bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2546: Regulation of CAR-T cell therapy in real time using bispecific small molecule adaptors and monospecific competitors
Authors: Chu Haiyan , Lu Yingjuan , Lee Yong Gu , Wheeler Leroy , Nelson Mellissa , Westrick Elaine , Vetzel Marilynn , Klein Patrick J. , Low Philip S. , Leamon Christopher P. 
Published: August 2018

Abstract
Chimeric antigen receptor modified T cell (CAR-T) therapy has revolutionized personalized cancer treatment. The recent FDA approval of two CAR-T therapies for hematological cancers has marked a pivotal milestone in this new era of cellular therapies. CAR-T cells are genetically modified to become activated and proliferate in the presence of tumor antigens. In patients with high tumor burden and rapid T cell expansion, however, severe side effects including severe cytokine release syndrome (sCRS) and life-threatening cerebral edema may occur.
To “fine-tune” CAR-T cell activity in real time, we devised a three-pronged therapeutic strategy by using (1) 4-1BB-CD3ζ CARs expressing anti-fluorescein (anti-FITC) scFv instead of an anti-tumor ligand/self-antigen scFv, (2) low-molecular-weight bi-specific adaptors comprised of a FITC hapten linked to a tumor-specific ligand, and (3) competitors that can interfere with the adaptor/CAR-T interaction with tumor cells. Using folate-FITC (EC17) as the bi-specific adaptor molecule, we evaluated the performance of FITC-CAR-T cells in various folate receptor (FR)-positive tumor models. Our results show that CAR-T activation and proliferation in-vivo was EC17- and tumor FR-dependent. Treatment-related toxicity (sCRS) was observed but could be easily controlled, or even prevented, by adjusting the concentration, dosing frequency or timing of bi-specific adaptor administration. Importantly, animals experiencing sCRS could be rescued by administrating competitors of the bi-specific adaptor. In the case of EC17/CAR-T therapy, improved animal behavior was observed as early as a few hours after dosing with a rescue agent and a rapid reduction of interferon-γ was also detected. Circulating CAR-T cells remained functional, and could be re-activated following subsequent EC17 doses.
Taken together, our bi-specific adaptor/CAR-T approach offers a unique combination of a man-made hapten (FITC), flexible dosing control, and sCRS prevention/rescue without compromising antitumor activity or permanently removing CAR-T cells. Further studies are warranted to provide a rational basis for translating such therapeutic practice to the clinic.
Footnotes
HC and JL contributed equally to this work.
Citation Format: Haiyan Chu, Yingjuan Lu, Yong Gu Lee, Leroy Wheeler, Mellissa Nelson, Elaine Westrick, Marilynn Vetzel, Patrick J. Klein, Philip S. Low, Christopher P. Leamon. Regulation of CAR-T cell therapy in real time using bispecific small molecule adaptors and monospecific competitors [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 2546.
Abstract 2577: Predictive value of multigene assay for chemotherapy benefit in patients with HR+/HER2- early breast cancer
Authors: Kwon Mi Jeong 
Published: August 2018

Abstract
Our risk score based on a combination of multigene expression and clinical variables was validated to predict the risk of distant metastasis in hormone receptor-positive and human epidermal growth factor 2-negative (HR+/HER2-) early breast cancer in our previous study. In addition to its prognostic value, we investigated the predictive value of the risk score for adjuvant chemotherapy benefit in lymph node-negative (LN-), HR+/HER2- breast cancer. 346 patients who treated with hormone therapy (n = 203) alone or hormone therapy plus chemotherapy (n = 143) were classified as low-risk and high-risk group according to the risk score. There was a significant improvement in 10-year distant metastasis-free survival (DMFS) by the addition of adjuvant chemotherapy to hormone therapy in patients with a high risk score (26.5%, P = 0.003), whereas no benefit of chemotherapy was observed in those with a low risk score. The test for interaction between chemotherapy treatment and risk score was significant. The risk score also identified patients who will not benefit from chemotherapy among clinical high-risk group. Our study suggests that the risk score predicts the benefit of adjuvant chemotherapy in LN-, HR+/HER2- breast cancer and the addition of the risk score in the traditional cliniopathological factors may aid the improved treatment decisions.
Citation Format: Mi Jeong Kwon. Predictive value of multigene assay for chemotherapy benefit in patients with HR+/HER2- early 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 2577.
Abstract 2585: Immunoseroproteomic profiling in autoantibodies to ENO1 as potential biomarkers in immunodiagnosis of osteosarcoma by serological proteome analysis (SERPA) approach
Authors: Li Jitian , Huang Manyu , Dai Liping , Han Zongchang , Qin Xiaofei , Xie Wen , Qian Wei , Li Wuyin , Zhang Jianying 
Published: August 2018

