bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3489: Comprehensive characterization of the SLC transporters in human cancer
Authors: Wang Ruiping , Zhang Shaojun , Futreal Andy , Wang Linghua 
Published: August 2018

Abstract
Metabolic reprogramming has now been well recognized as one of 10 hallmarks of cancer. The plasma membrane transporters, that enable efficient cellular metabolism and aid in nutrient sensing, are receiving increasing attention in recent years. Membrane transporters include 3 main classes: ABC transporters, p-type ATPases, and the solute carrier family (SLC). The SLC group of transporters includes nearly 400 members organized into 52 families that mediate the transport of a wide variety of substrates across biological membranes. Until recently, little was known about the role of these SLC transporters in the mechanisms of cancer development and progression. Yet, the genomic landscape and clinical relevance of SLC transporters in human cancer have not been investigated systematically. We here performed a comprehensive characterization of 396 SLC transporters by integrating multi-platform data across over 30 tumor types from The Cancer Genome Atlas. We observed frequent dysregulation of SLC transporters across cancer types and identified cancer type- and subtype-specific expression signatures. We identified significant correlations of these SLC transporters with the activity of cancer metabolic pathways and explored their complex regulatory networks. We also investigated the role of SLC transporters in tumor metastasis. We further evaluated the potential clinical relevance of these SLC transporters and identified multiple SLC transporters that were significantly associated with patients' clinical outcomes. Our study provided an in-depth understanding of the role of SLC transporters in cancer metabolic reprogramming, elucidated their mechanisms in cancer development and metastasis, and provided novel biomarkers and potential therapeutic targets that can be further developed for future clinical applications.
Citation Format: Ruiping Wang, Shaojun Zhang, Andy Futreal, Linghua Wang. Comprehensive characterization of the SLC transporters in human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3489.
Abstract 3519: Disrupting glutamine metabolism depletes glutathione and sensitizes atypical teratoid/rhabdoid tumor to carboplatin
Authors: Wang Sabrina Z. , Poore Brad , Alt Jesse , Rais Rana , Allen Sariah , Orr Brent , Slusher Barbara , Eberhart Charles , Raabe Eric , Rubens Jeffrey 
Published: August 2018

Abstract
Atypical teratoid rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy. Recent high-throughput molecular analyses identified 3 distinct subgroups of AT/RT. Preliminary studies show that subgroups with elevated MYC expressions are particularly aggressive, with 18.5% 5-year survival. MYC is challenging to directly target, but MYC increases tumor cells' reliance on glutamine for their metabolic demands. We hypothesize that MYC-driven ATRT can be targeted by inhibiting glutamine metabolism. 6-Diazo-5-oxo L-norleucine (DON) is a glutamine analogue that was well tolerated in a phase I pediatric clinical trial, but DON has never been tested in MYC-driven pediatric tumors. Approximately 1/3 of human AT/RT express high MYC protein (immunohistochemistry for c-MYC expression on 22 human AT/RT, H-score &gt; 1 standard deviation over the median for high c-MYC expression). DON slows cell growth and induces apoptosis in high MYC-expressing AT/RT while low MYC-expressing cells are resistant (MTS assay and Western blot for c-PARP, respectively). Transducing low MYC-expressing cell lines with lentivirus with MYC plasmid to force MYC expression confers sensitivity to DON therapy (decreased cell growth per MTS assay, increased apoptosis per Western for c-PARP). DON administered intraperitoneally 30mg/kg weekly nearly doubles median survival in orthotopic xenograft models of AT/RT (p&lt;0.001 by log rank test; median survival extended from 21 to 36 days). Metabolic flux experiments tracing 15N and 13C labeled glutamine reveal that DON reduces intracellular glutathione. We combine DON with carboplatin because glutathione is critical for detoxification of carboplatin and find that the combination works synergistically to further slow cell growth and induce higher rates of apoptosis (MTS assay, MUSE Cell Viability Assay). This study takes a novel approach to targeting cancer metabolism and serves as the first targeted therapeutic strategy addressing the MYC-expressing subgroup of AT/RT. These findings support the rationale for potential future clinical trials testing glutamine analogues against the MYC subgroup of AT/RT as well as other deadly MYC-driven tumors.
