bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3515: LHX9 is a novel oncogene bypassing KRAS addiction
Authors: Ly Seav Huong , Dai Chao , Hong Andrew L. , Ilic Nina , Krall Elsa B. , Hahn William C. 
Published: July 2017

Abstract
Background Oncogenic mutations of RAS are detected in approximately 30% of human cancers. KRAS is highly mutated in pancreatic, colorectal and lung cancers. Direct therapeutic targeting of Ras and its membrane association has been challenging due to high affinity of GTP to Ras and unexpected mechanism of alternative post-translational modification. While few inhibitors of downstream RAS effectors - MAPK and PI3K pathways - show some clinical efficacy, they are complicated by complex feedback loops, and as single agents are not effective in KRAS-mutant cancers. Combination therapies may be promising yet limited by narrow therapeutic window. Identification of alternative strategies to directly inhibiting RAS and MAPK/PI3K pathways is key to address this unmet need.
Methods To this end, we performed a genome-scale open reading frames screen to identify genes capable of restoring viability to KRAS-dependent cells following KRAS suppression. We tested the top 5-standard-deviation hits in low-throughput manner. One of the top hits included LIM homeobox 9 (LHX9), a homeobox family transcription factor essential for mouse gonad, limb, and brain development. While LHX9 is amplified in several cancers, little is known regarding its roles in cancers. We used hypothesis-driven as well as unbiased approaches including RNA-seq, ChIP-seq, and IP-mass spectrometry to investigate the basis of LHX9-mediated bypass of KRAS dependency.
Results We showed that LHX9 rescued KRAS suppression in multiple cell lines as well as xenograft. LHX9 overexpression substituted for KRAS in KRAS-driven xenograft. Moreover, in activated-MEK-overexpressing HA1E cells, LHX9 formed tumors as robustly as myristoylated AKT. LHX9 rescued KRAS suppression by both restoring KRAS-dependent pathways and activating KRAS-independent pathways. First, LHX9 reactivated the main KRAS effectors - MAPK and PI3K pathways and conferred resistance to MEK inhibitor Trametinib. Second, using ChIP- and RNA-seq, we observed LHX9 binding to promoters/enhancers of genes whose expression was regulated by KRAS, particularly YAP1. Third, LHX9 increased expression and activation of KRAS-independent genes, including STAT3.
Conclusions Here, we identified LHX9 as a novel bypass of KRAS addiction. Multiple unbiased approaches revealed at least three mechanisms by which LHX9 rescued KRAS suppression. Our findings contribute to our understanding of KRAS biology. Further investigation of downstream effectors of LHX9 may highlight potentially novel therapeutic targets for KRAS-dependent cancers.
Citation Format: Seav Huong Ly, Chao Dai, Andrew L. Hong, Nina Ilic, Elsa B. Krall, William C. Hahn. LHX9 is a novel oncogene bypassing KRAS addiction [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 3515. doi:10.1158/1538-7445.AM2017-3515
Abstract 3543: Targeting the metabolic mevalonate pathway with statins as anti-breast cancer agents
Authors: Leeuwen Jenna van , Pandyra Aleksandra , Goard Carolyn , Mullen Peter J. , Yu Rosemary , Penn Linda Z. 
Published: July 2017