Abstract
Background: Osteosarcoma (OS) is the most common highly malignant primary solid bone-tumor. Despite its relatively low incidence rate among overall cancers, it remains one of the most harmful primary malignant tumors in childhood and adolescence. It is now evident that serum autoantibodies against tumor-associated antigens (TAAs) could be used as serological cancer biomarkers in types of cancers.
Methods: Serological proteome analysis (SERPA) approach was applied to profile anti-TAA autoantibody responses in sera from patients with OS, and Normal Human, and explore differences of these responses. This approach can detect autoantibodies to TAAs that could serve as clinical biomarkers and immunotherapeutic agents. Sera from OS, Osteochondroma (OC) and Normal Human Sera (NHS) were probed by immunoblotting against cellular proteins extracted from U2-OS and Saos-2 cell lines, with OS sera showing stronger immunoreactivity. MALDI-TOF/TOF Mass Spectrometry (MS) analysis of immunoreactive protein spots revealed that several OS sera contained autoantibodies to a number of proteins, particularly to alpha-enolase (ENO1).
Results: Analysis of 172 serum samples from patients with OS, OC and NHS by ELISA showed higher frequency of anti-ENO1 autoantibodies in OS sera compared to others. Interestingly, descant of ENO1 immunoreactivity was observed in most patients after treatments, which may imply a potential association between anti-ENO1 autoantibody titers and disease progression. Nine of twelve sera reacted strongly against purified ENO1, but 3 weakly against purified ENO1, which indicates 75.0% sera with positive optimal density values from ELISA were consistently positive in Western blotting. The expression of ENO1 in Osteosarcoma tissues was evaluated by immunohistochemistry in tumor microarray.
Conclusion: Our intriguing findings firstly demonstrate that ENO1 is one of autoantigens that elicit autoimmune responses in OS and can be used as biomarkers in immunodiagnosis and progression of OS.
Key words: Osteosarcoma (OS), Tumor-associated antigen (TAA), Serological proteome analysis (SERPA), ENO1, Immunodiagnosis.
Citation Format: Jitian Li, Manyu Huang, Liping Dai, Zongchang Han, Xiaofei Qin, Wen Xie, Wei Qian, Wuyin Li, Jianying Zhang. Immunoseroproteomic profiling in autoantibodies to ENO1 as potential biomarkers in immunodiagnosis of osteosarcoma by serological proteome analysis (SERPA) approach [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 2585.
Abstract 2587: Imbalances in the disposition of estrogen and naphthalene in Taiwanese breast cancer patients
Authors: Lin Po-Hsiung , Chen Dar-Ren , Hsieh Wei-Chung , Ko Mao-Huei , Liao Yi-Lun 
Published: August 2018

