bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A58: Temporal dynamics underpin metabolism-driven cancer therapy cross-resistance
Authors: Goldman Aaron , Dhawan Andrew , Medhi Ragini , Kohandel Mohammad , Sengupta Shiladitya 
Published: May 2016

Abstract
The acquisition of resistance to chemotherapy is the underlying cause of relapse leading to metastasis and mortality. It is clear that the metabolic states of cancer cells contribute to cancer therapy failure. However, the inherent plasticity of cancer cells and the complexity of intratumoral heterogeneity have obscured a clear understanding for the role of metabolism in the development of resistance. Here, we used a computational biology approach in-tandem with functional assays at the single cell level to build a mechanistic understanding of an adaptive, metabolic cell-state-switch which leads to cross-therapy resistance of chemotherapies in cancer. We show that cytotoxic chemotherapies induce a temporally-dependent cell behavior via 1. induction of cell surface scaffold-kinase interactions 2. mitochondrial-induced reactive oxygen species (ROS) which are then requisite to drive 3. redox stress-mediated glucose uptake. Interestingly, we identified that the early-enhanced mitochondrial ROS promotes a delayed glucose shunt towards the pentose phosphate pathway (PPP) which was mediating cross-drug resistance. Using pharmacologic inhibitors of proteins in the PPP as well as inhibitors of upstream glycolysis intermediates, we were able to restore cancer cell sensitivity to combination therapies producing robust tumor responses in otherwise resistant cancer cells. These findings unveil a systems analysis of metabolic plasticity leading to therapy failure and provide novel strategies for treatment.
Citation Format: Aaron Goldman, Andrew Dhawan, Ragini Medhi, Mohammad Kohandel, Shiladitya Sengupta. Temporal dynamics underpin metabolism-driven cancer therapy cross-resistance. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A58.
Abstract A74: Preclinical evaluation of a fatty acid synthase inhibitor in pancreatic cancer
Authors: Ahmed Roshan A. 
Published: May 2016

Abstract
Fatty Acid Synthase (FASN) is a key enzyme in lipid biosynthesis and is overexpressed in many cancers, including pancreatic ductal adenocarcinoma (PDA). Upregulation of FASN in pancreatic cancer is correlated to poor prognosis, poor differentiation, and advanced tumor grade. In contrast, most normal cells have very low rates of de novo fatty acid synthesis and negligible FASN expression, making FASN inhibition an attractive therapeutic option.
Current strategies for treating pancreatic cancer have severe side effects and low response rates. An alternative strategy is to target the changes in metabolic state that arise during tumor development, including an increase in anabolic processes such as de novo fatty acid synthesis. Both the de novo fatty acid synthesis pathway and FASN have been targeted previously. However past agents suffered from issues of poor bioavailability, metabolic stability, and potency. In addition several of the drugs induced significant side effects in mice, including weight loss and decreased appetite.
IPI-9119 is an irreversible inhibitor of FASN with excellent pharmacological properties. This agent is highly potent and has been shown to inhibit FASN and have anti-proliferative effects in pancreatic cancer cell lines and in vivo. We utilize a clinically relevant genetically engineered mouse model of PDA and an advanced preclinical infrastructure to evaluate IPI-9119 as a therapeutic for PDA. Preliminary in vivo studies demonstrated effective delivery of IPI-9119 to pancreatic tumor tissues, resulting in near-complete inhibition of FASN function. Short-term studies found elevated levels of apoptosis and reduced proliferation in IPI-9119 treated tumors. Combination with the genotoxic agent gemcitabine did not alter drug delivery or biochemical efficacy. These results will serve as a foundation for a comprehensive preclinical evaluation of IPI-9119 in which we will explore pharmacology, tolerability, and mechanisms of IPI-9119 action.
Citation Format: Roshan A. Ahmed. Preclinical evaluation of a fatty acid synthase inhibitor in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A74.
Abstract B05: Inhibition of ER/Stat3 signaling pathways drive the evolution of ER+ metastatic breast cancer through the generation of ER-independent OXPHOShi self-renewing cells
Authors: Sansone Pasquale , Berishaj Marjan , Chang Qing , Strillacci Antonio , Giacco Ferdinando , Bromberg Jacqueline 
Published: May 2016

