bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 549: The CUG-translated WT1, not AUG-WT1, is an oncogene
Authors: Lee Kun Yeong , Kim Hong-Gyum , Ryu Joohyun , Lim Do Young , Chen Hanyong , Bode Ann M. , Dong Zigang 
Published: August 2018

Abstract
The Wilms' tumor 1 (WT1) gene is believed to act as a canonical tumor suppressor. However, it has also been reported to function as an oncogene. Germline WT1 deletion is associated with Wilms' tumor, and exogenous WT1 cDNA introduction into cells induces the transcriptional suppression of its oncogenic target genes. In contrast, high WT1 expression is associated with poor prognosis in patients with various cancers. Why WT1 acts as a tumor suppressor under certain conditions but as an oncogene under other conditions is unknown. Here, we report that CUG initiation site for WT1 protein synthesis (CUG)-translated WT1 (cugWT1), an N-terminally extended form of canonical AUG initiation site for WT1 protein synthesis (AUG)-translated WT1 (augWT1), was overexpressed in most cancer cell lines and cancer tissues and functioned as an oncogene, whereas the classical augWT1 acted as a tumor suppressor as reported previously and inhibited the function of cugWT1. Translation of cugWT1 is initiated from a CUG codon upstream and in-frame with the coding region of augWT1. cugWT1 induced cell transformation and increased the gene expression of c-myc, bcl-2 and egfr, whereas overexpression of augWT1 repressed colony formation of cancer cells and inhibited the expression of the same target genes by recruiting histone deacetylase 1 (HDAC1). In addition, we found that protein kinase B (AKT)-phosphorylated cugWT1 on Ser62 and protected cugWT1 from proteasomal degradation induced by the F-box/WD repeat-containing protein 8 (FBXW8). These results provide an important breakthrough in the field of cancer biology and contribute significantly to the resolution of the chameleon function of WT1.
Citation Format: Kun Yeong Lee, Hong-Gyum Kim, Joohyun Ryu, Do Young Lim, Hanyong Chen, Ann M. Bode, Zigang Dong. The CUG-translated WT1, not AUG-WT1, is an oncogene [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 549.
Abstract 5490: Targeting mitochondrial function in lung tumor growth and progression
Authors: Kalainayakan Sarada Preeta , Ghosh Poorva , Dey Sancharika , Liu Li , Zhang Li 
Published: August 2018

Abstract
Contrary to Warburg's hypothesis, mitochondrial oxidative phosphorylation contributes significantly to fuel cancer cells. Besides oxidative phosphorylation, mitochondria are also involved in heme synthesis. Heme serves as a prosthetic group for several proteins that constitute the complexes of mitochondrial electron transport chain. Therefore, heme plays a pivotal role in mitochondrial oxidative phosphorylation. Recently, our lab demonstrated that non-small cell lung cancer (NSCLC) cells exhibit intensified mitochondrial respiration. Targeting increased mitochondrial respiration with therapeutic agents effectively hampers proliferation of NSCLC cells in vitro. Previous results from our lab also demonstrated that NSCLC cell lines exhibited elevated heme synthesis, heme uptake, and expression of hemoproteins. These results suggest that increased mitochondrial respiration is facilitated by excess intracellular heme that is incorporated into hemoproteins. Our study aims to assess whether targeting mitochondrial function and heme synthesis affects NSCLC tumor growth and progression in vivo. To this end, luciferase-expressing NSCLC cells were implanted in NOD/SCID mice to generate lung orthotopic xenografts. The mice bearing orthotopically implanted NSCLC tumors were treated with various agents that target mitochondrial function alone (MTA1 or MTA2) and in combination with heme synthesis inhibitor. Tumor growth was monitored by noninvasive bioluminescence imaging (BLI). Our BLI data demonstrated that there was a significant reduction in radiance in mice that received the mitochondria-targeting agent alone (MTA1) and a combination of mitochondrial-targeting agents (MTA1 and MTA2). BLI data also demonstrated that there was a considerable reduction in radiance in mice that received combination of MTA and heme synthesis inhibitor. Treatments with combination of MTAs and heme inhibitor are under way. Our Immunohistochemistry data indicate that there was a reduction in expression of proteins involved in heme transport as well as hemoproteins involved in mitochondrial respiration in mice treated with the mitochondria-targeting agent. Our results suggest that targeting mitochondria significantly inhibits lung tumor growth by affecting proteins involved in heme synthesis and degradation, and consequently decreasing mitochondrial respiration.
Citation Format: Sarada Preeta Kalainayakan, Poorva Ghosh, Sancharika Dey, Li Liu, Li Zhang. Targeting mitochondrial function in lung tumor growth and progression [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 5490.
Abstract 5491: Blocking acyl-CoAs synthesis inhibits prostate cancer progression
Authors: Cai Houjian , Ma Yongjie 
Published: August 2018

