bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 468: Evaluation of microRNA inhibition in medulloblastoma
Authors: Vavra Alexander , Stoops Sydney , White Jonathan 
Published: July 2017

Abstract
Medulloblastoma is the most common pediatric malignant brain tumor. The current treatment plan consists of a combination of surgery, radiation, and chemotherapy which results in an 80% five year survival rate. However, the survival rate does not take into account the developmental delays and learning disabilities inherited as a result of the aggressive treatment plan on a developing brain. As such the development of new treatment options is needed. While many protein targets are currently being explored for therapeutic intervention, the role of non-coding RNAs is of increasing interest. Specifically microRNA profiling in medulloblastoma has been performed by others to highlight expression profiles which can be mapped to the disease state and also to potentially identify associated protein targets. Moreover, it is particularly intriguing that microRNAs themselves may be directly targeted as therapeutic points of intervention. With this in mind, our lab is currently investigating methods for directly targeting microRNAs in medulloblastoma and we have recently validated several upregulated miRNAs for further investigation. Specifically, we evaluated the expression profile eighteen selected miRNAs in DAOY and D341 cell lines. Our results indicate that four miRNAs (miR-196a, miR-183, miR-96, and miR-182) are statistically overexpressed in both cell lines. Results of these findings and our initial efforts to target these selected miRNAs will be described.
Citation Format: Alexander Vavra, Sydney Stoops, Jonathan White. Evaluation of microRNA inhibition in medulloblastoma [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 468. doi:10.1158/1538-7445.AM2017-468
Abstract 4681: Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib resistance in EGFR-mutant lung cancer
Authors: Tanimoto Azusa 
Published: July 2017

Abstract
Purpose:The BIM deletion polymorphism is associated with apoptosis resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.
Experimental Design:We used EGFR-mutated NSCLC cell lines which were either heterozygous or homozygous for the BIM deletion polymorphism to evaluate the effect of osimertinib in vitro and in vivo. Protein expression was examined by western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.
Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.
Conclusions:These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism.
Note: This abstract was not presented at the meeting.
Citation Format: Azusa Tanimoto. Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib resistance in EGFR-mutant 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 4681. doi:10.1158/1538-7445.AM2017-4681
Abstract 4684: MYC inhibition in human malignancy by BET-Bromodomain inhibitor JQ1, using a 3-D human tumor primary culture micro-spheroid platform to explore clinically relevant observations
Authors: Nagourney Robert Alan , Evans Steven S. , Nagourney Alexander J. , Bernard Paula J. , Francisco Federico R. , Sheth Milan , Vora Nilesh , Deo Eknath 
Published: July 2017

Abstract
The transcription factor MYC is associated with the regulation of over 15% of human gene expression. Deregulation of MYC is found in up to 70% of human cancers. As MYC is responsible for the reprogramming of cell metabolism, growth and survival, it is an attractive therapeutic target, yet effective drug development has been slow. As the Bromodomain/BET proteins epigenetically regulate MYC, BET inhibitors like JQ1 have been developed as MYC therapeutics. We used the Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) previously shown to correlate with response, time to progression and survival, to examine JQ1 activity in 46 human tumor specimens isolated from surgical biopsies.
Methods: Surgical biopsies were mechanically and enzymatically disaggregated, with micro spheroids of desired size isolated by density centrifugation. Five-Point dose response curves were interpolated to provide LC50 values for comparison by Z-score. Synergy was conducted by median-effect.
Results: JQ1 revealed activity in hematologic, breast, glial & gastrointestinal (GI) tumors. By rank order, JQ1 activity favored hematologic (AML & NHL) & breast tumors over Lung, Ovary and GI with inter-patient differences observed within tumor types. MYC association with histone acetylation and aurora kinase (AURK) activity, led to an exploration of JQ1 synergy with SAHA (HDACi), MLN 8054 & Tozasertib (both AURKi). JQ1 synergy analysis revealed SAHA &gt; Tozasertib &gt; MLN 8054.
Conclusions: Based upon JQ1 activity, several tumor types appear to be candidates for agents that target MYC-mediated cell survival, offering potential treatment options for patients with advanced malignancies. JQ1 synergy with HDACi & AURKi suggests novel drug combinations for future development. As MYC signaling influences thousands of gene targets, phenotypic analyses like the EVA/PCD platform can offer insights into cellular cell death events that serve as surrogate markers for clinical response to MYC inhibition. Supported in part by the Vanguard Cancer Foundation, the Nagourney Institute and the Malcolm C. Todd Cancer Institute.
Citation Format: Robert Alan Nagourney, Steven S. Evans, Alexander J. Nagourney, Paula J. Bernard, Federico R. Francisco, Milan Sheth, Nilesh Vora, Eknath Deo. MYC inhibition in human malignancy by BET-Bromodomain inhibitor JQ1, using a 3-D human tumor primary culture micro-spheroid platform to explore clinically relevant observations [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 4684. doi:10.1158/1538-7445.AM2017-4684
Abstract 4691: Polarization of macrophages with STING agonists
Authors: Henare Kimiora L. , Tijono Sofian M. , Ching Lai-Ming 
Published: July 2017

