the HSS group (p=0.002). All statistical tests were two sided. HSS 7.5% is a potential vehicle to transiently increase blood supply in specific tumors, and therefore could be used to enhance intratumoral delivery of different molecules for either tumor diagnosis or treatment. Supported by an UICC Yamagiwa-Yoshida grant and FAPESP (2013/06120-8 and 2015/22814-5).
Citation Format: Angelica M. Patiño, Mara S. Junqueira, Xiaomeng Zhang, Kate Bailey, Arig Ibrahim-Hashim, Robert J. Gillies, Roger Chammas. Transient increase of tumor perfusion using hypertonic saline [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A121.
Abstract A136: KDM5A activity inhibition by 2-PCPA: overcoming tolerance to bortezomib
Authors: Terui Yasuhito , Mishima Yuji , Hatake Kiyohiko 
Published: August 2018

Abstract
Purpose: The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for myeloma treatment. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance remain to be understood. However, resistance to bortezomib as a single agent develops in the majority of patients, and activity in other malignancies has been less impressive. To overcome bortezomib resistance, we compared differential gene expression profiles of bortezomib-resistant and bortezomib-sensitive IM-9 cell lines in response to bortezomib, and expressions of KDM5A genes were significantly increased. Methods: The differential gene expression profiles of bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 cell lines in response to bortezomib were performed using Affymetrix GeneChip. To confirm the results, real-time PCR and Western blot analysis were performed. Bortezomib-resistant IM-9 cells were treated with or without bortezomib and&lt;/&gt;or histone demethylase inhibitor, trans-2-phenylcyclopropylamine hydrochloride (2-PCPA). Moreover, level of histone methylation was examined by Western blot analysis. Results: At concentrations that effectively inhibited proteasome activity (maximum dose with 100nM), bortezomib induced cell death in bortezomib-sensitive IM-9 cells, but not in bortezomib-resistant IM-9. In comparison of differential gene expression profiles between bortezomib-resistant IM-9 and bortezomib-sensitive IM-9 cells, we showed overexpression of KDM5A, which is associated with chromatin-mediated reversible drug-tolerant state, Moreover, 2-PCPA overcomes bortezomib resistance in a dose-dependent manner. The histone demethylation at H3K4, H3K9, and H3K27 was suppressed with 2-PCPA. Conclusion: Histone lysine-specific demethylase inhibitor, 2-PCPA, with bortezomib may be useful for overcoming bortezomib resistance in myeloma cells by suppression of KDM3A and KDM5A activities.
Citation Format: Yasuhito Terui, Yuji Mishima, Kiyohiko Hatake. KDM5A activity inhibition by 2-PCPA: overcoming tolerance to bortezomib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A136.
Abstract A145: SHP2 inhibition restores sensitivity to ALK inhibitors in resistant ALK-rearranged NSCLC
Authors: Dardaei Leila , Wang Hui Qin , Singh Manrose , Fordjour Paul , Yoda Satoshi , Kerr Grainne , Liang Jinsheng , Cao Yichen , Chen Yan , Gainor Justin , Friboulet Luc , Dagogo-Jack Ibiayi , Myers David , Labrot Emma , Ruddy David , Parks Melissa , Lee Dana , DiCecca Richard , Moody Susan , Hao Huaixiang , Mohseni Morvarid , LaMarche Matthew , Williams Juliet , Hoffmaster Keith , Caponigro Giordano , Shaw Alice , Hata Aaron , Benes Cyril , Li Fang , Engelman Jeffrey 
Published: August 2018