Citation Format: Sabrina Z. Wang, Brad Poore, Jesse Alt, Rana Rais, Sariah Allen, Brent Orr, Barbara Slusher, Charles Eberhart, Eric Raabe, Jeffrey Rubens. Disrupting glutamine metabolism depletes glutathione and sensitizes atypical teratoid/rhabdoid tumor to carboplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3519.
Abstract 3528: Anti-CD47 immunotherapy regulates T cell metabolism and hypoxia in the tumor microenvironment
Authors: Feliz-Mosquea Yismelin R. , Stirling Elizabeth , Cook Katherine L. , Wilson Adam , Bharadwaj Manish , Molina Anthony J. , Yamaleyeva Liliya , Triozzi Pierre L. , Soto-Pantoja David R. 
Published: August 2018

Abstract
Dysfunction of infiltrating CD8+ effector T cells can be induced by hypoxia and aberrant tumor metabolite uptake in the microenvironment causing an “exhausted” T cell phenotype that limits anti-tumor immunosurveilance. Hence- therapeutic strategies aimed at improving T cell bioenergetics have the potential to reinvigorate T cell responses to reduce tumor burden. CD47 is a widely expressed receptor that controls phagocytic activity by engaging its counter receptor, SIRPα, in macrophages. Also autonomously or by binding to its ligand Thrombospondin-1 CD47 activation can control cell fate under stress. Our prior work shows that targeting CD47 on CD8+ T cells enhanced cytotoxicity against cancer cells. Moreover, depletion of CD8+ T cells in murine models reversed the anti-tumor effect of anti-CD47 therapy. Our new data shows that targeting CD47 reduced the growth of B16 melanoma tumors by approximately 50% (1607 ± 213.7, saline vs. 815.1 ± 67.8, CD47 (-) *p&lt;0.02 n=5-6). Further examination of tumors by live photoacoustic imaging showed that tumors of animals treated with anti-CD47 had reduction in oxygen tension and reduced vascularity when compared to control. This suggests that the reduction in tumor hypoxia by CD47 may shift metabolic competition in the microenvironment to increase metabolite availability allowing optimal activation of cytotoxic T cells. Cell respirometry measurements using an Agilent Seahorse bioanalyzer showed increased levels of mitochondrial function and glycolytic flux in CD47 null T cells when compared to WT. Moreover, these cells showed increased mitochondrial density and increased levels of the mitochondrial biogenesis regulator, PGC1-a. Treatment with CD47 antibody enhanced Pmel-1 CD8+ T cell effector function by reducing B16 melanoma target cell viability by over 60%. Anti-CD47 treatment of these T cells also resulted in upregulation of cell bioenergetics, suggesting that targeting CD47 may impact T cell metabolism to enhance cytotoxic activity against cancer cells. Therefore, our studies show a new role of CD47 immunotherapy regulating immunometabolism of T cells to enhance effector function which may lead to improvement of clinical outcomes in melanoma patients.
Citation Format: Yismelin R. Feliz-Mosquea, Elizabeth Stirling, Katherine L. Cook, Adam Wilson, Manish Bharadwaj, Anthony J. Molina, Liliya Yamaleyeva, Pierre L. Triozzi, David R. Soto-Pantoja. Anti-CD47 immunotherapy regulates T cell metabolism and hypoxia in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3528.
Abstract 354: Role of KAT5 in lung tumorigenesis
Authors: Pan Gilbert , Heo Eunyoung , Ando Mariko , Fujii Masanori , Kobayashi Ikei , Tenen Daniel G. , Watanabe Hideo , Kobayashi Susumu S. 