Abstract
Fatty acid metabolism is essential for the biogenesis of cellular components and ATP production to sustain proliferation of cancer cells. Bioconversion of exogenous or de novo synthesized fatty acids to their corresponding fatty acyl-CoAs, which is required for the fatty acids to participate in metabolic processes, is catalyzed by long chain fatty acyl-CoA synthetases (ACSLs). However, the influence of individual ACSL isoforms on the progression of prostate cancer remains unknown. The goal of this study is to analyze how ACSLs regulates the biosynthesis of acyl-CoAs, thereby prostate cancer progression. In this study, lentivirus carrying shRNA of ACSL1 was constructed and produced in house. Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR) were measured by Seahorse. The amount of protein and acyl-CoAs was analyzed by immunoblotting and LC-MS/MS, respectively. Additionally, the amount of triglyceride and neutral lipid were measured by gas Chromatography and Oil red O staining. TCGA database was also used for analysis of ACSL1 expression levels in different stages of prostate cancer. Finally, inhibition of cell proliferation, migration, invasion assays and cell cycle analysis were examined in numerous cancer cells. Prostate xenograft tumor models were applied for in vivo studies. Prostate tumor tissue array was utilized for the analysis of ACSL1 expression. Based on the systematic analysis on the correlation of ACSL expression levels and the amount of intracellular acyl-CoAs, we demonstrate that expression levels of ACSL1 were significantly associated with the levels of a variety of acyl-CoAs, and were elevated in human prostate tumors. ACSL1 increased the biosynthesis of fatty acyl-CoAs including C16:0-, C18:0-, C18:1- and C18:2-CoA, triglycerides and lipid accumulation in cancer cells. In addition, ACSL1 modulated mitochondrial respiration through regulation of carnitine palmitoyltransferase 1A (CPT1A) activity. Knockdown of ACSL1 expression inhibited the cell cycle, and suppressed the proliferation and migration of prostate cancer cells in vitro, and growth of prostate xenograft tumors in vivo. Our study demonstrates ACSL1 plays an important role in prostate tumor progression. Our results provide a therapeutic strategy of targeting fatty acid metabolism for the treatment of prostate cancer.
Citation Format: Houjian Cai, Yongjie Ma. Blocking acyl-CoAs synthesis inhibits prostate cancer progression [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 5491.
Abstract 5497: Effective combination therapy for breast cancer targeting BACH1 and mitochondrial metabolism
Authors: Lee Jiyoung , Yesilkanal Ali , Frankenberger Casey , Elbaz Mohamad , Rabe Daniel , Yan Jielin , Rustandy Felicia , Hart Peter , Kang Christie , Grossman Elizabeth , Locasale Jason , Nomura Daniel , Bonini Marcelo , Rosner Marsha 
Published: August 2018