Abstract
Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. After tumors develop resistance to highly potent 2nd-generation ALK inhibitors, approximately half harbor ALK resistance mutations, while the other half have other mechanisms of resistance. The latter often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to the 3rd-generation ALK inhibitor, lorlatinib, which is able to overcome all clinically identified ALK resistance mutations, and further therapeutic options are limited. Herein, we deployed an shRNA screen of 1000 genes in multiple ALK inhibitor-resistant patient-derived cells (PDC) to discover sensitizers to ALK inhibition. This approach identified SHP2, a non-receptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. The recently discovered small-molecule SHP2 inhibitor, SHP099, in combination with the ALK TKI (tyrosine kinase inhibitor), ceritinib, halted the growth of resistant PDCs by preventing compensatory RAS and ERK1/2 reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent resistance mechanisms.
Citation Format: Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Satoshi Yoda, Grainne Kerr, Jinsheng Liang, Yichen Cao, Yan Chen, Justin Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice Shaw, Aaron Hata, Cyril Benes, Fang Li, Jeffrey Engelman. SHP2 inhibition restores sensitivity to ALK inhibitors in resistant ALK-rearranged NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A145.
Abstract A156: Traditional chemotherapeutic agents as selective inhibitors of glutaminase isozymes
Authors: Katt William P. , Cerione Richard A. 
Published: August 2018

Abstract
Most cancer cells undergo a number of metabolic changes, which dramatically alter their nutritional and energetic pathways. One such alteration is an addiction to glutamine, an abundant nutrient in blood that is much less utilized by healthy tissues. The glutaminase enzymes help cancer cells satisfy their metabolic requirements by acting as the first step in glutamine’s supply of carbon into the citric acid cycle. Two major isozymes of glutaminase exist, a kidney isozyme and a liver isozyme, and these are differentially expressed across different cancers. While the importance of these enzymes has been increasingly appreciated in the literature, and the inhibition of either enzyme has been shown to be detrimental to the growth of numerous cancers both in cell culture and in vivo, medicinal chemistry efforts to target either enzyme have largely involved just one class of compound, based around the scaffold of BPTES, which potently inhibits only the kidney glutaminase isozyme. It is generally accepted that most drugs have at least one off-target or biologic activity that was not intended. In order to determine new inhibitors of either isozyme of glutaminase, we examined the approved oncology drug set from the NIH, which included 119 FDA-approved, clinically relevant compounds. By assaying inhibition of the function of recombinantly expressed purified enzymes, and examining the production of ammonia (a byproduct of glutaminase catalytic activity) in drug-treated cancer cells, we found that several of the drugs in the library, such as cisplatin, not only inhibit glutaminase at biologically meaningful concentrations, but inhibit one isozyme much more potently than the other. This study both shows the power of screening traditional chemotherapeutic agents against more recently identified therapeutic targets and reveals several new scaffolds that might be optimized to potently inhibit these critical enzymes.
Citation Format: William P. Katt, Richard A. Cerione. Traditional chemotherapeutic agents as selective inhibitors of glutaminase isozymes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A156.
Abstract A165: Novel thiosemicarbazone, Dp44mT, promotes NDRG1 to downregulate oncogenic signaling pathways in cancer
Authors: Menezes Sharleen V. , Kovacevic Zaklina , Richardson Des 
Published: August 2018

Abstract
Introduction: The novel thiosemicarbazone, Dp44mT, has shown potent anticancer activity against various cancer types. The activity of this agent is, at least in part, mediated by its ability to upregulate the growth and metastasis suppressor, N-myc Downstream Regulated Gene 1 (NDRG1). NDRG1 inhibits cell proliferation, migration, and invasion by negatively regulating numerous oncogenic signaling pathways. However, the mechanisms by which NDRG1 modulates all these pathways remain to be elucidated. To examine how NDRG1 and Dp44mT affect multiple signalling pathways, we assessed their effects on the ErbB-family of receptor tyrosine kinases, namely epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), as these molecules are key regulators of downstream oncogenic signaling. Methods: PANC1 pancreatic and HT-29 colon human cancer cells were utilized to examine the effects of NDRG1 and Dp44mT on EGFR, HER2, and HER3 levels, localization, and phosphorylation in vitro. PANC1 xenografts were also utilized to examine the effects of Dp44mT on these molecules in vivo. Results: For the first time, we demonstrate that NDRG1 and Dp44mT markedly inhibit the expression, localization, and activation of EGFR, HER2, and HER3. NDRG1 also reduced activation of the MAPK-signalling pathway, which is downstream of the ErbB family of receptors. Further, the anticancer agent, Dp44mT, significantly reduced expression of EGFR, HER2, and HER3 in vivo. Conclusions: This study demonstrates for the first time that the novel thiosemicarbazone, Dp44mT, inhibits the ErbB family of proteins through its upregulation of NDRG1, providing an interesting insight into the mechanisms behind its compelling anticancer activity.
Citation Format: Sharleen V. Menezes, Zaklina Kovacevic, Des Richardson. Novel thiosemicarbazone, Dp44mT, promotes NDRG1 to downregulate oncogenic signaling pathways in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A165.
Abstract A198: The leptin transduction pathway may be targeted against invasive ductal carcinoma of breast
Authors: Rahman Shaikh M. , Al-Shibli Saad M. , Amjad Nasser M. , Al-Kubaisi Muna K. , Harun Norra B. , Nafie Emad M. 
Published: August 2018

