bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4980: Engineering adoptive T cell therapy for efficacy in ovarian cancer
Authors: Anderson Kristin G. , Bates Breanna M. , Chiu Edison Y. , Greenberg Philip D. 
Published: July 2017

Abstract
Over 20,000 women are diagnosed with ovarian cancer annually - more than half will die within 5 years and this rate has changed very little in the last 20 years, highlighting the need for innovative therapies. One promising new treatment strategy has the potential to control tumor growth without toxicity to healthy tissues, by employing immune T cells engineered to target proteins uniquely overexpressed in tumors. Recent technological advances have helped identify and validate Wilms’ Tumor Antigen 1 (WT1) and mesothelin (MSLN) as valid antigen targets for ovarian cancer, as these proteins contribute to malignant and invasive phenotypes and have limited expression in healthy cells. In preclinical studies using either patient-derived cell lines or the mouse ID8 ovarian tumor model, we found that T cells engineered to express either a WT1- or MSLN- specific high-affinity T cell receptor (TCR) can kill human and murine ovarian tumor cells in vitro. Moreover, in a disseminated in vivo murine model, adoptively transferred TCR-engineered T cells preferentially accumulated within established ID8 tumors, delayed ovarian tumor growth and prolonged mouse survival. However, our data also revealed that the tumor microenvironment (TME) can limit engineered T cell persistence and killing capacity. Cellular and molecular analyses showed human therapy will face similar TME-mediated obstacles. The ovarian cancer TME is a nutrient- and oxygen-deprived milieu, and adaptive metabolic responses by infiltrating T cells have protean effects on T cell function. Thus, strategies that modulate T cell metabolic pathways, and thereby influence activity in the TME, might enhance T cell function and improve anti-tumor efficacy by overcoming a critical component of immune evasion by solid tumors. Ongoing studies will be discussed that are exploring strategies to overcome elements common to the human and murine TME, including direct modulation of the environment and T cell engineering to promote T cell survival and function.
Citation Format: Kristin G. Anderson, Breanna M. Bates, Edison Y. Chiu, Philip D. Greenberg. Engineering adoptive T cell therapy for efficacy in ovarian 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 4980. doi:10.1158/1538-7445.AM2017-4980
Abstract 4985: Understanding the vulnerabilities in cancer cells upon inhibition of glutathione synthesis
Authors: Harris Isaac S. , Endress Jennifer E. , Brugge Joan S. 
Published: July 2017

Abstract
A hallmark of cancer is the rewiring of cellular metabolic pathways, including those that mediate oxidative stress. Cancer initiation and progression, which demands increased production of ATP and synthesis of proteins, also results in elevated generation of toxic by-products such as reactive oxygen species (ROS). Cancer cells counteract ROS by increasing the production of antioxidants, which convert ROS into benign species. It has been shown that production of glutathione (GSH), the most abundant intracellular antioxidant, is necessary for many cancers to initiate malignant transformation. Whether inhibition of GSH synthesis can impact the survival of established malignant tumors remains poorly understood. In this study we investigated the extent to which GSH is required in cancer cells and across different subtypes of breast cancer. Profiling of an extensive panel of breast cancer cell lines demonstrated that the majority of cells are resistant to death after acute GSH depletion, while only luminal breast cancer cells are sensitive to chronic GSH depletion. To understand how most tumor cells are resistant to GSH depletion and oxidative stress, we conducted a small-molecule high-throughput screen interrogating more than 500 compounds in a 10-point dilution format. Importantly, screening plates were imaged and cell numbers quantified to avoid any false positives/negatives potentially associated with interrogating cellular metabolism using classical high throughput techniques, such as CellTiter-Glo. This screen revealed that depletion of glutathione sensitized breast cancer cells to inhibition of deubiquitinases, resulting in a drastic induction of a proteotoxic stress response. Furthermore, this sensitivity was found to be specific to malignant cells, as non-transformed cells were resistant to the combined treatments. It has been hypothesized that GSH, acting as an abundant thiol group, non-enzymatically reacts with ubiquitin and limits ubiquitination of proteins. Loss of glutathione, in combination with deubiquitinase inhibitors, leads to deregulation of ubiquitinated protein pools, and cancer cells undergo proteotoxic stress and cell death. These findings elucidate a novel vulnerability in cancers cells and shed light on an unexpected relationship between cancer metabolism and protein homeostasis.