Abstract
The aims of this study were to measure the background level of quinone metabolites of 17β-estradiol (E2), including E2-2,3-Q and E2-3,4-Q, and naphthalene quinone (1,2-NPQ and 1,4-NPQ)-derived protein adducts in human albumin (Alb) derived from breast cancer patients (n=143) and healthy controls (n=122) in Taiwanese women and to explore the relationships between these adducts with risk factors of breast cancer. Results from the analysis indicated that Alb adducts of estrogen quinones, including E2-2,3-Q-4-S-Alb and E2-3,4-Q-2-S-Alb were detected in all subjects with mean levels at 400 and 676 pmole/g in cancer patients and 204 and 67 pmole/g in controls, respectively. In addition, the mean levels of Alb adducts of 1,2-NPQ and 1,4-NPQ on human serum albumin were estimated to be 209 and 73.6 pmole/g in cancer patients and 113 and 174 pmole/g in controls, respectively. Levels of E2-2,3-Q-4-S-Alb correlated significantly with those of E2-3,4-Q-2-S-Alb. Similarly, levels of 1,4-NPQ-Alb correlated significantly with those of 1,2-NPQ-Alb. Additionally, we noticed that E2-2,3-Q-4-S-Alb and E2-3,4-Q-2-S-Alb positively correlated with 1,4-NPQ-Alb (p&lt;0.001) whereas levels of E2-2,3-Q-4-S-Alb associated with 1,2-NPQ-Alb (p&lt;0.01). Furthermore, we observed that ratio of E2-3,4-Q-2-S-Alb to E2-2,3-Q-4-S-Alb in breast cancer patients were ~5 fold greater than those of healthy controls whereas ratio of 1,2-NPQ-Alb to 1,4-NPQ-Alb in cancer patients were ~4 fold greater than those of healthy controls. This evidence suggests that the cumulative body burden of estrogen quinones is a significant indicator of the risk of developing breast cancer and that breast cancer risk is associated with the imbalances in the disposition of estrogen and naphthalene in Taiwanese women.
Citation Format: Po-Hsiung Lin, Dar-Ren Chen, Wei-Chung Hsieh, Mao-Huei Ko, Yi-Lun Liao. Imbalances in the disposition of estrogen and naphthalene in Taiwanese breast cancer patients [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 2587.
Abstract 259: Integrated multi-omics analyses reveal α-lipoic acid-regulated cell proliferation via Grb2-mediated signaling in colorectal cancer cells
Authors: Yang Lan , Hu Chunlei , LV Guoqing , Li Bei , Xiong Shaowei 
Published: August 2018

Abstract
Background: The use of antioxidants as cancer prevention and treatment agents has become a focus of research in recent years due to their limited adverse effects. Alpha lipoic acid (α-LA), a naturally occurring antioxidant and metabolic enzyme co-factor, has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α-LA on colorectal cancer cells development remain unclear.
Methods: In this study, we combined the use of an RNA sequencing (RNA-Seq) database and isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomics data to investigate the dynamic genomic/proteomic response of human colorectal cancer cells (HT29) to α-LA stress. The CCK-8 assay was used to assess cell proliferation in CRC cell lines after α-LA treatment. The expression of proteins were evaluated by western blotting. Grb2 levels were restored in α-LA-treated cells by transfection of a plasmid carrying Grb2 and were reduced in CRC cells via specific siRNA-mediated knockdown.
Results: A total of 4,107 differentially expressed genes (2,259 downregulated and 1,848 upregulated) were identified via RNA-Seq in HT29 after exposure to α-LA for 24 h. Moreover, GO and KEGG pathway analyses showed that cancer-relevant cell membrane proteins were significantly affected. An interaction network analysis predicted that Grb2 may mediate the key target pathways activated by exposure to α-LA. In verifying the multi-omics results, Grb2 was confirmed to mediate the α-LA-induced inhibition of cell proliferation in vitro. Moreover, additional experiments indicated that Grb2 inhibition partially abolished EGF-induced phospho-EGFR and phospho-ERK1/2 activity. Furthermore, the analysis of human colorectal cancer specimens obtained from the GEO database showed that the expression of EGFR correlated with that of Grb2.
Conclusion: These findings provide a novel mechanism by which α-LA regulates cell colorectal cancer proliferation via the down-regulation of growth factor-stimulated Grb2 signaling.
Citation Format: Lan Yang, Chunlei Hu, Guoqing LV, Bei Li, Shaowei Xiong. Integrated multi-omics analyses reveal α-lipoic acid-regulated cell proliferation via Grb2-mediated signaling in colorectal cancer 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 259.
Abstract 2591: Role of EGFR-AS1 lncRNA in growth factor addiction and treatment response in squamous cell cancers
Authors: Tan Daniel SW , Chong Fui-Teen , Leong Hui-Sun , Toh Shen Yon , Lau Dawn P. , Kwang Xue Lin , Zhang Xiaoqian , Tan Gek San , Skanderup Anders J. , Lim Tony KH , Dasgupta Ramanuj , Iyer N Gopalakrishna 
Published: August 2018