Abstract
Despite some controversies, it is generally suggested that obesity imparts a higher risk of breast cancer, the most common cancer among women all over the world. Since obese people usually have higher serum levels of leptin, a hormone secreted by white adipose tissue, the hormone is suspected as the link between adiposity and breast cancer. In this study we tried to explore a possible causal association of obesity and serum leptin with breast cancer by studying a sample of healthy controls and patients from Malaysian population. The control group comprised 40 women with negative mammogram for breast cancer, while the patient group comprised 51 women with invasive ductal carcinoma (IDC) of breast, who were going to be operated. We measured the common obesity parameters, confirmed the diagnosis of IDC of breast in the patients by standard histopathologic examination using hematoxylin and eosin stain, and estimated serum leptin levels using ELISA procedure. We estimated both pre- and postoperative samples of leptin from the patient group. Our results showed a highly significant difference in the serum leptin level between the control group and the patient group with a mean of 20.59 ± 14.4 ng/ml and 38.71 ± 12.2 ng/ml, respectively, having a P value of &lt; 0.001. Our study showed no difference between the pre- and postoperative serum leptin levels in the patient group (P = 0.414). We found no significant difference between body mass index (BMI) of the control and the patient groups (P=0.699), and while in the control group there was strongly positive correlation between serum leptin level and BMI (rs = 0.598, P &lt; 0.01), the patient group showed a positive but much weaker correlation (rs = 0.217, P &gt; 0.05). Our results suggest that compared to BMI, serum leptin has a much stronger association with IDC; since the source of high leptin in serum is not breast cancerous tissue, leptin cannot be a marker for IDC of breast; however, the hormone most likely is causally associated with the tumorigenesis of breast cancer. The results also indicate that obesity, as indicated by BMI, is weakly associated with IDC; however, broader studies with much larger sample sizes are needed to draw any definitive conclusion. We hypothesize that reducing leptin levels, blocking its downstream tissue specific signal transduction, and/or blocking the upstream leptin receptor pathway might help in the prevention and therapy of breast cancer.
Citation Format: Shaikh M. Rahman, Saad M. Al-Shibli, Nasser M. Amjad, Muna K. Al-Kubaisi, Norra B. Harun, Emad M. Nafie. The leptin transduction pathway may be targeted against invasive ductal carcinoma of breast [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A198.
Abstract A201: Discovery of TSR-033, a novel, potent anti-human LAG-3 therapeutic antibody
Authors: Ghosh Srimoyee , Laken Haley , Travers Jon , Kamar Sujatha , Jun H. Toni , Kehry Marilyn R. , Jenkins David 
Published: August 2018

