bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 927: Cancer stem cell proliferation in human prostate cancer cells utilizing a new defined 3D spheroid culture system
Authors: Asbrock Nick , Chu Vi , Saito Kan 
Published: July 2017

Abstract
Solid tumors grow in a three-dimensional (3D) spatial conformation, resulting in a heterogeneous exposure to oxygen and nutrients as well as to other physical and chemical stresses. To mimic the 3D spatial conformation, 3D in vitro culture models have been used in cancer research since the diffusion-limited distribution of oxygen (hypoxia), nutrients, metabolites, and signaling molecules is not mimicked in conventional two-dimensional (2D) monolayer cultures. One of the 3D in vitro culture models, the tumorsphere culture is an emerging model for studying and expanding the cancer stem cell (CSC) population. E006AA cell line is a spontaneously immortalized cell line derived from a Gleason 6 localized prostate cancer in a hormone-naive prostate cancer patient of African American descent. This cell line expresses androgen receptor and was repeatedly reported to be non-tumorigenic in nude mice. However this cell line forms continuously growing tumor in NOG-SCID triple-deficient mice (i.e., NOG-SCID mice not having NK, B, and T-cells) and an establishment of highly tumorgenic subline E006AA-hT was reported suggesting this cell line has a potential for CSC proliferation by 3D sphere cultures. Here we report tumorsphere cultures of E006AA cells by a new 3D spheroid culture media system. The cells showed continuous proliferation supported during serial passage of 3D tumorsphere cultures. In addition to the stable proliferation, increases of Aldehyde Dehydrogenase (ALDH) expressing CSC population were observed with the increase of passages of 3D tumorsphere cultures.
Citation Format: Nick Asbrock, Vi Chu, Kan Saito. Cancer stem cell proliferation in human prostate cancer cells utilizing a new defined 3D spheroid culture system [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 927. doi:10.1158/1538-7445.AM2017-927
Abstract 934: EGFR induces ILF3 and G9a expressions to maintain Oct4-mediated stemness property in lung cancer
Authors: Cheng Chun-Chia , Chang Jungshan , Lin Huan-Chau , Ho Ai-Sheng , Lim Ken-Hong , Chang Chun-Chao , Chang Yi-Fang , Wu Cheng-Wen 
Published: July 2017

Abstract
Cancer stem cells survive and lead to tumor recurrence in tumor therapeutic treatments. Lung cancer cells highly express epidermal growth factor receptor (EGFR), which is critical for tumor progression. We hypothesized that EGFR may play a pivotal role in the induction of cancer stemness cells (CSCs). The aim of this study attempted to investigate the molecular mechanism of EGFR-mediated cancer stemness, and to discover the potent therapeutic agents. A high expression level of cancer stemness markers, ALDH1, CD133, Oct4, and Nanog was observed in tumorspheres derived from HCC827. External EGF further elevated the expression of Oct4 in HCC827 cells. Moreover, chemical inhibition and genetic knockdown of EGFR reduced the Oct4 expression and also tumorsphere formation. We found that inhibitors targeting to EGFR (afatinib), ILF3 (YM155), and G9a (UNC0642) are potential to reduce the formations of tumorspheres. The results revealed that EGFR triggered the formation of tumorspheres through elevating the activations of G9a-mediated stemness genes. In addition, YM155 effectively inhibited tumor growth and formation of tumorspheres as an anti-lung cancer agent blocking the EGFR-G9a cell initiating program pathway. This study demonstrated that EGFR participated in maintain of cancer stemness property through expressing ILF3 and G9a expressions. YM155 inhibited the EGFR-G9a stemness pathway, and reduced the formation of tumorspheres as a potent anti-lung cancer agent.
Citation Format: Chun-Chia Cheng, Jungshan Chang, Huan-Chau Lin, Ai-Sheng Ho, Ken-Hong Lim, Chun-Chao Chang, Yi-Fang Chang, Cheng-Wen Wu. EGFR induces ILF3 and G9a expressions to maintain Oct4-mediated stemness property in lung 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 934. doi:10.1158/1538-7445.AM2017-934
Abstract 967: Development of fluorescent-cell based high throughput assay to identify novel therapeutics of bladder cancer cells through upregulation of SPARC expression
Authors: Patel Chirayu M. 
Published: July 2017