Abstract
Squamous-cell cancers (SCCs) represent one of the commonest lethal malignancy worldwide. Despite evidence demonstrating that majority are addicted to Epidermal Growth Factor Receptor (EGFR)-signaling, targeting with monoclonal antibodies or tyrosine-kinase inhibitors (TKIs) has been met with limited success. We recently demonstrated that TKI-sensitivity is modulated by a long non-coding RNA (lncRNA) situated in the antisense strand of EGFR (EGFR-AS1). ‘Synonymous' alterations in EGFR-AS1 affected TKI-response in patient-derived models, and could be used to predict response in a small patient cohort. The lncRNA likely functions in cis by altering EGFR splicing, favouring expression of a truncated EGFR isoform (isoform D), with previously unknown function. Importantly, mediation of this effect requires EGFR ligand derived from paracrine or autocrine sources. Remarkably, even modest EGFR-AS1 knockdown showed profound effects on TKI sensitivity and tumor growth in vivo; the latter suggesting lncRNA-addiction. TKI-resistance models were established from patient-derived lines, through serial passaging with sub-lethal drug doses. Detailed analyses of four of these models demonstrate alterations that affect each of the steps involved in this addiction pathway: ligand binding, EGFR-AS1 expression/amplification and isoform D expression. Based on our mechanistic insights, we propose that patient-response to EGFR inhibitors is contingent on establishing a comprehensive suite of inter-related biomarkers as delineated here. This data also supports a novel therapeutic approach that involves modulating a lncRNA and/or splice variants of a well-established oncogenic driver.
Citation Format: Daniel SW Tan, Fui-Teen Chong, Hui-Sun Leong, Shen Yon Toh, Dawn P. Lau, Xue Lin Kwang, Xiaoqian Zhang, Gek San Tan, Anders J. Skanderup, Tony KH Lim, Ramanuj Dasgupta, N Gopalakrishna Iyer. Role of EGFR-AS1 lncRNA in growth factor addiction and treatment response in squamous cell cancers [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 2591.
Abstract 2593: AR-V7 and AR-V9 expression is not predictive of response to AR-axis targeting agents in metastatic castration-resistant prostate cancer
Authors: To Sarah Q. , Kwan Edmond , Fettke Heidi , Mant Andrew , Docanto Maria , Martelotto Luciano , Bukczynska Patricia , Ng Nicole , Graham Lisa-Jane , Parente Phillip , Pezaro Carmel , Mahon Kate , Horvath Lisa , Todenhöfer Tilman , Azad Arun 
Published: August 2018

Abstract
In 2014, a landmark study was published demonstrating that androgen receptor splice variant (AR-V) AR-V7 expression was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumor cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR splice variants and treatment response. To further investigate, we designed a highly sensitive and specific whole blood assay for detecting AR-V7 and AR-V9. We then examined for a correlation between baseline AR-V7/V9 status and treatment outcome in 37 mCRPC patients commencing abiraterone or enzalutamide. Blood was taken in a PAXgene RNA tube at baseline prior to the commencement of therapy and at end of treatment (if applicable). 24% (9/37) of patients were AR-V-positive. Notably, PSA response rates did not significantly differ between AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs. 64%, p=0.896). Likewise, median PSA progression-free survival was not significantly different between AR-V-positive and AR-V-negative patients (9.2 months vs. not reached; p=0.894). Additionally, we identified 2 patients who were AR-V7 negative at baseline but had converted to AR-V7 positive in their end-of-treatment sample. This was associated with much shorter PSA-PFS than those that remained negative (2.58 months vs. no reached), suggesting gain of AR-V expression may be a marker of acquired resistance. These data, which support the findings of the pivotal ARMOR3-SV clinical trial, suggest that baseline AR-V expression does not predict outcomes in mCRPC patients receiving abiraterone or enzalutamide.
Citation Format: Sarah Q. To, Edmond Kwan, Heidi Fettke, Andrew Mant, Maria Docanto, Luciano Martelotto, Patricia Bukczynska, Nicole Ng, Lisa-Jane Graham, Phillip Parente, Carmel Pezaro, Kate Mahon, Lisa Horvath, Tilman Todenhöfer, Arun Azad. AR-V7 and AR-V9 expression is not predictive of response to AR-axis targeting agents in metastatic castration-resistant prostate 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 2593.
Abstract 2600: Resistance biomarkers in patients with head and neck squamous cell carcinoma treated with cetuximab
Authors: Kamal Maud , Leblanc Olivia , Vacher Sophie , Lecerf Charlotte , Jeannot Emmanuelle , Klijanienko Jerzy , Berger Frederique , Hoffmann Caroline , Calugaru Valentin , Badois Nathalie , Chilles Anne , Lesnik Maria , Krhili Samar , Jouffroy Thomas , Bieche Ivan , Tourneau Christophe Le 
Published: August 2018