Abstract
The functional plasticity of macrophages and their ability to support tumour growth or promote potent antitumor immunity make them an attractive target cancer therapy. Macrophages have been implicated in the complex antitumor activity of murine STING agonist, DMXAA, including disruption of tumor vasculature, induction of cytokine production, and promotion of durable antitumor immune responses. Many of these activities are lost in STING-/- mice, and DMXAA does not bind to human STING, providing a pertinent explanation for why the anti-tumour effects of DMXAA observed in mice were not recapitulated human clinical trials. Using PMA-differentiated THP-1 macrophages, we sought to identify human active analogues of DMXAA in vitro, comparing their capacity to induce cytokines indicative of a classically activated antitumour phenotype; the non-canonical STING agonist 2'3'-cGAMP was also included in our investigation. IP-10 (CXCL10) production, measured by ELISA, was used as an initial marker for activity, followed by multiplex cytokine analysis for broader characterisation compared to M(IFN-γ/LPS), M(IL-4/IL-13), and ‘resting’ M(media alone) macrophage phenotypes. Parallel experiments were also conducted with RAW264.7 murine macrophages to compare the DMXAA-induced cytokine profile directly with that of 2'3'-cGAMP. 2'3'-cGAMP induced 22-fold and 18-fold increases in IP-10 production in resting and M(IL-4/IL-13) THP-1 macrophages, respectively. By comparison, THP-1 macrophages were much less responsive to DMXAA and analogues tested to date. Furthermore, 2'3'-cGAMP induced a spectrum of cytokines similar to that observed in M(IFN-γ/LPS) macrophages, and markedly different to that of M(IL-4/IL-13) THP-1 macrophages. DMXAA, and analogues previously shown to have cytokine-inducing activity in human leukocytes did not produce cytokine spectra indicative of a classic M(IFN-γ/LPS) phenotype. Unlike human cells, however, cytokine spectra produced by RAW264.7 murine macrophages were comparable between DMXAA- and 2'3'-cGAMP-treated cells. These findings support previous data that suggest that STING agonists can promote macrophage polarisation towards an antitumour phenotype. While DMXAA is active in murine macrophages, only 2'3'-cGAMP can induce in human THP-1 cells, an M(IFN-γ/LPS)-like spectrum of cytokines often attributed to an antitumour macrophage phenotype.
Citation Format: Kimiora L. Henare, Sofian M. Tijono, Lai-Ming Ching. Polarization of macrophages with STING agonists [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 4691. doi:10.1158/1538-7445.AM2017-4691
Abstract 4696: Development of an inhaled TLR9 agonist for the immunotherapy of lung cancer
Authors: Gallotta Marilena , Assi Hikmat , Coffman Robert L. , Guiducci Cristiana 
Published: July 2017

Abstract
CpG-oligonucleotides (CpG-ODN) stimulate innate immune responses through Toll-like receptor-9 (TLR9). Intratumoral (IT) administration of CpG-ODN has been shown to be safe and clinically effective in humans and in multiple animal species. An important feature of local administration of a CpG-ODN is the ability to stimulate immune responses that control the growth of distant, uninjected tumors. Such treatment is especially effective when combined with a complementary mode of immunotherapy, such as anti-PD-1 or radiation. However, repeated IT injection is not practical for many tumor types, including most lung cancers. In mild asthmatic patients and healthy subjects, CpG-ODN have demonstrated safety and pharmacologic activity when delivered by inhalation directly to the lungs. Thus, inhaled CpG presents an alternative to IT injection for primary lung cancers and for other tumor types with prominent lung metastases. In the 4T1 mouse model of metastatic breast cancer, treatment of mice with a CpG-ODN administered intranasally led to a marked reduction in the number of lung metastases. This reduction was accompanied by infiltration of tumors with activated CD8+ and CD4+ T cells and the formation of highly organized tertiary lymphoid structures. These changes are similar to those observed after IT injection of solid tumors growing subcutaneously, and are consistent with changes observed in human tumors responsive to immunotherapy. In the 4T1 model, intranasal CpG-ODN strongly synergized with systemic anti-PD-1 treatment and induced complete clearance of lung tumors, as well as metastases in tissues not exposed to the CpG-ODN, including liver, pancreas and bone. This generation of systemic immunity resulted in long-term survival in the majority of mice. Immune cell subset depletion studies implicate both CD8 and CD4 T cells in the rejection of lung tumors treated with inhaled CpG-ODN plus anti-PD1. Dynavax has developed a CpG-ODN, DV281, that is optimized for aerosol delivery and plans to initiate clinical studies in NSCLC patients in 2017.
Citation Format: Marilena Gallotta, Hikmat Assi, Robert L. Coffman, Cristiana Guiducci. Development of an inhaled TLR9 agonist for the immunotherapy of 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 4696. doi:10.1158/1538-7445.AM2017-4696
Abstract 4707: Evaluation of efficacy and immune response to PD1 checkpoint inhibition in human immune-reconstituted mice using patient-derived xenograft models
Authors: Izadi Hooman , Broudy Tommy , Yan Deborah , Thatte Jayant 
Published: July 2017