Citation Format: Isaac S. Harris, Jennifer E. Endress, Joan S. Brugge. Understanding the vulnerabilities in cancer cells upon inhibition of glutathione synthesis [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 4985. doi:10.1158/1538-7445.AM2017-4985
Abstract 4986: Pancreatic cancers develop metabolic resistance pathways to glutaminase inhibition
Authors: Mancias Joseph D. , Biancur Douglas E. , Paulo Joao A. , Rey Maria Quiles Del , Sousa Cristovão M. , Wang Xiaoxu , Chu Gerald C. , Gygi Steven P. , Harper J. Wade , Kimmelman Alec C. 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognosis. Therefore, novel treatment options are essential to combat this highly refractory disease. Oncogenic Kras can promote a metabolic rewiring of pancreatic cancers, including the non-canonical use of glutamine to support growth and proliferation through redox homeostasis. Indeed, inhibition of downstream components of glutamine metabolism leads to a decrease in tumor growth. The first step in glutamine metabolism is mediated by the enzyme glutaminase (GLS) which catalyzes the conversion of glutamine to glutamate in the mitochondria where, in PDAC, glutamine-derived glutamate is metabolized ultimately resulting in increased reducing potential in the form of increased NADPH and GSH. An outstanding question in pancreatic cancer is whether GLS inhibition is a viable therapeutic strategy given it is the most proximal enzyme in the PDAC-specific glutamine metabolism pathway, and how this may differ from targeting distal parts of the pathway. Using a combination of in vitro and in vivo models of pancreatic cancer, we tested whether recently developed highly potent inhibitors of GLS are an effective therapy for PDAC. We demonstrate that despite dramatic early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that allow them to sustain proliferation in vitro and in vivo. Through an integrated proteomic and metabolomic analysis, we identify multiple compensatory pathways that may explain the resistance to GLS inhibition and show as proof of concept that combining inhibitors to these pathways with GLS inhibitors may have therapeutic utility.
Citation Format: Joseph D. Mancias, Douglas E. Biancur, Joao A. Paulo, Maria Quiles Del Rey, Cristovão M. Sousa, Xiaoxu Wang, Gerald C. Chu, Steven P. Gygi, J. Wade Harper, Alec C. Kimmelman. Pancreatic cancers develop metabolic resistance pathways to glutaminase inhibition [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 4986. doi:10.1158/1538-7445.AM2017-4986
Abstract 4987: ASS1 downregulation facilitates cancer cell survival in acidic environment
Authors: Erez Ayelet , Silberman Alon , Jacob Adi , Limanovich Shiran , Boukobza1 Odeya , Persi Erez , Keshet Rom , Sarver Alona , Lee Joo Sang , Brandis Alexander , Halpern Keren Bahar , Eilam Raya , Pode Ben , Anikster Yair , Ulitsky Igor , Nagamani Sandesh , Ruppin Eytan 
Published: July 2017

Abstract
”pH gradient reversal”, namely the alkalinization of intracellular pH (pHi) and acidification of extracellular pH (pHe), is a unique phenotype of cancer cells which enable cancer survival, migration and invasion. Hence, not surprisingly, pH gradient reversal is emerging as a new hallmark of cancer. Argininosuccinate synthase, ASS1, is a urea cycle enzyme found to be downregulated by methylation in multiple different types of cancers in correlation with increased metastasis and poor prognosis. We recently showed that ASS1 downregulation increases proliferation by channeling aspartate towards pyrimidine synthesis by CAD. We now show that under hypoxia and acidic environments, ASS1 is downregulated together with CAD by HIF1α as part of an essential network necessary for cancer cells’ survival, invasion and migration. Similar to germline deficiency of ASS1 which increases the levels of glutamine and ammonia, ASS1 downregulation by HIF1αenables the cancer cells to increase glutamine levels allowing its utilization for glutathione and importantly, for preservation of alkali pHi by elevating ammonia levels and buffering the acidity caused by cancers’ enhanced glycolysis and the consequent increase in lactic acid. Moreover, cancer cells which express ASS1 when grown in culture, downregulate its expression in hypoxic regions when grown in vivo, suggesting that these cancers might also be sensitive to drugs previously utilized only in ASS1 deficient cancers. Finally, we show that treating cancers with ASS1 deficiency with ammonia scavengers as given to ASS1 deficient patients, increases apoptosis and restricts migration, and is hence beneficial therapeutically. In summary, ASS1 downregulation is regulated differently at altered carcinogenic states, promoting proliferation as well as cancer survival and metastasis.