Abstract
A better understanding of the molecular features of the metastatic switch might reveal new cancer cell liabilities to develop novel therapeutics for metastatic cancer patients. Here we demonstrated that the generation of dormant and tumor-initiating cells takes place in the tumor microenvironment through a metabolic reprogramming in luminal (ER+) breast cancer. The expression of the surface markers interleukin 6 receptor (IL6R) and CD44 identify distinct tumor initiating and dormant cells. We demonstrated that IL6Rlo/CD44hi cells originate in hypoxic niches and self-renew following re-oxygenation via estrogen receptor alpha (ER)-dependent up-regulation of oxidative phosphorylation (OXPHOS). Conversely, IL6Rhi/Stat3hi cells are dormant populations arising in an environment defined by recurrent episodes of hypoxia/normoxia. These cells were characterized by decreased OXPHOS and ER activities. Reducing Stat3 expression resulted in cells resistant to hypoxia/re-oxygenation-mediated dormancy. Molecularly, Stat3lo cells had reduced ER signaling, high OXPHOS and increased metastatic capacity. Thus we propose that inhibition of ER/Stat3 signaling pathways drive the evolution of ER+ metastatic breast cancer through the generation of ER-independent-OXPHOShi self-renewing cancer cells.
Citation Format: Pasquale Sansone, Marjan Berishaj, Qing Chang, Antonio Strillacci, Ferdinando Giacco, Jacqueline Bromberg. Inhibition of ER/Stat3 signaling pathways drive the evolution of ER+ metastatic breast cancer through the generation of ER-independent OXPHOShi self-renewing cells. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B05.
Abstract B09: Mitochondrial respiration controlled by survivin directs mitochondrial dynamics and tumor cell invasion
Authors: Rivadeneira Dayana B. , Caino M. Cecilia , Seo Jae Ho , Angelin Alessia , Douglas Wallace C. , Languino Lucia R. , Altieri Dario C. 
Published: May 2016

Abstract
Recent studies have focused on unraveling the molecular processes by which cancer cells undergo metabolic reprogramming. The switch from oxidative phosphorylation to glycolysis allows cancer cells to adapt to harsh conditions, evade cell death and perpetuate cell growth and cell invasion. Survivin, a member of the Inhibitor of Apoptosis (IAP) gene family, is multifunctional protein. Survivin plays a critical role in promoting cell proliferation by regulating cell division, and protecting cancer cells from apoptosis. Most importantly, survivin has been shown to be highly expressed in cancers, associated with poor disease outcome and metastatic dissemination. In addition, previous studies have identified a novel pool of survivin that localizes to mitochondria selectively in tumors. This pool of survivin prevents cancer cell apoptosis and contributes to tumor progression, but the underlying mechanism is uncertain. In this study, with the use of sirRNA and pharmacological approaches against survivin, as well as protein reconstitution experiments, we dissect the role of mitochondrial survivin in modulating tumor bioenergetics. Biochemically, this study identifies mitochondrial survivin as part of a multi-protein complex with mitochondrial chaperone TRAP-1 and oxidative phosphorylation Complex II subunits. Survivin recruitment to this complex ensures protein folding and oxidative phosphorylation activity. Interference with this pathway inhibits cellular respiration, ATP production and induces cellular starvation. Functionally, this multiprotein complex suppresses tumor cell migration, invasion and affects metastatic progression in vivo. Overall, this study identifies mitochondrial bioenergetics, regulated by mitochondrial survivin, as a modulator of tumor cell invasion and metastasis.
Citation Format: Dayana B. Rivadeneira, M. Cecilia Caino, Jae Ho Seo, Alessia Angelin, Wallace C. Douglas, Lucia R. Languino, Dario C. Altieri. Mitochondrial respiration controlled by survivin directs mitochondrial dynamics and tumor cell invasion. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B09.
Abstract B35: Association between acute leukemias and levels of leptin in blood: A meta-analysis
Authors: Dendi Vijaya SenaReddy , Aloor Sivakanth , Gadde Rahul , Kunkalla Kranthi , Reddy Roopesh Reddy Sadashiva , Gryn Jeffrey 
Published: May 2016