Published: August 2018

Abstract
Epigenetic modifications in oncogenesis have long been an area of interest in cancer research. Histone modifications are crucial in activities such as transcriptional activation, gene silencing, and epigenetic cellular memory. In particular, lysine acetylation via lysine (K) acetyltransferases (KATs) have been implicated in cancer development. Interestingly, KAT5, also known as Tip60, has been reported to possess both tumor promoting and tumor suppressing properties depending on the context of malignancy. Herein we report that KAT5 contributes to tumorigenesis in EGFR-mutated lung cancer, and Kat5-knockout mice models demonstrate significantly reduced lung tumor burden. To probe the aberrant modification of KAT5, we demonstrated that KAT5 binds to and is phosphorylated by oncogenic EGFR in co-immunoprecipitation experiments. Next, to investigate whether KAT5 is involved in cell proliferation and survival, H1975 cells harboring L858R-T790M double-activating mutations were transfected with doxycycline inducible shRNA targeting KAT5 (shKAT5). Following treatment, shKAT5 cells were observed to have suppressed proliferation rates. Pharmacological inhibition using TH1834, a known KAT5 inhibitor, also suppressed proliferation rates in shKAT5 cells; in contrast BEAS-2B cells, an immortalized normal bronchial cell line, surprisingly exhibited increased viability compared to the transformed H1975 cells, supporting KAT5's context-dependent role in normal and abnormal cell homeostasis. To further investigate KAT5 in lung tumorigenesis in vivo, we generated EGFR-mutant conditional Kat5 knockout mice using a tetracycline-induced Cre/loxP system. Following doxycycline treatment for 10 weeks, isolated mice lungs for EGFRTL/CCSP-rtTA/Cre/Kat5F/F possessed significantly lower tumor volume compared to EGFRTL/CCSP-rtTA/Cre/Kat5W/F and EGFRTL/CCSP-rtTA/Cre/Kat5W/W mice lungs. Hemotoxylin and eosin staining showed no evident hyperproliferation in lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5F/F mice whereas lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5W/W and EGFRTL/CCSP-rtTA/Cre/Kat5W/F did, signifying that KAT5 has a potential regulatory role in cellular proliferation. RNA-Seq and ChIP-Seq analysis of shKAT5 H1975 cells identified downstream targets involved in tumorigenic pathways. Further studies are in progress to validate the mRNA and protein expression levels of reported targets. Taken together, these data offer insight into a KAT5 mediated oncogenic pathway that can provide novel therapeutic approaches in treating lung cancer.
Citation Format: Gilbert Pan, Eunyoung Heo, Mariko Ando, Masanori Fujii, Ikei Kobayashi, Daniel G. Tenen, Hideo Watanabe, Susumu S. Kobayashi. Role of KAT5 in lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 354.
Abstract 3552: Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ
Authors: Liu Zhijun 
Published: August 2018

Abstract
Glioblastomas (GBM) are the most aggressive brain cancers without effective therapeutics. The Hippo pathway transcriptional coactivators YAP/TAZ were implicated as drivers in GBM progression and could be therapeutic targets. Here, we found in an unbiased screen of 1650 compounds that amlodipine is able to inhibit survival of GBM cells by suppressing YAP/TAZ activities. Instead of its known function as an L-type calcium channel blocker, we found that amlodipine is able to activate Ca2+ entry by enhancing store-operated Ca2+ entry (SOCE). Amlodipine as well as approaches that cause store depletion and activate SOCE trigger phosphorylation and activation of Lats1/2, which in turn phosphorylate YAP/TAZ and prevent their accumulation in the cell nucleus. Furthermore, we identified that protein kinase C (PKC) beta II is a major mediator of Ca2+-induced Lats1/2 activation. Ca2+ induces accumulation of PKC beta II in an actin cytoskeletal compartment. Such translocation depends on inverted formin-2 (INF2). Depletion of INF2 disrupts both PKC beta II translocation and Lats1/2 activation. Functionally, we found that elevation of cytosolic Ca2+ or PKC beta II expression inhibits YAP/TAZ-mediated gene transcription. In vivo PKC beta II expression inhibits GBM tumor growth and prolongs mouse survival through inhibition of YAP/TAZ in an orthotopic mouse xenograft model. Our studies indicate that Ca2+ is a crucial intracellular cue that regulates the Hippo pathway, and that triggering SOCE could be a strategy to target YAP/TAZ in GBM.