Abstract
The statin family of drugs target the mevalonate pathway and have been used for decades in the control of hypercholesterolemia, however recent evidence suggests these approved agents may also be useful as anti-cancer therapeutics (see our recent Nature Review Cancer article1). For example, statins can trigger tumor-specific apoptosis and two independent pre-op clinical trials in breast cancer, evaluating cholesterol-lowering doses of fluvastatin and atorvastatin, resulted in breast tumor shrinkage due to decreased growth and increased apoptosis. Our hypothesis is that statins have utility as anti-breast cancer agents. To maximize efficacy and speak to personalized medicine, our objectives are to develop biomarkers to distinguish which patients will benefit from the addition of statins to their treatment regimen and how best to use statins in combination with other agents to augment anti-tumor efficacy. To identify biomarkers of statin sensitivity we evaluated fluvastatin activity across a panel of BCa cell lines and showed that the basal, estrogen receptor-negative subtype were significantly sensitive to statin-induced apoptosis. As this included the difficult-to-treat triple negative BCa (TNBCa) we have extended this work and further evaluated a panel of TNBCa cell lines for statin sensitivity. From these results we are identifying features associated with robust apoptosis in response to statin exposure. To identify how best to use statins, we conducted two unbiased screens and have shown that blocking the restorative feedback response to statin exposure potentiates statin-induced apoptosis. This is reversible with exogenous mevalonate, reinforcing that this is an on-target effect. We also identified another approved agent, dipyridamole, as able to potentiate the anti-cancer activity of statins. Mechanistically we have shown that dipyridamole blocks the feedback response to statin exposure. We have extended these studies and shown that the combination of statins and dipyridamole is effective against TNBCa both in vitro and in vivo. Thus, we provide essential pre-clinical data to support the further evaluation of statins and dipyridamole in BCa.
Reference: Mullen, P.J. et al. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer. 16, 718-731 (2016).
Citation Format: Jenna van Leeuwen, Aleksandra Pandyra, Carolyn Goard, Peter J. Mullen, Rosemary Yu, Linda Z. Penn. Targeting the metabolic mevalonate pathway with statins as anti-breast cancer agents [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 3543. doi:10.1158/1538-7445.AM2017-3543
Abstract 3545: Glucose-dependent regulation of PXR is modulated by AMPK
Authors: Oladimeji Peter O. 
Published: July 2017

Abstract
The sensitivity of patients to drugs depends on the pharmacokinetics of the drugs, but largely on the bioavailability of the drugs in the body. Orally administered drugs must pass through the intestinal wall and the portal circulation to reach the liver; both are sites of first-pass metabolism. Thus, many drugs may be metabolized before optimal plasma concentrations are reached, or before getting to target tissues, resulting in diminished drug efficacy and acquired drug resistance. Among the several drug-metabolizing enzymes (DME) is cytochrome P450 (CYP) enzyme 3A4, the most abundant in the liver, metabolizes approximately 50 percent of marketed drugs and a main target of pregnane X receptor (PXR) In addition, transporters including MDR1 are also regulated by PXR. There is increasing evidence that drug metabolism can be affected by energy metabolism and vice versa. PXR has been implicated to have a complex role in energy homeostasis, and increased drug clearance was observed in untreated diabetic patients. The elimination of any chemotherapeutic agents in humans is markedly dependent on the relative expression and activity of the various DMEs and drug transpoters. The heterotrimeric AMP-activated protein kinase (AMPK) serves as a monitor of cellular energy status in most eukaryotic cell, and is activated under energy stress conditions. Interestingly, AMPK is also regarded as a tumor suppressor in various cancers because of its inhibitory effects on anabolic processes that are important for tumor development. Despite the knowledge of the cross-regulation between drug metabolism and energy metabolism, the molecular pathways of this interaction remain vague. In our study, we exposed HepG2 cells to varying glucose concentrations and observed that PXR is greatly induced in high glucose conditions. This finding is consistent with clinical observation of increased drug clearance in untreated diabetic patients. We demonstrate that AMPK modulates PXR transcriptional activity. As such, the pharmacological manipulations of AMPK activation status show an inverse relationship with PXR activity. Activation of AMPK was shown to decrease PXR activity as observed by decreased CYP3A4 transcription, and consistent with that a potentiation of response to drugs. Interestingly, we observed that PXR is not a direct target of AMPK: it remains to be determined what the intermediary between AMPK and PXR is. Taken together, our studies identify novel links between the energy status of the cell, the activation of AMPK and down regulation of PXR.
Citation Format: Peter O. Oladimeji. Glucose-dependent regulation of PXR is modulated by AMPK [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 3545. doi:10.1158/1538-7445.AM2017-3545
Abstract 3547: B cell receptor signaling regulates cellular metabolism in Chronic Lymphocytic Leukemia
Authors: Vangapandu Hima V. , Havranek Ondrej , Wierda William G. , Keating Michael J. , Davis Richard Eric , Stellrecht Christine M. , Gandhi Varsha 
Published: July 2017