Abstract
Bladder cancer is the most common malignancy affecting the urinary system with an estimated 76,960 new cases and projected 16,390 deaths in 2016 in the United States. The role of SPARC in various cancers is contextual and differs based on the tumor classification, malignancy and progression. We have recently reported the tumor suppressor effect of SPARC in urinary bladder cancer. We have shown that the loss of SPARC in bladder cancer resulted accelerated bladder carcinogenesis and metastasis multiple pathways involving cell cycle deregulation, inflammation and angiogenesis. We have also reported that SPARC protein expression significantly decreased in the cancerous compartment in advanced human bladder cancer as well as in carcinogen-induced murine urothelial cancer. However, the mechanism of the downregulation of SPARC expression in cancer in general and in bladder cancer in particular is still unraveled. The purpose of our study is to develop a robust, high throughput assay to identify therapeutic candidates as regulators of SPARC expression in bladder cancer. We cloned SPARC promoter in a third generation lentiviral vector coupled with fluorescent GFP or mCherry fluorescent protein to quantitatively measure SPARC expression. We generated stable bladder cancer cell lines expressing SPARC expression in bladder cancer cell lines. UMUC3 bladder cancer cells were transduced with lentiviral vector to generate SPARC-promoter reporter system to screen regulators of SPARC expression. Reporter cells were plated in 96 well plates and treated with 10uM of FDA-approved and natural product drug libraries. Real time monitoring of changes in SPARC expression was done by measuring GFP fluorescence intensity using IncuCyte® ZOOM Live Imaging Analysis System. We identified drugs that consistently exhibited dosage-dependent augmentation or down-regulation of SPARC expression in UMUC3 cells. Our screens identified novel up-regulators of SPARC expression that are both standard of care and novel bladder cancer therapeutics. Our efforts produced an efficient robust assay to identify novel therapeutics and regulators of the tumor suppressor SPARC in the bladder cancer ecosystem that can be used in the adjuvant and neoadjuvant settings.
Citation Format: Chirayu M. Patel. Development of fluorescent-cell based high throughput assay to identify novel therapeutics of bladder cancer cells through upregulation of SPARC expression [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 967. doi:10.1158/1538-7445.AM2017-967
Abstract 975: A multiscale computational model for spatio-temporal tumor immune response
Authors: Gong Chang , Milberg Oleg , Wang Bing , Vicini Paolo , Narwal Rajesh , Roskos Lorin , Popel Aleksander S. 
Published: July 2017

Abstract
When the immune system responds to tumor development, patterns of immune infiltrates emerge, highlighted by expression of immune checkpoint-related molecules such as PD-L1 on cancer cells and its receptor PD-1 on cytotoxic T cells. Pre-treatment tumor spatial heterogeneity could bear information on intrinsic characteristics of the tumor lesion for individual patient, and thus has the potential to comprise biomarkers for anti-tumor therapeutics. We developed a systems biology computational multiscale agent-based model to capture the interactions between immune cells and cancer cells during tumor progression. Cytotoxic T cells and cancer cells are modeled as free-moving agents in a 3-dimensional grid, where each cell acts in response to its local microenvironment and carries out functions such as division, apoptosis, cytotoxic killing and switching between states with different PD-1 or PD-L1 expression levels. Subsequently, we analyzed the emergent behavior of tumor progression by looking at all these local interactions as a whole. Using this model, we are able to reproduce temporal dynamics of cytotoxic T cells and cancer cells during general tumor progression, as well as 3-dimensional spatial distributions of these cells over the time course of the simulation. By varying the characteristics of the neoantigen profile of individual patients, such as mutational burden and immunogenicity, a spectrum of pre-treatment spatial patterns of PD-1/PD-L1 expression is generated in our simulations, resembling immune-architectures obtained via immunohistochemistry from patient biopsies. We evaluate potential prognostic biomarkers by correlating these spatial characteristics with in silico treatment results with immune checkpoint inhibitors. Simulation results demonstrate that the percentage of PD-L1 positive cancer cells which are not in close proximity of the tumor boundary or vasculature is more indicative of successful anti-PD1/anti-PD-L1 treatment. Our findings suggest that tumor spatial heterogeneity, especially its immune-architecture, reflects the course of tumor progression as well as patient-specific properties, and is thus likely to carry important information about tumor susceptibility to treatment such as with immune checkpoint inhibitors. We demonstrated how prognostic biomarkers could be realistically simulated in a general cancer scenario. The model is further refined for use to predict treatment/biomarker combinations in specific cancer types.
Citation Format: Chang Gong, Oleg Milberg, Bing Wang, Paolo Vicini, Rajesh Narwal, Lorin Roskos, Aleksander S. Popel. A multiscale computational model for spatio-temporal tumor immune response [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 975. doi:10.1158/1538-7445.AM2017-975
Abstract CT145: A phase I window, dose escalating and safety trial of Metformin in combination with induction chemotherapy (VPLD)in relapsed/refractory acute lymphoblastic leukemia: NCT01324180
Authors: Trucco Matteo , Barredo Julio , Goldberg John , Hale Gregory , Gill Jonathan , Setty Bhuvana , Smith Tiffany , Lee Jae , Reed Damon 
Published: July 2017