Citation Format: Ayelet Erez, Alon Silberman, Adi Jacob, Shiran Limanovich, Odeya Boukobza1, Erez Persi, Rom Keshet, Alona Sarver, Joo Sang Lee, Alexander Brandis, Keren Bahar Halpern, Raya Eilam, Ben Pode, Yair Anikster, Igor Ulitsky, Sandesh Nagamani, Eytan Ruppin. ASS1 downregulation facilitates cancer cell survival in acidic environment [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 4987. doi:10.1158/1538-7445.AM2017-4987
Abstract 4988: Genome-wide CRISPR screen and metabolite profiling reveal a new mechanism of methotrexate sensitivity
Authors: Kanarek Naama , Freinkman Elizaveta , Cantor Jason , Abu-Remaileh Monther , Wang Tim , Sabatini David M. 
Published: July 2017

Abstract
The chemotherapeutic drug methotrexate (MTX) inhibits nucleotide biosynthesis and causes cell death by blocking DNA and RNA production. While MTX has had tremendous success as an anti-cancer treatment and is the subject of nearly a thousand ongoing clinical trials, we do not fully understand why certain cancers are more sensitive to it and why resistance emerges. To study these questions, we used a CRISPR-based genetic screen to identify genes that confer sensitivity to MTX. We identified an enzyme that plays a key role in a metabolic pathway that was not known to be associated with MTX sensitivity. Inhibition of the pathway, either by genetic loss of several genes in the pathway or through nutritional modulations, causes dramatic resistance to MTX in cultured cancer cells. Our results improved our understanding of the cellular response to MTX, and suggest that expression levels of enzymes in the pathway may serve as clinical predictor for MTX response in patients.
Citation Format: Naama Kanarek, Elizaveta Freinkman, Jason Cantor, Monther Abu-Remaileh, Tim Wang, David M. Sabatini. Genome-wide CRISPR screen and metabolite profiling reveal a new mechanism of methotrexate sensitivity [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 4988. doi:10.1158/1538-7445.AM2017-4988
Abstract 499: IgH enhancers hs3b/hs4 are dispensable for c-Myc deregulation in mouse plasmacytomas with T(12;15) translocations
Authors: Kovalchuk Alexander L. , Morse Herbert C. 
Published: July 2017

Abstract
c-Myc deregulating t(12;15) chromosomal translocation is the hallmark cytogenetic abnormality of murine plasmacytomas (PCTs). In the great majority of PCTs, the immunoglobulin heavy chain (IgH) locus is broken between Eμ enhancer and the 3’ regulatory region (3’RR), making the latter the major candidate for orchestrating c-Myc deregulation. To elucidate the role of 3’RR in tumorigenesis, we induced PCTs in mice deficient for the major 3’RR enhancer elements, namely hs3b and hs4 (3’KO). Unexpectedly, and contrary to the previous observations made in a mouse lymphoma model, Hs3b/Hs4 3’KO mice did develop t(12;15)-positive PCTs, although with a lower incidence than wild-type controls. In heterozygous mice, there was no allelic bias in targeting IgH for the t(12;15). Molecular analysis of IgH/Myc junctions revealed dominance of Sμ region breakpoints compared to the prevalence of hits into Sγ or Sα in the controls. Analysis of c-Myc expression as well as Ig secretion in 3’KO PCT cell lines revealed no significant differences from the controls. Our current findings highlight the complexity of the 3’RR and the potential of its components to compensate for each other in the context of differentiation from B-lymphocyte to plasma cell. We next extended our observations to include a PCT model where Cre-mediated deletion can remove all four 3'IgH enhancers: hs3a, hs1,2, hs3b and hs4. In PCT cell lines where c-Myc is translocated to an IgH BAC transgene with a floxed 3’IgH enhancer region, induction of retrovirally-expressed Cre-recombinase causes gradual Myc downregulation and complete cell death within 96 hours. The later observation confirms the requirement of the full 3’RR for c-Myc deregulation by T(12;15).