Abstract
Background: Leptin, a secretory protein of adipocytes, shown to induce differentiation, proliferation, anti-apoptotic and activation of hematopoietic cells through paracrine interaction in the bone marrow microenvironment. Existing literature provides conflicting evidence as to the association between levels of serum leptin and acute leukemia's.
Purpose: The aim of this study is to conduct a meta-analysis to investigate the association between serum leptin levels and presence of acute leukemia's.
Methods: We searched MEDLINE, CIINHAL and COCHRANE databases for studies reporting serum leptin levels in the peripheral blood and bone marrow with and without acute leukemia's [Acute lymphoblastic leukemia (ALL)/Acute myleogenous leukemia (AML)]. We included case controls, cohort and cross-sectional studies. We calculated the weighted standardized mean difference (SMD) in serum leptin levels between the acute leukemia's patients and control groups.
Results: Our search strategy yielded 70 articles and we included 10 studies enrolling 354 participants with 176 patients and 178 controls of matched age, sex and BMI (body mass index). We included 108 ALL patients compared with 126 controls and136 AML patients compared with 104 controls. The median age of the ALL and AML group compared to controls was 8.12 yrs. (IQR 7.17 - 26.25) and 42 yrs. (IQR 28.8 – 52.88). The median percentage of females of ALL and AML compared to controls was 45 (IQR 27 – 66) and 52.5 (IQR 47 – 60). The unweighted median serum leptin levels in the ALL and AML groups were 21.2 ng/ml (13.4 – 27.4) and 29.9 ng/ml (5.55 – 55.83) compared to 9.43 ng/ml (6.6 – 17.8) and 31.5 ng/ml (6.43 – 89.77) in the control groups.
The SMD's of having abnormal serum leptin levels of ALL and AML compared to controls was 1.27 (95% CI 0.53 - 2.00) P = 0.001 and – 0.97 (95% CI -1.39 - -0.55) P &lt;0.001.
Conclusion: Increased and decreased serum leptin levels are significantly associated with ALL and AML respectively. Further investigation into the molecular mechanism underlying leptin's role in acute leukemia's and its use as an adjunctive screening tool are warranted.
Citation Format: Vijaya SenaReddy Dendi, Sivakanth Aloor, Rahul Gadde, Kranthi Kunkalla, Roopesh Reddy Sadashiva Reddy, Jeffrey Gryn. Association between acute leukemias and levels of leptin in blood: A meta-analysis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B35.
Abstract B39: PTP1B deficiency potentiate prostate cancer invasiveness by sensitizing Pten-null tumors to high-fat diet
Authors: Labbé David P. , Uetani Noriko , Vinette Valérie , Aubry Isabelle , Migon Eva , Sirois Jacinthe , Haigh Jody J. , Lessard Laurent , Bégin Louis R. , Trotman Lloyd C. , Paquet Marilène , Tremblay Michel L. 
Published: May 2016