Abstract
Oxidative phosphorylation is an attractive target for cancer therapy. Reprogramming metabolic pathways by promoting oxidative phosphorylation could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options like triple negative breast cancer (TNBC). Here we show that BACH1, a heme-binding transcription factor whose expression is enriched in patients with TNBC, inhibits oxidative phosphorylation through direct transcriptional regulation of electron transport chain (ETC) gene expression. Treatment of cells with hemin, which induces BACH1 degradation, mimics BACH1 depletion with shRNA. Pretreatment of TNBC tumors with BACH1 shRNA or hemin overcame resistance to metformin, an anti-diabetic drug, and abolished the growth of both cell line and patient-derived tumor xenografts. BACH1 gene expression inversely correlated with ETC gene expression in breast cancer patients as well as other tumor types, highlighting the clinical relevance. This study demonstrates that oxidative phosphorylation represents an Achilles heel that can be exploited through targeting BACH1 to sensitize breast cancer and potentially other tumor tissues to mitochondrial inhibitors.
Citation Format: Jiyoung Lee, Ali Yesilkanal, Casey Frankenberger, Mohamad Elbaz, Daniel Rabe, Jielin Yan, Felicia Rustandy, Peter Hart, Christie Kang, Elizabeth Grossman, Jason Locasale, Daniel Nomura, Marcelo Bonini, Marsha Rosner. Effective combination therapy for breast cancer targeting BACH1 and mitochondrial metabolism [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 5497.
Abstract 55: Intrinsic molecular characteristics of bone marrow-disseminated tumor cells
Authors: Maeshiro Manabu , Shinriki Satoru , Nakamura Takuya , Jono Hirofumi , Nakayama Hideki , Ando Yukio , Matsui Hirotaka 
Published: August 2018

Abstract
Dormant or slow-cycling disseminated tumor cells (DTC) in bone marrow (BM) are known to persist in patients with various types of cancer including head and neck squamous cell carcinoma (HNSCC). BM-DTC has been thought to have possible metastatic stem cell traits although functional and clonal analysis of BM-DTC remain elusive. Recently, we reported that the intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis was crucial for drug resistance dependent on a slow-cycling state in BM-DTC but not in lung metastatic cells. This study aimed to elucidate intrinsic molecular characteristics in BM-DTC. We used the human HNSCC cell line HEp3-originated sublines [i.e. parental line (P-HEp3), BM-DTC-derived (BM-HEp3), and lung metastases-derived sublines (Lu-HEp3)]. Our transcriptome analyses for these sublines revealed that slow-cycling and drug-resistant BM-HEp3 cells had unique gene expression signatures. In addition, our investigation for phosphorylation of 39 kinases associated with tumor progression showed enhanced activation of only Src in BM-HEp3 compared with P- and Lu-HEp3. Importantly, Src inhibition by dasatinib in these sublines led to a remarkable reduction in cell viability only in BM-HEp3. These data suggest that intrinsic molecular characteristics of BM-DTC are distinct from primary and lung metastatic tumor cells. Src activation may be important for survival of dormant or slow-cycling BM-DTC. Further studies should contribute to better understanding of biology of minimal residual disease in BM and metastatic initiation.
Citation Format: Manabu Maeshiro, Satoru Shinriki, Takuya Nakamura, Hirofumi Jono, Hideki Nakayama, Yukio Ando, Hirotaka Matsui. Intrinsic molecular characteristics of bone marrow-disseminated tumor cells [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 55.
Abstract 555: Loss of function Cbl-c mutations in solid tumors
Authors: Daniels Silvano R. , Kales Stephen C. , Liyasova Mariya , Nau Marion M. , Ryan Phil E. , Green Jeffrey E. , Lipkowitz Stanley 
Published: August 2018