Abstract
Peripheral blood B cells in chronic lymphocytic leukemia (CLL) are quiescent, yet have an active RNA transcription and protein translation processes, suggesting that these malignant lymphocytes may be metabolically active. However, CLL metabolism and its relationship to disease biology has not been well-explored. In our previous investigation, we reported that compared with proliferative B-cell lines, metabolic fluxes of oxygen and lactate were low in quiescent peripheral blood B lymphocytes from CLL patients (Vangapandu, H.V. et al, AACR 2014). In 45 patient samples tested, glycolysis (extracellular acidification rate, ECAR) was consistently low (1 to 15 mpH/min/5 x 105 lymphocytes), whereas, oxygen consumption rate (OCR) varied considerably (5 to 190 pMoles/min/5 x 105 lymphocytes). Among the prognostic factors, high OCR correlated strongly with ZAP 70 positivity, unmutated IGHV status, greater β2M levels and higher Rai stage. In contrast, glycolytic flux (ECAR) from same patient samples did not associate with prognostic factors. Further, OCR did not vary on the basis of frequently occurring cytogenetic abnormalities, 13q14, 17p, and 11q deletions or trisomy 12. Since, ZAP 70 and IGHV unmutated status are associated with augmented B-cell receptor (BCR) pathway signaling, we tested the impact on OCR after genetic ablation of B-cell receptor (CH2 region of IgM). A CRISPR-Cas9-mediated BCR knockout mitigated OCR in a malignant B cell line without impacting the rate of proliferation. A critical node in the BCR pathway is PI3 Kinase and PI3K isoforms, δ and γ are involved in B-cell malignancies. Consistent with BCR ablation results, knocking out PIK3CD (codes for catalytic subunit δ), dramatically reduced OCR and ECAR. Pharmacological inhibitors of the PI3K pathway, duvelisib (a PI3K δ/γ inhibitor in phase III clinical trials) or idelalisib (FDA approved PI3K δ inhibitor) also decreased OCR. Direct inhibition of AKT with MK-2206 showed similar results. Collectively, these data suggest that CLL cellular metabolism is associated with prognostic factors and linked to BCR signaling pathway. Since, the PI3K inhibitors used in our study are being tested clinically for patients with CLL, investigations on the impact on metabolomics during therapy and translation of results to combination strategies need to be explored.
Note: This abstract was not presented at the meeting.
Citation Format: Hima V. Vangapandu, Ondrej Havranek, William G. Wierda, Michael J. Keating, Richard Eric Davis, Christine M. Stellrecht, Varsha Gandhi. B cell receptor signaling regulates cellular metabolism in Chronic Lymphocytic Leukemia [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 3547. doi:10.1158/1538-7445.AM2017-3547
Abstract 3559: Functional characterization of HNF4α in gastric cancer
Authors: Xu Chang , Ooi Wen Fong , Qamra Aditi , Tan Patrick 
Published: July 2017