Citation Format: Alexander L. Kovalchuk, Herbert C. Morse. IgH enhancers hs3b/hs4 are dispensable for c-Myc deregulation in mouse plasmacytomas with T(12;15) translocations [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 499. doi:10.1158/1538-7445.AM2017-499
Abstract 4999: Stress, spiritual wellbeing and cancer risk among diverse racial faith-based communities: Elevated levels of stress proteomic biomarkers in breast cancer patients
Authors: Uppala Padma P. Tadi , Krivak Gretchen , Brown-Fraser Sherine , Anjejo Dixon , Mejia Alfredo , wakefield Dominique , Kolli Kumar 
Published: July 2017

Abstract
Spiritual wellbeing is associated with decreased risk for cancer. Stress and depression are common among cancer patients and may be inversely associated with spiritual wellbeing. The purpose of the study is to examine if stress and depression as indicators of cancer risk are lower in a racially diverse faith-based community. Methods: 752 individuals from a faith-based community completed a behavioral assessment survey that mapped the current patterns of behavior in key categories that include: stress, depression, exercise and nutrition using the E-wellness platform FitThumb. To identify stress biomarkers in cancer patients we examined levels of stress serum proteomic biomarkers that were previously identified in our study by proteomic profiling using 2D-DIGEMS analysis and a subset of samples by shotgun LCMS technology. The serum proteomic study included serum samples from 15 African American breast cancer patients and 12 healthy controls who were from a faith-based community. Results: The behavioral assessment surveys that included 752 individuals who were racially diverse showed a low stress risk of 47.74% vs 8.24 % of high stress risk for chronic disease; and low depression risk of 85.11% vs 1.99% high risk for chronic disease. Elevated levels of stress and inflammatory serum proteomic biomarkers such as ceruloplasmin known to increase in stressed animals and humans; heptaglobin, apolipoproteins, and heat shock proteins were significantly elevated in breast cancer patients compared to healthy controls. Conclusions: Our results indicate that spiritual well-being is associated with significantly low stress and depression in a faith-based community regardless of race or ethnicity, posing a low risk for cancer as shown in previous Adventist Health Cohort studies. Future efforts will focus on validating and identifying panel of biomarkers from this cohort to gain insight into their role(s) in the mechanisms of stress hormones and cancer risk. Funded by Susan G Komen for the cure.
Citation Format: Padma P. Tadi Uppala, Gretchen Krivak, Sherine Brown-Fraser, Dixon Anjejo, Alfredo Mejia, Dominique wakefield, Kumar Kolli. Stress, spiritual wellbeing and cancer risk among diverse racial faith-based communities: Elevated levels of stress proteomic biomarkers in breast cancer 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 4999. doi:10.1158/1538-7445.AM2017-4999
Abstract 500: Impairment of DNA double strand break repair in human primary alveolar type II cells in emphysema
Authors: Kosmider Beata , Vlasenko Liudmila , Marchetti Nathaniel , Bolla Sudhir , Mandapati Chenna , Xander Nathaniel , Criner Gerard , Bahmed Karim 
Published: July 2017

Abstract
Rationale Emphysema is caused by the destruction of alveolar wall septa. The major risk factor for this disease is cigarette smoke and effective therapies are very limited. Alveolar type II (ATII) cells are in the gas exchange portion of the lung. They make and secrete pulmonary surfactant, and proliferate to restore the epithelium after damage to the more sensitive alveolar type I cells.