Abstract
Receptor Tyrosine Kinase (RTK) signaling, which is essential for cellular growth and proliferation, can lead to malignant transformation and tumorigenesis when aberrantly activated. Cbl proteins (Cbl, Cbl-b, and Cbl-c) are a conserved family of RING finger (RF) ubiquitin ligases (E3) that negatively regulate the activity of several tyrosine kinases such as the EGFR. Cbl mutations have recently been identified in 5% of human myeloid neoplasms, with a majority of mutations clustered within the RF and linker domains. Cbl-c is the most recently identified Cbl protein and is exclusively expressed in epithelial cells. We recently identified a novel cDNA isolated from a mouse mammary tumor in the C3(1) Large T Antigen transgenic mouse model. This mutant cDNA encodes a protein that has a deletion in the RF domain of Cbl-c, thereby resembling known Cbl family mutations associated with myeloid neoplasias. Genomic analyses of both parental and transgenic lines show no evidence of germline mutation, suggesting that this mutation is most likely somatic. The mutant Cbl-c protein enhances transformation of NIH 3T3 cells when co-transfected with SV40 Large T Antigen. In overexpression studies, this mutant Cbl-c fails to mediate ubiquitination of activated EGFR and acts in a dominant negative manner to prevent ubiquitination of activated EGFR by wildtype Cbl proteins. Datamining also reveals Cbl-c mutations associated with human solid tumors. Cell-based analyses demonstrate a similar loss of E3 function in some of these human mutations. These data collectively suggest that, like Cbl mutations in myeloid neoplasms, loss of function Cbl-c mutants may also contribute to the pathogenesis of solid tumors in murine models and in humans.
Citation Format: Silvano R. Daniels, Stephen C. Kales, Mariya Liyasova, Marion M. Nau, Phil E. Ryan, Jeffrey E. Green, Stanley Lipkowitz. Loss of function Cbl-c mutations in 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 555.
Abstract 5570: Analytical and clinical validation of blood-based NGS panel for detection of genomic alterations in DNA repair pathways
Authors: Wang Xiaohong , Yu Jianjun 
Published: August 2018

Abstract
Response to DNA-damaging agents, such as PARP inhibitors (PARPi), is associate with homologous recombination deficiency (HRD). In fact, patients with advanced breast, prostate, and ovarian cancers who carry harmful mutations in BRCA1/2 have benefited greatly from olaparib, niraparib, and rucaparib as reported in multiple clinical trials. However, current available assays either require tumor biopsy which may be of insufficient quantity or unobtainable or only examine very limited genes such as BRCA1, BRCA2, and ATM from patient blood. We recently developed a blood-based NGS panel to accurately detect genomic alterations in 51 genes related to DNA damage and repair. With in-house proprietary ultra-sensitive DeepSeaTM(Deterministic, Efficient, Precise, Sensitive Algorithm) variant detection algorithm, analytical performance was rigorously assessed via serial dilutions of reference materials and also further validated by clinical plasma samples in prostate, ovarian, lung and breast cancer.
Key words: cfDNA, DNA damage repair, PARP, BRCA1, BRCA2, liquid biopsy, biomarker
Citation Format: Xiaohong Wang, Jianjun Yu. Analytical and clinical validation of blood-based NGS panel for detection of genomic alterations in DNA repair pathways [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 5570.
Abstract 5582: Use of circulating tumor DNA (ctDNA) to predict superiority of dosing schedules in early clinical development
Authors: Chmielecki Juliann , Lai Zhongwu , Potts Kristy , Garg Kavita , Li Mark , Barrett J Carl 
Published: August 2018

Abstract
Changes in ctDNA can be used as a surrogate molecular marker of response to determine clinical efficacy and often precede imaging changes. This analysis is valuable to early clinical trials for dose optimization as response data may not be available for patients because of the short period of time on drug. Unlike other ctDNA applications where tumor-specific single gene mutations are followed over time, inclusion of “all comers” populations in phase I trials necessitates a comprehensive assay design optimized to detect multiple ctDNA changes from diverse tumors. Therefore, we developed a highly sensitive bespoke ctDNA panel (Resolution Bioscience) suitable for monitoring applications in “all comers” solid tumor populations. The panel uses next-generation sequencing technology to interrogate mutational hotspots from 8 oncogenes as well as the complete coding sequences of 3 tumor suppressor genes. Validation studies established the mutant allele frequency (MAF) limit of detection for short variants and small insertions/deletions as 0.1%; additionally, mutant alleles detected at or above this frequency can be followed below this threshold in serial samples. The assay requires 2mL plasma and results are reported within 14 days. In silico analysis predicted detection of at least one monitorable somatic alteration from ~63% of solid tumors that shed ctDNA. To demonstrate applicability, we used this assay to analyze serial ctDNA samples from patients enrolled in dose-escalation cohorts for the Wee1 inhibitor, AZD1775 (NCT02610075). Dosing schedules were compared for the degree of ctDNA clearance after completion of the first cycle, and correlated with subsequent RECIST response data, where available. To date, 15 patients were evaluable, with more anticipated as additional cohorts accrue. Greater ctDNA decreases were observed with higher drug dose, and longer drug exposure. Together with safety and exposure data, our studies demonstrate that ctDNA dynamics can be used to inform decisions around optimal dosing schedule. This enables rapid decision making before imaging studies are available, and complements traditional measurements of target engagement.
Citation Format: Juliann Chmielecki, Zhongwu Lai, Kristy Potts, Kavita Garg, Mark Li, J Carl Barrett. Use of circulating tumor DNA (ctDNA) to predict superiority of dosing schedules in early clinical development [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 5582.
Abstract 5599: Noninvasive genomic profiling of cerebral spinal fluid in breast cancer patient with leptomeningeal disease
Authors: Oikawa Masahiro , Ramesh Naveen , Sei Emi , Bai Shanshan , Hu Min , John de Groot F. , Rshmi Murthy , O'Brien Barbara , Navin Nicholas 
Published: August 2018