Abstract
Gastric cancer (GC) is a leading cause of cancer mortality worldwide and particularly common in East Asia. Transcription factors are frequently amplified or overexpressed in GC and might contribute to tumorgenesis, however the underlying mechanisms largely remain unknown. Our previous data indicates that HNF4α is a common target of three amplified transcription factors (GATA4, GATA6 and KLF5) in gastric cancer. HNF4α had also been found to be related to diverse aspects of tumorigenesis. In liver and colon cancers, there are reports indicating that the targets of HNF4α are mainly involved in intermediary metabolism, however, its tissue-specific downstream targets and pathways have not been systemically studied yet. Therefore, a comprehensive functional characterization of HNF4α is required to identify its tissue-specific role in gastric cancer. In this study, we analyzed the expression features of HNF4α in GC, and found the expression level of HNF4α is significantly higher in early stage tumor and in CIN and MSI compared to GS and EBV subtypes of GC according to TCGA classification method. In addition, we performed the HNF4α ChIP in GC cell lines, and the results revealed a number of HNF4α binding sites in GC. Comparison with the published ChIP-seq data of Caco2 and HepG2 cell lines indicated the existence of GC-exclusive targets. Furthermore, functional annotation analysis revealed that the GC-exclusive targets are significantly related to the negative regulation of cellular metabolic process compared to the common targets. These preliminary data suggests that HNF4α might play a tissue specific role in GC, especially in metabolic related processes. Through further target validation and biological function studies, this study hopes to systemically investigate of HNF4α’s role in GC tumorigenesis, especially in metabolism related pathways.
Citation Format: Chang Xu, Wen Fong Ooi, Aditi Qamra, Patrick Tan. Functional characterization of HNF4α in gastric cancer [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 3559. doi:10.1158/1538-7445.AM2017-3559
Abstract 3565: Recurrently detected germline mutation of FLT3 (D358V) associated with prevalence of hematopoietic malignancy and prognosis of AML patients
Authors: SONG SEULKI 
Published: July 2017

Abstract
FLT3 is most frequently mutated gene in acute myeloid leukemia patients. While somatic mutation of FLT3 is well known, germline mutation of FLT3 and predispose to AML remain poorly understood. Here we identify a germline FLT3 p.D358V affected prognosis of AML patients. We performed whole exome sequencing (WES) using 76 patients’ saliva sample to detect FLT3 germline mutation in buccal epithelial cell and demonstrate FLT3 p.D358V mutation for 6 patients among 76 patients. The frequency of FLT3 p.D358V mutation in AML patients is significantly higher in general population (p=9.50E-07), suggesting association of FLT3 mutation with AML predisposition. Asian population especially carried this locus more than other ethic population. When we compared between AML patients and general population of Asian, the chi-square p-value was 0.07 and odd ratio was 2.26. Overall survival was significantly reduced in patients who had FLT3 p.D358V mutation (p=0.03) and disease free survival was show a tendency of reducing in the patients with FLT3 p.D358V mutation.
Citation Format: SEULKI SONG. Recurrently detected germline mutation of FLT3 (D358V) associated with prevalence of hematopoietic malignancy and prognosis of AML patients [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 3565. doi:10.1158/1538-7445.AM2017-3565
Abstract 3585: Determination of gene amplifications with a next-generation sequencing cancer panel
Authors: Deras Ina L. , Wise Aaron , Zhao Chen , Glidewell-Kenney Christine , Le Phillip , Aderhold Elizabeth Upsall , Gutekunst Karen 
Published: July 2017

Abstract
TruSight® Tumor 15* (TST15) uses next-generation sequencing technology to detect somatic point mutations, insertions, and deletions in 15 genes that are commonly mutated in solid tumors. It accurately detects low-frequency mutations with low DNA input and is optimized for formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The test is a multiplexed PCR panel that includes primers to support amplification detection in the EGFR, ERBB2, and MET genes.
Here we describe development of a bioinformatics analysis method to enable detection of these gene amplifications. DNA extracted from 31 FFPE samples with amplifications in EGFR, ERBB2, or MET—some with dual amplifications—were diluted with DNA extracted from 18 normal FFPE samples to create a total of 67 unique samples at low-level amplification. Undiluted and diluted samples were assessed for quality based on amplifiability (ΔCq or library yield) and tested with TST15. For comparison, the samples were also tested with droplet digital PCR (ddPCR) to determine the copy ratio of target to wild type. For amplifiable samples, the TST15 algorithm was able to detect amplifications in EGFR and ERBB2 at ddPCR ratios of 1.4 and 1.6, respectively. ddPCR was unable to accurately quantify low MET amplifications; therefore, expected ddPCR ratios were used for comparison. The TST15 algorithm was able to detect amplifications in MET samples at an expected ddPCR ratio of 1.3. Poor sample quality (i.e., high ΔCq or low library yield) impaired amplification detection. In some samples, the presence of multiple amplifications also impaired detection.
The addition of this algorithm to the TST15 workflow will allow researchers to more accurately characterize tumor samples by detecting somatic mutations and amplifications simultaneously.
*For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Ina L. Deras, Aaron Wise, Chen Zhao, Christine Glidewell-Kenney, Phillip Le, Elizabeth Upsall Aderhold, Karen Gutekunst. Determination of gene amplifications with a next-generation sequencing cancer panel [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 3585. doi:10.1158/1538-7445.AM2017-3585
Abstract 3611: Proteasome subunit PSMD1 participates in p53 degradation and regulates proliferation of breast cancer cells
Authors: Okumura Toshiyuki , Ikeda Kazuhiro , Sato Wataru , Horie-Inoue Kuniko , Inoue Satoshi , Takeda Satoru , Okamoto Koji 
Published: July 2017