Abstract
Background: Relapsed Acute Lymphoblastic Leukemia (ALL) remains a major cause of cancer-related deaths in children. We identified the AMP activated protein kinase (AMPK) as a potential target for ALL therapy due to its regulatory effects on the unfolded protein response (UPR), leading to increased vulnerability of ALL cells to endoplasmic reticulum (ER) stress inducers. In vitro, metformin leads to ALL cell death via AMPK-mediated inhibition of the UPR. Methods: Metformin was administered twice daily continuously on a 28 day cycle in addition to the Vincristine, Dexamethasone, PEG-Asparaginase and Doxorubicin (VPLD) systemic regimen and CNS-directed therapy in pediatric patients with relapsed/refractory ALL. Metformin doses were increased in a standard 3+3 phase I design with three dose levels evaluated, 666, 1,000 and 1,333 mg/m2/day. Pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways were ascertained on days 1 and 7, and treatment response was assessed on day 29. Results: Fourteen patients were enrolled, 11 evaluable. DL3 was the maximum administered dose with 2 related DLT’s of diarrhea and acidosis. A single DLT of hypoglycemia and acidosis during an episode of sepsis was observed in DL2. Infectious SAE’s occurred in 7 patients. Two patients had posterior reversible encephalopathy syndrome; both died of disease progression within 30 days of coming off study. A single patient had stable disease, 2 had a partial response, and 3 achieved a complete response. PK studies demonstrated levels within the therapeutic range for patients with diabetes, and PD evaluation showed induction of ER stress and inhibition of the UPR. Conclusions: This trial has been completed. We found induction of ER stress with inhibition of UPR consistent with that observed in vitro leading to metformin-induced apoptosis. The chemotherapeutic backbone was tolerable and the combination with metformin yielded responses in a heavily pretreated population. Toxicities attributable to metformin occurred in all dose levels, but DLT’s were only observed in dose levels above the standard dosing for diabetes. Clinical trial information: NCT01324180
Citation Format: Matteo Trucco, Julio Barredo, John Goldberg, Gregory Hale, Jonathan Gill, Bhuvana Setty, Tiffany Smith, Jae Lee, Damon Reed. A phase I window, dose escalating and safety trial of Metformin in combination with induction chemotherapy (VPLD)in relapsed/refractory acute lymphoblastic leukemia: NCT01324180 [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 CT145. doi:10.1158/1538-7445.AM2017-CT145
Abstract CT159: IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker
Authors: Kallinteris Nikoletta , Horn Leora , Tang Min , Guennel Tobias , Yin Shen , Lai Jennifer , Shan Joseph , Sanborn Rachel E. 
Published: July 2017