Abstract
Specific diets can affect the risk and progression of prostate cancer (PCa). However, the interplay between diet and genetic alterations remains ill defined. Here we show that progression of PCa that is driven by Pten loss is mostly unresponsive to a high fat diet; however, in the absence of protein tyrosine phosphatase Ptpn1 (which encodes PTP1B) mice that are fed a high fat diet develop a highly invasive disease that is characterized by increased cell proliferation and Akt activation. Together with the finding that prostate-specific PTP1B overexpression does not initiate PCa by itself, we conclude that PTP1B act as an environment-dependent tumor suppressor in the context of Pten-null prostate tumors. PTP1B is a validated therapeutic target at the crossroad of metabolism (diabetes, obesity) and cancer (breast), and is currently being investigated in clinical trials. Due to PTP1B's nutrient sensing capabilities, we suggest that a careful monitoring of the balance between improving metabolic syndrome and promoting oncogenic effects under particular diets be pursued when using PTP1B-targeted therapeutics.
Citation Format: David P. Labbé, Noriko Uetani, Valérie Vinette, Isabelle Aubry, Eva Migon, Jacinthe Sirois, Jody J. Haigh, Laurent Lessard, Louis R. Bégin, Lloyd C. Trotman, Marilène Paquet, Michel L. Tremblay. PTP1B deficiency potentiate prostate cancer invasiveness by sensitizing Pten-null tumors to high-fat diet. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B39.
Abstract B47: Unraveling tumor metabolism with in silico IHC multiplexing supported by automated imaging analysis
Authors: Harring Suzana Vega , Canamero Marta , Korski Konstanty , Marchal Georges , Grimm Oliver , Ferreira Claudia , Bredno Joerg , Chefd`hotel Christophe , Gaire Fabien 
Published: May 2016

Abstract
The aim of our study is to understand and characterize tumor biology and its metabolism by evaluating some of the most relevant hallmarks of cancer like hypoxia, apoptosis, tumor proliferation, angiogenesis and immune status.
We selected from our tissue bank FFPE blocks from 3 main tumor indications (CRC, GC, RCC) analyzed with 9 different markers: CA9, CC3, Ki67, CD34, aSMA, Podoplanin, CD3, CD8 and FOXP3 in consecutive sections. We applied 2 triplex, one duplex and one single IHC assays. After quality check made by board certified pathologist, all slides were scanned with the iScan-HT scanner (VENTANA) at 20x magnification and the whole slide sections were analyzed with help of automated imaging algorithms developed in house.
Tumors harbor different metabolic states. Our cutting-edge approach enables comprehensive understanding of the interactions among different tumor components with respect to tumor metabolism and immune infiltration. Our automated image analysis tool is able to reconstruct and understand the architectural patterns of different tumor metabolic states and to show distribution of hypoxia (CA9), proliferation (Ki67), cell death (CC3), angiogenesis (CD34/aSMA/Podoplanin) and immune cells (CD8/CD3, FOXP3).
Deep understanding of tumor biology and metabolism is crucial for guiding drug development and overcoming challenges in clinical translation.
Citation Format: Suzana Vega Harring, Marta Canamero, Konstanty Korski, Georges Marchal, Oliver Grimm, Claudia Ferreira, Joerg Bredno, Christophe Chefd`hotel, Fabien Gaire. Unraveling tumor metabolism with in silico IHC multiplexing supported by automated imaging analysis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B47.
Abstract B53: The role of RPL39 induced autophagy in resistance of breast cancer stem cells
Authors: Dave Bhuvanesh , Choi Dong Soon , Wong Helen , Liu Yi , Gunamalai Prem Siddharth , Chang Jenny C. 
Published: May 2016