Methods Control ATII cells were isolated from deidentified control non-smoker and smoker organ donors whose lungs were not suitable for transplantation and donated for medical research. Furthermore, as a unique approach, we have developed a new method on how to isolate ATII cells from excess tissue from lung transplants obtained from patients with emphysema using magnetic microbeads. We determined DNA damage, DNA repair, oxidative stress, injury, and inflammation in human primary ATII cells isolated from these individuals in comparison with controls.
Results Our data indicates high oxidative stress in human ATII cells induced by cigarette smoke extract in vitro as measured by 4-HNE staining by immunocytofluorescence. We also observed DNA double strand breaks, high DNA damage, and low DNA repair in these cells. Moreover, we found greater proinflammatory response as determined by IL-8 and IL-6 levels by ELISA. Furthermore, ATII cells obtained from patients with emphysema had greater injury compared to cells obtained from control non-smokers and smokers.
Conclusion Our results indicate oxidative ATII cell damage induced by cigarette smoke and in emphysema. Observed DNA damage/repair imbalance may contribute to cell death in this disease. The study of ATII cell injury may improve our knowledge on this disease pathogenesis and may lead to novel therapeutic strategies to slow the progression of emphysema.
Note: This abstract was not presented at the meeting.
Citation Format: Beata Kosmider, Liudmila Vlasenko, Nathaniel Marchetti, Sudhir Bolla, Chenna Mandapati, Nathaniel Xander, Gerard Criner, Karim Bahmed. Impairment of DNA double strand break repair in human primary alveolar type II cells in emphysema [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 500. doi:10.1158/1538-7445.AM2017-500
Abstract 5007: Role of the interferon-gamma response pathway in immune escape of colorectal carcinoma
Authors: Britzen-Laurent Nathalie , Straube Julia , Tripal Philipp , Waldner Maximilian , Becker Christoph , Merkel Susanne , Croner Roland S. , Sturzl Michael 
Published: July 2017

Abstract
The presence of an interferon-dominated Th1 immune response in colorectal carcinoma (CRC) has been associated with improved clinical outcome. We have previously identified the guanylate-binding protein 1 (GBP-1), one of the major IFN-γ-induced proteins, as a marker for the Th1 immune response and an independent positive prognostic factor in CRC. We also found that GBP-1 is a necessary mediator of the anti-tumorigenic effects of IFNγ. Interestingly, the expression of GBP-1 in CRC was observed more frequently in the desmoplastic stroma than in the directly adjacent tumor cells, suggesting that CRC tumor cells might become resistant to IFN-γ in the course of tumorigenesis. Indeed, we found that several colorectal carcinoma cell lines failed to express GBP-1 or other interferon-stimulated genes after treatment with IFN-γ, and were resistant to IFN-γ-induced apoptosis or proliferation inhibition. In these cell lines, the loss of IFN-γresponsiveness correlated either with the down-regulation of the IFN-γ receptor alpha chain (IFNγRα) or with the presence of a mis-glycosylated form of IFNγRα, which displayed an aberrant intracellular localization. We further validated these findings at the clinical level by showing that the expression of IFNγRα is decreased in CRC compared to normal tissue. In addition, the down-regulation of IFNγRα expression in CRC correlated with a reduced cancer-related survival together with a higher rate of distant metastasis. In addition, in-vivo colon tumorigenesis models using conditional knock-out mice revealed that the absence of IFNγRα expression by intestinal epithelial cells fosters tumor growth. Altogether, our data suggest that the loss of IFN-γ responsiveness is a common event in CRC and protects tumor cells against the anti-tumorigenic effects of IFN-γ.
Citation Format: Nathalie Britzen-Laurent, Julia Straube, Philipp Tripal, Maximilian Waldner, Christoph Becker, Susanne Merkel, Roland S. Croner, Michael Sturzl. Role of the interferon-gamma response pathway in immune escape of colorectal carcinoma [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 5007. doi:10.1158/1538-7445.AM2017-5007