Citation Format: Zhijun Liu. Induction of store operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the Hippo pathway transcriptional coactivators YAP/TAZ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3552.
Abstract 3584: Characterization of a novel class of engineered (TCR) fusion constructs (TRuCTMs) aimed to treat solid tumors
Authors: Patel Ekta , Ding Jian , Thorausch Nikolaus , Krishnamurthy Janani , Choudhary Rashmi , Weiler Solly , Le Bonnie , Tavares Patrick , Zieba Adam , Quinn Justin , Wang Yan , Schamel Wolfgang , Scarfo Irene , Maus Marcela , Baeuerle Patrick , Getts Dainel , Hofmeister Robert 
Published: August 2018

Abstract
T cells expressing chimeric antigen receptors (CARs) have demonstrated remarkable clinical benefit in certain hematological malignancies albeit with side effect such as cytokine release syndrome, on Target off tumor response and limited efficacy in solid tumors. Here, we present the preclinical evaluation of a novel T cell engineering platform designed to overcome potential hurdles of CARs and other T cell receptor modalities. Specifically, we have generated novel T Cell Receptor Fusion Constructs (TRuC™s) that fuse binder domains to subunits of the T cell receptor. These constructs when introduced using lentiviral technology, integrate into endogenous TCR, reprograming T cells to target tumor antigen in a non-major histocompatibility complex (MHC) restricted fashion and harnessing the full spectrum of TCR signaling. TRuC™ variants were constructed by recombinant fusion of an scFv or sdAb to various TCR subunits via a flexible linker sequence. Likewise, CD28ζ and 41BBζ CARs were generated using the same binders for side-by-side comparison. We demonstrated that TRuC™ variants can effectively reprogram T cells to recognize tumor surface antigens in a non-MHC-restricted fashion. TRuC™s are distinct from CARs in their ability to activate T cells through the entire TCR without additional costimulatory domains. In vitro, TRuC™ T cells were equally potent as CAR T cells in eliminating tumor cells. Compared to CAR-T cells, TRuC-T cells produced lower cytokine levels and proliferated less. Despite these difference, TRuC™ T cells were more efficient in clearing tumors in subcutaneous Raji and MSTO-211H mesothelioma models. Our findings support the development of TRuC-T cells for the treatment of solid tumors.
Citation Format: Ekta Patel, Jian Ding, Nikolaus Thorausch, Janani Krishnamurthy, Rashmi Choudhary, Solly Weiler, Bonnie Le, Patrick Tavares, Adam Zieba, Justin Quinn, Yan Wang, Wolfgang Schamel, Irene Scarfo, Marcela Maus, Patrick Baeuerle, Dainel Getts, Robert Hofmeister. Characterization of a novel class of engineered (TCR) fusion constructs (TRuCTMs) aimed to treat solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3584.
Abstract 3605: Next generation sequencing from cerebral spine fluid yields actionable targets in leptomeningeal carcinomatosis
Authors: Baumgarten Louisa von , Reischer Anna , Kumbrink Jörg , Jung Andreas , Liebmann Sibylle , Ormanns Steffen , Metzeler Klaus , Holch Julian , Heinemann Volker , Kirchner Thomas , Westphalen Benedikt 
Published: August 2018

Abstract
Background and Rationale: Leptomeningeal carcinomatosis is a cause of major morbidity and mortality in many solid malignancies. Therapeutic options are limited and include radiation therapy as well as intrathecal administration of cytotoxic agents. Accordingly, novel diagnostic and therapeutic modalities are needed in order to improve the prognosis of patients diagnosed with leptomeningeal carcinomatosis. Liquid biopsies are safe and offer great potential to define actionable targets in a variety of cancers. However, a role for liquid biopsies from cerebral spine fluid (CSF) has not been defined to date.
Patients and Methods: CSF samples from ten consecutive patients diagnosed with leptomeningeal carcinomatosis were collected as part of clinical routine and evaluated by next generation sequencing. All cases were discussed in the Molecular Tumorboard (MTB) as part of the “Molecular Diagnostics and Therapy” unit at the Comprehensive Cancer Center Munich.