Abstract
Leptomeningeal disease (LMD) involves the dissemination of tumor cells from the primary breast tumors into the membranes surrounding the central nervous system and spinal cords. LMD occurs in about 5% of breast cancer patients and is associated with very poor survival. The genomic evolution of LMD in breast cancer patients has remained difficult to study, in part due to technical challenges in collecting longitudinal biopsy samples from the central nervous system. Liquid biopsies of the cerebral spinal fluid (CSF) may provide a unique opportunity to profile circulating tumor DNA (ctDNA) and has not been compared directly to non-invasive monitoring of ctDNA in blood samples. Furthermore, most non-invasive ctDNA profiling methods are limited to a targeted set of genes and have not allowed unbiased whole-genome profiling. To address these limitations, we developed an unbiased method for ctDNA analysis called PEGASUS (Plasma Exome and Genome Analysis by Size-selection and Unbiased Sequencing) that enables whole-genome sequencing of copy number aberrations and somatic mutations from ctDNA. We applied PEGASUS to sequence matched blood samples and CSF from 10 breast cancer patients with LMD. Quantitation of ctDNA levels showed that ctDNA was detected in CSF samples from 9/10 patients, while blood ctDNA was detected in only 1 LMD patient with extensive metastatic disease. Whole-genome copy number profiling at 220kb resolution and mutational profiling of a 2000 cancer gene panel of the matched CSF and blood samples was performed in 10 LMD patients using PEGASUS. Our data identified aneuploid copy number aberrations and somatic mutations (range: 11-25) in the CSF of 7 patients, including mutations in known driver genes such as BRAF, RB1, TP53 and amplifications of MYC and ERBB2. In contrast the matched blood samples showed only diploid copy number profiles and no detectable somatic mutations in 9/10 LMD patients. In one patient with extensive cranial metastatic disease with matched CSF and blood ctDNA, we found a high concordance in copy number profiles (R= 0.75) and modest concordance of somatic mutations (59.5%), but also additional CNAs and mutations that were specific to the CSF. Collectively, these data show that genomic profiling of ctDNA in CSF is technically feasible for patients with LMD, and provides a major advantage over blood ctDNA which cannot be detected in mostcases.
Citation Format: Masahiro Oikawa, Naveen Ramesh, Emi Sei, Shanshan Bai, Min Hu, de Groot F. John, Murthy Rshmi, Barbara O'Brien, Nicholas Navin. Noninvasive genomic profiling of cerebral spinal fluid in breast cancer patient with leptomeningeal disease [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 5599.
Abstract 5606: Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1
Authors: Lim Seung-Oe , Li Chia-Wei , Hung Mien-Chie 
Published: August 2018

Abstract
EGF signaling inhibits GSK3β-β-TrCP-mediated degradation of N-linked glycosylated programmed death ligand-1 (PD-L1), resulting in PD-L1 protein destabilization and enhanced immune checkpoint blockade efficacy. Here we show that EGF also mediates PD-L1 and receptor programmed cell death protein-1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer cells. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces potent cell-killing effect as well as bystander-killing effect on adjacent cancer cells without PD-L1 expression with virtually no detectable toxicities. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy.
Citation Format: Seung-Oe Lim, Chia-Wei Li, Mien-Chie Hung. Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1 [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 5606.