Abstract
Introduction: Autophagy is an evolutionarily conserved lysosomal pathway for degradation of cytoplasmic proteins, macromolecules, as well as organelles, and is a survival pathway under nutrient and environmental stress. Tumor initiating cells (TICs) survive standard radiation, and chemotherapy that ultimately cause breast tumor recurrence and metastasis. Our previous studies have identified autophagy as the mechanism of survival in treatment-resistant populations in patient samples. Recent evidence from our group has defined for the first time two previously unidentified cancer genes, ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) that play a crucial role in tumor initiation and metastasis. Additionally, RPL39 and MLF2 genes in TIC self-renewal utilize hypoxia and reactive nitrogen species for their action. In this study, we aim to determine the mechanism by which RPL39 and MLF2 modulate TICs and their relationship to tumor microenvironment.
Experimental Procedures: Analysis of clinical samples was performed using low density array analysis. This data was then confirmed using real time PCR analysis. The mechanism of action of RPL39 as related to autophagy was identified utilizing western analysis.
Results and Discussion: We confirmed our in silico bioinformatics based findings by using a real time PCR low density array of 84 genes related to autophagy in 9 paired pre- vs. post-treatment clinical samples, where 60 out of 84 genes demonstrated a statistically significant change (p&lt;0.05) in this pathway. Using western analysis in three cell lines (SUM159, BT549, HS578T); we have demonstrated the activation of mTOR dependent translational initiation complex in TIC survival. Our results demonstrate that RPL39 binds to EIF4G and 4EBP-1 as an immunoprecipitated complex. Downstream analysis describes a RPL39-dependent modulation in 4EBP-1 and EIF4G which can be altered by over- or under- expression of the gene. In conclusion, TICs survive therapy by activating the autophagy pathway using RPL39-dependent inducible nitric oxide synthase process, through 4EBP-1 and EIF4G. Understanding this process may allow us to target TICs and breast tumor metastasis.
Citation Format: Bhuvanesh Dave, Dong Soon Choi, Helen Wong, Yi Liu, Prem Siddharth Gunamalai, Jenny C. Chang. The role of RPL39 induced autophagy in resistance of breast cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B53.
Abstract B55: Role of HSF1 in chemotherapy-induced autophagy and endoplasmic reticulum stress response in breast cancer
Authors: Desai Shruti , Tan Ming 
Published: May 2016

Abstract
Heat Shock Factor 1 (HSF1), a master regulator of heat shock response, plays an important role in tumorigenesis. In this study we demonstrate that HSF1 is required for chemotherapeutic agents induced cytoprotective autophagy and Endoplasmic Reticulum (ER) stress response. HSF1 can transcriptionally regulate autophagy related gene ATG7 and ER membrane protein IRE1α. Interestingly, most of this regulation is independent of HSF1's heat shock function.
Treatment of cancer cells with FDA approved chemotherapeutic agent induced autophagy which was significantly decreased upon HSF1 knockdown. Mechanistic studies revealed that HSF1 regulates autophagy by directly binding to the ATG7 promoter and transcriptionally upregulating its expression. HSF1 also may play a role in regulating autophagy by modulating levels of phosphorylated AMPK, a key protein that can trigger autophagy. Thus HSF1 regulates the process of autophagy in a multi-pronged manner, through regulation of key autophagy protein as well as regulation of key inducer of autophagy. Furthermore, a strong positive correlation was observed between levels of HSF1 and ATG7 in breast cancer patient samples, thus validating our in vitro findings. Similarly, knockdown of HSF1 reduced the induction of ER stress response by chemotherapeutic agents. Mechanistic studies have revealed that HSF1 regulated cytoprotective ER stress response by directly regulating IRE1α expression and sustained activation. IRE1α, a resident ER protein, is a key sensor of ER stress. It activates Xbp1 leading to expression of protein chaperone genes that help alleviate the ER stress response. This HSF1/IRE1α pathway was further validated in cancer patients by immunohistochemistry staining of breast cancer patient tissue array.
This study identifies a critical role for HSF1 in controlling cytoprotective stress response pathways of autophagy and ER stress response in tumor cells. HSF1 does this by not only regulating transcription of key proteins required in these pathways but also by regulating activation of key inducers of these pathways. The findings from this study can be further used to design more robust treatment strategies for breast cancer patients thus improving their prognosis.
Citation Format: Shruti Desai, Ming Tan. Role of HSF1 in chemotherapy-induced autophagy and endoplasmic reticulum stress response in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B55.