Results: Samples from patients diagnosed with cholangiocarcinoma (1), ewing's sarcoma (1), breast (5), lung (2) and gastric cancer (1) were submitted for panel sequencing. Sequencing was technically successful in nine out of ten patients and circulating tumor DNA (ctDNA) was found in all of these nine patients. Of note, ctDNA was also detectable in cases in which microscopy did not reveal malignant cells in the CSF sample (4/10 cases). Tumorigenic alterations were found in seven out of these nine patients. Importantly, NGS of cerebral spine fluid detected previously unknown and therapeutically relevant alterations in this cohort. Case discussion in the Molecular Tumorboard led to therapeutic recommendations in three cases and targeted therapy was ultimately initiated in one case.
Conclusions: Next generation sequencing from cerebral spine fluid is feasible in clinical practice and yields tumorigenic alterations in a large fraction of patients. Importantly, our approach demonstrated the therapeutic relevance of this approach in patients with leptomeningeal carcinomatosis.
Citation Format: Louisa von Baumgarten, Anna Reischer, Jörg Kumbrink, Andreas Jung, Sibylle Liebmann, Steffen Ormanns, Klaus Metzeler, Julian Holch, Volker Heinemann, Thomas Kirchner, Benedikt Westphalen. Next generation sequencing from cerebral spine fluid yields actionable targets in leptomeningeal carcinomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3605.
Abstract 3608: Molecular fingerprint sequencing for minimal residual disease detection in breast cancer
Authors: Comino-Mendez Iñaki , Cutts Ros , García-Murillas Isaac , Chopra Neha , Afentakis Maria , Evans Abigail , Wheatley Duncan , Skene Anthony , Russell Simon , Varughese Mohini , Dowsett Mitch , Smith Ian E. , Turner Nick 
Published: August 2018

Abstract
Introduction: The substantial majority of breast cancers present with early-stage disease, although micro-metastatic disease may be established at the time of diagnosis and may ultimately result in metastatic disease recurrence. Prior studies have shown that analysis of circulating tumour DNA (ctDNA) can detect micro-scopic minimal residual disease (MRD) serving as biomarker to anticipate future cancer recurrence, although sensitivity of current assays is limited. We present a novel molecular fingerprint ctDNA assay that exploits tumour whole genome sequencing (WGS) to develop highly personalised assays.
Methods: WGS was conducted on paired tumor and germline DNA from 11 early breast cancer patients to identify tumour specific small indels (SIs) to track in plasma as individual molecular fingerprints. Patient-specific amplicon-based panels were designed and validated to identify somatic reporters with no sequencing background. DNA was extracted from plasma samples taken at pre-surgery (baseline), post-surgery, and every 3 months until 1 year and every 6 months thereafter, and sequenced to 100,000X.
Results: Molecular fingerprint assays were demonstrated to detect less than a single cancer genome, with undetectable background in control samples. Using plasma samples from patients with early stage breast cancer, we detected ctDNA in 80% of the baseline plasma time-points with 100% specificity (95% confidence limits (CI) 98.7%-100%). ctDNA was detected in all patients prior to relapse, with an observed lead-time of 15.5 months, substantially improved compared with previous techniques, detecting residual disease that was not detectable by tracking mutations using digital PCR.
Conclusions: This proof-of-principle study demonstrates that tumor-specific molecular fingerprints combined with ultra-deep plasma DNA sequencing have the potential to transform MRD detection. Identifying those patients who have undetectable recurrence would pave the way for identifying who is cured by surgery alone and who requires further therapy.
Citation Format: Iñaki Comino-Mendez, Ros Cutts, Isaac García-Murillas, Neha Chopra, Maria Afentakis, Abigail Evans, Duncan Wheatley, Anthony Skene, Simon Russell, Mohini Varughese, Mitch Dowsett, Ian E. Smith, Nick Turner. Molecular fingerprint sequencing for minimal residual disease detection in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3608.