Abstract
Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on immune cells. Similar to other immune inhibitory receptors such as programmed death-1 (PD-1), LAG-3 ligation suppresses T-cell activation and cytokine production following antigen stimulation. Despite favorable response rates observed with PD-1 or PD-1 ligand blockade in the treatment of human cancers, there remain many patients who either derive little clinical benefit from such therapies (primary resistance) or suffer a relapse (acquired or adaptive immune resistance). LAG-3 has been implicated in tumor extrinsic resistance mechanisms, due in part to its upregulation following PD-1 blockade, suggesting that targeting this pathway in addition to PD-1 may engender stronger and more durable antitumor immune responses. TSR-033 is a potent and selective humanized monoclonal antibody of the IgG4/kappa isotype, generated through the use of a proprietary in vitro somatic hypermutation antibody discovery technology platform. TSR-033 binds to human LAG-3 and blocks the interaction between LAG-3 and its ligand, major histocompatibility complex class II, expressed on Daudi cells. When evaluated for C1q and CD16a binding, TSR-033 displays properties typical of a human IgG4 antibody, suggesting that it is unlikely to mediate appreciable complement-dependent cytotoxicity or antibody-dependent cell cytotoxicity. Functionally, TSR-033 enhanced T-cell activation in vitro in both SEB-driven and mixed lymphocyte reaction assays. The combination of TSR-033 with a ligand blocking anti-PD-1 antibody further augmented T-cell activation in both systems, as evidenced by increased cytokine production, relative to each individual reagent. Analogous studies using surrogate anti-mouse antibodies also demonstrated that combined blockade of PD-1 and LAG-3 significantly boosted IFNγ production in an in vitro model of murine CD4 T cell exhaustion. Furthermore, anti-LAG-3 combined with anti-PD-1 improved therapeutic efficacy in mouse syngeneic tumor models, eliciting durable immunologic memory upon tumor rechallenge and altering intratumoral and splenic T-cell populations, consistent with heightened immune activation. Taken together, the pharmacologic activity of TSR-033 demonstrates that it is a potent anti-LAG-3 therapeutic antibody and supports its clinical investigation in cancer patients.
Citation Format: Srimoyee Ghosh, Haley Laken, Jon Travers, Sujatha Kamar, H. Toni Jun, Marilyn R. Kehry, David Jenkins. Discovery of TSR-033, a novel, potent anti-human LAG-3 therapeutic antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A201.
Abstract B002: CD47 expression predicts efficacy of macrophage-mediated phagocytosis of tumor cells
Authors: Yang Huajun , Li Zhongliang , Tang Beibei , Xing Frank , Shi Qian 
Published: August 2018

Abstract
Most human cancers express CD47 to escape the macrophage surveillance. To reinstate macrophage functionality in clearing tumor cells, targeting CD47 has been an important strategy in immune-oncology therapy. We profiled a large panel of tumor cell lines of both solid and blood tumors that are frequently used in cancer drug research and in Mixeno® animal study in Crown Bioscience for CD47. Despite its being reported as a ubiquitously expressed immune-escape marker in cancer cells, the expression levels of CD47 vary among different tumor cell lines when the cells were examined by flow cytometry. It is of interest that a portion of tumor cells in fact do not present CD47 despite gene expression data, such as RNA-seq data, suggesting that they do. To establish a robust and reproducible in vitro assay platform to support anti-CD47 drug research, we applied a macrophage differentiation system using isolated CD14+ monocytes as starting material, and were able to achieve &gt; 80% of M1 and M2 populations, respectively, through the 6-day differentiation. Differentiated macrophage was cocultured with target tumor cells labeled for flow cytometry analysis. In the presence of anti-CD47 antibody, steady phagocytosis effect was observed with aCD47 BRIC126 antibody and target tumor cells expressing high level of CD47 markers. BRIC126 antibody blocks the CD47-SIRPalpha interaction. To prove the finding, we constructed isogenic cell models from the same parental cells in that CD47 gene is knocked out in one sub-cell line and overexpressed in another sub-cell line. The isogenic systems are also subject to the CD47 biology studies and can be served as positive and negative controls in phagocytosis assays. Detailed data will be discussed.
Citation Format: Huajun Yang, Zhongliang Li, Beibei Tang, Frank Xing, Qian Shi. CD47 expression predicts efficacy of macrophage-mediated phagocytosis of tumor cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B002.