Abstract
BACKGROUND: Cetuximab, a monoclonal antibody targeting EGFR, improves overall survival in the locally advanced setting in combination with radiotherapy and in first-line recurrent setting in combination with chemotherapy in HNSCC patients. No predictive biomarker of efficacy of cetuximab in these settings. We aimed at identifying biomarkers of sensitivity/resistance to cetuximab.
PATIENTS AND METHODS: HNSCC patients treated with cetuximab at Institut Curie, for which complete clinicopathological data and formalin-fixed, paraffin-embedded (FFPE) tumor tissue were available and collected before cetuximab treatment, were included in this retrospective study. Immunohistochemistry analyses of PTEN and EGFR were performed to assess expression levels. PIK3CA and KRAS mutations were analyzed using high resolution melting (HRM) and Sanger sequencing. The predictive value of these alterations on progression-free survival (PFS) was evaluated.
RESULTS: PIK3CA and KRAS/HRAS mutations were associated with poor PFS in HNSCC patients treated with cetuximab in first-line recurrence setting but not in patients treated with cetuximab in combination with radiotherapy. PTEN loss of expression had a negative prognostic impact in HNSCC patients treated with cetuximab and radiotherapy, while EGFR high expression was not found to be a sensitivity biomarker for cetuximab in our patient population.
CONCLUSIONS: PIK3CA and RAS mutations were resistance biomarkers of cetuximab in first-line recurrent setting, whereas PTEN loss was a resistance biomarker of cetuximab when given in combination with radiotherapy.
Citation Format: Maud Kamal, Olivia Leblanc, Sophie Vacher, Charlotte Lecerf, Emmanuelle Jeannot, Jerzy Klijanienko, Frederique Berger, Caroline Hoffmann, Valentin Calugaru, Nathalie Badois, Anne Chilles, Maria Lesnik, Samar Krhili, Thomas Jouffroy, Ivan Bieche, Christophe Le Tourneau. Resistance biomarkers in patients with head and neck squamous cell carcinoma treated with cetuximab [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 2600.
Abstract 265: Epi-magnolin suppresses EGF-induced neoplastic cell transformation by inhibition of Akt/mTOR signaling pathway in JBC Cl41 cells
Authors: Lee Cheol-Jung , Yoo Sun-Mi , Kim Seung-Min , Cho Seon-Yeon , Park Juhee , Shin Yu-Mi , Cho Yong-Yeon , Lee Hye Suk 
Published: August 2018

Abstract
The phosphatidylinositol-3-kinase (PI3K)/Akt/the mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in human cancer and plays a pivotal role in cell proliferation and transformation. In this study, we reveal epi-magnolin, a phytochemical found in Magnolia flos, as an inhibitor of Akt/mTOR signaling pathway. Epi-magnolin inhibits EGF-induced Akt phosphorylation at Thr308 and Ser473, but not extracellular signal-regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathway. Moreover, we demonstrate that epi-magnolin suppresses JB6 cell proliferation by impairing EGF-induced G1/S cell cycle transition in a dose-dependent manner. Notably, epi-magnolin abrogates phosphorylation of c-Jun at Ser63 and 73 as well as total c-Jun protein level, which leads to downregulation of AP-1 transactivation activity. The inhibition effect of Akt/mTOR signaling pathway and AP-1 transactivation activity by epi-magnolin suppressed EGF-induced anchorage-independent cell transformation. Based on these results, epi-magnolin might be a chemopreventive agent by targeting Akt/mTOR signaling pathway.
Key words: chemoprevention, cell transformation, Akt/mTOR signaling pathway
Citation Format: Cheol-Jung Lee, Sun-Mi Yoo, Seung-Min Kim, Seon-Yeon Cho, Juhee Park, Yu-Mi Shin, Yong-Yeon Cho, Hye Suk Lee. Epi-magnolin suppresses EGF-induced neoplastic cell transformation by inhibition of Akt/mTOR signaling pathway in JBC Cl41 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 265.