Abstract
Background
SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer (NSCLC), demonstrated similar overall survival (OS) in both treatment arms. Immune correlate analyses including pre-treatment IFN-γ levels in blood and tumor tissue were used to potentially identify prognostic and/or predictive correlation with clinical outcome.
Methods
Serum was isolated from all randomized NSCLC patients at screening, periodically during treatment and at disease progression for evaluation of IFN-γ levels using the SimoaTM assay (Myriad RBM, Austin, TX, USA). Available archival tissue was also tested for 91- immune gene activation markers, including IFN-γ by the Fluidigm-based gene-expression platform (Sirona Dx, Lake Oswego, OR, USA). Kaplan-Meier statistical methods and Cox proportion hazards models were utilized to evaluate and contrast the correlation of peripheral and intratumoral IFN-γ levels with OS. Patients were classified paradoxically as IFN-γ "low" with a favorable disease prognosis versus "high" associated with more aggressive disease based on the median.
Results
Pretreatment serum results were available for 582 out of the 597 randomized patients. Each patient was classified to be pre-treatment IFN-γ high or low (&lt; cut-off) using cut-off 0.093 pg/ml, which is the median IFN-γ value in the D+B group. Median overall survival (mOS) in all patients with IFN-γ low is 11.3 months (95% confidence interval [CI], 10.1-13.5) versus 10.4 months (95% CI, 8.4-11.3) in all IFN-γ high; p=0.047. mOS of D+B arm is 11.6 months (95% CI, 10.2-13.9) and 11.1 months (95% CI, 9.1-14.7) in the D group; p=0.982 for IFN-γ low. mOS of D+B arm is 9.0 months (95% CI, 6.7-11.2) and 10.6 months (95% CI, 8.9-13.0) in the D group; p=0.252 for IFN-γ high. With the limited intratumoral IFN-γ gene expression data (n=33), no statistically significant correlation with OS was observed.
Conclusions
Correlative approaches identified low peripheral low IFN-γ at pretreatment as a biomarker of interest correlating with more favorable clinical outcomes and is consistent with the hypothesis that bavituximab may demonstrate more immunomodulatory effects in patients with “immune cold” tumors.
Citation Format: Nikoletta Kallinteris, Leora Horn, Min Tang, Tobias Guennel, Shen Yin, Jennifer Lai, Joseph Shan, Rachel E. Sanborn. IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker [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 CT159. doi:10.1158/1538-7445.AM2017-CT159
Abstract LB-068: From intracellular antibody fragments to small molecule inhibitors of mutant KRAS
Authors: Quevedo Camilo E. , Cruz Abimael , Tulmin Hanna , Bataille Carole J. , Tanaka Tomoyuki , Petch Donna , Russell Angela J. , Phillips Simon , Rabbitts Terence H. 
Published: July 2017

Abstract
Our aim was to develop methods to employ intracellular antibody fragments as lead macromolecules for small compound selections. We have used this approach to identify small molecules binding to mutant RAS with potential to inhibit the RAS-effector interactions. Mutation in RAS family members is among the most frequent in human cancer and the mutant RAS proteins are tumour-specific proteins for therapy. We have previously selected an intracellular antibody single domain fragment that binds to mutant forms of KRAS and HRAS and used this antibody fragment to demonstrate that blocking RAS-effector interaction-dependent signal transduction prevents tumour initiation and overt tumour growth in mouse preclinical models. The antibody fragment binds to GTP-bound RAS with high pM affinity and we have used this property to isolate compounds from a fragment library using a competitive SPR method that places the compounds in the region of the binding site of the antibody fragment. Using a combination of X-ray crystallography and medicinal chemistry, we have obtained a family of compounds that bind adjacent to the KRAS switch I region with nM affinity and that inhibit the downstream phosphorylation of AKT and ERK that results from RAS signaling. The chemical evolution and interaction characteristics of the KRAS-binding compounds will be described and their biochemical and cell-based properties presented. We have validated our approach using an antibody fragment as a screening tool for the
identification of small molecule inhibitors of the RAS-effector interaction. This approach has yielded small compound fragments that are currently being developed as potential RAS-effector inhibitors in our medicinal chemistry programme.
Citation Format: Camilo E. Quevedo, Abimael Cruz, Hanna Tulmin, Carole J. Bataille, Tomoyuki Tanaka, Donna Petch, Angela J. Russell, Simon Phillips, Terence H. Rabbitts. From intracellular antibody fragments to small molecule inhibitors of mutant KRAS [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 LB-068. doi:10.1158/1538-7445.AM2017-LB-068
Abstract LB-082: Targeted inactivation of STAT3 inhibits proliferation and invasion of breast cancer cells and enhances antitumor activity of doxorubicin through reversion of EMT
Authors: Ding Yi , Jiang Yu , Li Wenqing , Liu Shurong , Lu Zhong , Shi Lihong , Wang Xuejian , Zhang Jian , Wang Lihua 
Published: July 2017