Abstract
Breast cancer is the most common cancer among women in developed countries. Generally, 70% of primary breast cancer patients express estrogen receptor, thus endocrine therapy is often efficient for the disease using antiestrogen such as tamoxifen as well as aromatase inhibitor. During long-term therapy, however, a substantial proportion of women recurrent and acquire resistance to endocrine therapy. Understanding of the mechanism underlying acquired endocrine resistance would be a first step toward overcoming hormone-refractory cancer. In this study, we identified candidate genes that contributed to tamoxifen resistance in MCF-7 breast cancer cells by functional screening based on short hairpin RNA (shRNA) library. We found that several candidate genes were overexpressed in breast cancer patients and their abundance was positively associated with poor prognosis of cancer patients in clinical database. Moreover, the genes associated with poor prognosis also showed positive association with shorter survival for patients treated with tamoxifen. Expression levels of these candidate genes were upregulated in hydroxytamoxifen (OHT)-resistant MCF-7 cells (OHTR) compared with parental cells. Proliferation of OHTR cells was repressed by siRNAs targeting 26S subunits, non-ATPase 1 (PSMD1) and tetraspanin12 (TSPAN12). Furthermore, knockdown of PSMD1 inhibited cell cycle progression and p53 protein degradation. p21 and 14-3-3σ, target genes of p53, were upregulated by PSMD1 knockdown. These findings would be used for the development of alternative diagnostic and therapeutic options for endocrine-resistant breast cancers.
Citation Format: Toshiyuki Okumura, Kazuhiro Ikeda, Wataru Sato, Kuniko Horie-Inoue, Satoshi Inoue, Satoru Takeda, Koji Okamoto. Proteasome subunit PSMD1 participates in p53 degradation and regulates proliferation of breast cancer cells [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 3611. doi:10.1158/1538-7445.AM2017-3611
Abstract 3615: Combined targeting of estrogen receptor alpha and nuclear transport pathways remodel metabolic pathways to induce apoptosis and overcome tamoxifen resistance
Authors: Kulkoyluoglu-Cotul Eylem , Madak-Erdogan Zeynep , Landesman Yosef , Wrobel Kinga 
Published: July 2017

Abstract
There is a critical need for novel therapeutic approaches to re-sensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Using Cignal Finder pathway analysis, Seahorse metabolic profiling and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tam and Selinexor (SXR), being evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies, inhibited Akt phosphorylation by changing the localization of the kinase. Since we observed dramatic changes in Akt activity we hypothesized that glucose utilization pathways and metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. These cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We showed that combined targeting of XPO1 and ERα rewires metabolic pathways, increase demand on mitochondria and causes increased production of ROS that would eventually lead to apoptosis. Re-modelling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences.
Citation Format: Eylem Kulkoyluoglu-Cotul, Zeynep Madak-Erdogan, Yosef Landesman, Kinga Wrobel. Combined targeting of estrogen receptor alpha and nuclear transport pathways remodel metabolic pathways to induce apoptosis and overcome tamoxifen resistance [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 3615. doi:10.1158/1538-7445.AM2017-3615