Abstract
Breast cancer is one of the most common malignant diseases in women. Epithelial-mesenchymal transition (EMT) has been documented to play an important role in proliferation, invasion and metastasis of tumor cells as well as drug resistance. Even though the signal transducer and activator of transcription 3 (STAT3) is not a master transcription factor of EMT, STAT3 is involved in the regulation of EMT-related gene expression. However, it remains unclear whether targeted inhibitors of STAT3 affect EMT-mediated proliferation, migration, invasion and drug resistance of tumor cells. In this paper, we investigated the effects of STAT3 and its interaction with Twist, a master transcription factor, in EMT program and subsequent changes in proliferation, migration and invasion of breast cancer cells by interfering STAT3 signaling pathway with different strategies such as STAT3 inactivation and STAT3 silencing. Furthermore, we explored the role of inhibiting STAT3 phosphorylation in the EMT regulation of the sensitivity of tumor cells response to doxorubicin. The results showed that the expression and activation of STAT3 correlated with cell phenotype and invasive ability of breast cancer cells. IL-6 induced phosphorylation of STAT3 can promote the EMT of breast cancer cells. WP1066 completely inhibited STAT3 autophosphorylation and IL-6-induced phosphorylation in breast cancer cells. WP1066 reversed EMT to MET through inhibiting the phosphorylation of STAT3 in breast cancer cells and significantly inhibited the proliferation and invasion in breast cancer cells. Silence STAT3 with siRNA also reversed EMT to MET in breast cancer cells. The expression of EMT transcription factor Twist1 was positively correlated with the activation of STAT3 but not with the expression of STAT3. WP1066 increased doxorubicin antitumor activity through inhibiting the STAT3 phosphorylation. These data provide a proof of concept that targeted inactivation of STAT3 can inhibit proliferation and invasion of breast cancer cells and reduce the resistance of Doxorubicin through reversion of EMT. Support by Natural Science Foundation of China (No.81472489) and Science and Technology Development Plan of Shandong (No.2014GSF118040)
Citation Format: Yi Ding, Yu Jiang, Wenqing Li, Shurong Liu, Zhong Lu, Lihong Shi, Xuejian Wang, Jian Zhang, Lihua Wang. Targeted inactivation of STAT3 inhibits proliferation and invasion of breast cancer cells and enhances antitumor activity of doxorubicin through reversion of EMT [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 LB-082. doi:10.1158/1538-7445.AM2017-LB-082
Abstract LB-084: Histone chaperone HIRA is required for Setd1a H3K4 methylation recruited by TAL1 oncoprotein in leukemogenesis
Authors: Li Ying 
Published: July 2017

Abstract
TAL1/SCL is a hematopoietic specific member of the basic Helix-Loop-Helix (bHLH) family of transcription factors important for the development of all hematopoietic lineages and pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), which plays a coordinating role in establishing the proper chromatin dynamics and gene regulation. We have previously demonstrated that TAL1 associated with H3K4 methyltransferase SETD1A, which mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis. We now find that a novel interaction between TAL1 and histone cell cycle regulation defective homolog A (HIRA) histone chaperone. TAL1 directly interacts with HIRA, which is not only essential for promoter H3K4 hypermethylation by Setd1a, but is also critical for the transcriptional activation of target genes mediated by TAL1 and Setd1a in T cell acute lymphoblast leukemia (T-ALL) Jurkat cells, such as CDK6 and NKX3.1. Our data revealed a collaborative role by which transcription factor-directed recruitment of histone chaperone and histone modification enzyme can lead to chromatin structure alterations at specific promoters in leukemogenesis.
Citation Format: Ying Li. Histone chaperone HIRA is required for Setd1a H3K4 methylation recruited by TAL1 oncoprotein in leukemogenesis [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 LB-084. doi:10.1158/1538-7445.AM2017-LB-084