Abstract
Background: Human Immune-reconstituted Mice, generated by transplanting pre-validated human CD34+ hematopoietic stem cells (HSC) into immune-compromised mice, are extremely useful in basic and applied human disease research. Many cancer therapies, including immune checkpoint inhibitors such as the anti-PD-1 monoclonal antibody, rely on an intact immune system to release immunosuppression and destroy cancer cells.
Material and methods: We evaluated the effects of anti-PD-1 in humanized mice in donor cohorts utilizing the cancer matrix of 5 HSC donor cohorts of humanized animals with PDX models from 7 small cell lung cancer (SCLC). We also tested anti-PD-1 in 1 triple negative breast cancer (TNBC) model and in 1 MDA-MB-231 study.
Results: Here, we show that HSC derived human immune cell engraftment does not have significant effects on patient derived xenograft (PDX) tumor growth. However, humanization is required for anti-tumor response to anti-PD-1. In MDA-MB-231 study, tumors showed complete regression after the first round of treatment. Re-engraftment of same animals with MDA-MB-231 cells showed minor tumor growth before complete regression again. Aged match control naïve animals engrafted with same cells showed normal tumor growth. In SCLC studies anti-PD-1 efficacy varied between the models, which clearly underscores the inherent donor to donor variability in this humanized model system. Tumors from these studies were then analyzed to determine target engagement of anti-PD-1, tumor infiltrating lymphocytes (TILs) characterization and histology comparing anti-PD-1 responders vs non-responders. As expected, in this study, we demonstrate humanization of the animals is necessary to evaluate the efficacy of anti-PD-1 therapy and can elicit an immunotherapy mediated anti-tumor effect.
Conclusion: Here we demonstrate the development of humanized mouse studies with ability to run multi point analysis to determine the outcome of treatment.
Citation Format: Hooman Izadi, Tommy Broudy, Deborah Yan, Jayant Thatte. Evaluation of efficacy and immune response to PD1 checkpoint inhibition in human immune-reconstituted mice using patient-derived xenograft models [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 4707. doi:10.1158/1538-7445.AM2017-4707
Abstract 4713: Deubiquitination and stabilization of programmed cell death-ligand 1 by CSN5
Authors: Lim Seung-Oe , Li Chia-Wei , Hung Mien-Chie 
Published: July 2017

Abstract
Chronic inflammation in cancer is often associated with disease aggressiveness. Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of antitumor immunity and enhanced tumor cell survival. In the current study, we identified TNFα as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNFα-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. The role of CSN5 in modulating PD-L1 stabilization prompted us to use CSN5 inhibitor, curcumin, to show that it could destabilize PD-L1. Curcumin reduced CSN5 activity to attenuate TNFα-mediated PD-L1 stabilization and enhanced anti-tumor immunity. Preclinical data demonstrated inhibition of CSN5 sensitized cancer cells to anti-CTLA4 therapy, suggesting CSN5 inhibitor may be a useful adjuvant to enhance immune-based therapies.
Note: This abstract was not presented at the meeting.
Citation Format: Seung-Oe Lim, Chia-Wei Li, Mien-Chie Hung. Deubiquitination and stabilization of programmed cell death-ligand 1 by CSN5 [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 4713. doi:10.1158/1538-7445.AM2017-4713
Abstract 4728: Plasma interleukin-6 level predicts prognosis of patients who received sorafenib for advanced hepatocellular carcinoma
Authors: Shao Yu-Yun , Lin Hang , Li Yong-Shi , Lee Ying-Hui , Chen Ho-Min , Cheng Ann-Lii , Hsu Chih-Hung 
Published: July 2017

Abstract
Background: No biomarker has been proven to predict the treatment outcomes of sorafenib, the only approved first-line therapy for advanced hepatocellular carcinoma (HCC). We explored predictive and prognostic values of plasma interleukin (IL)-6 levels for patients who received sorafenib as first-line therapy for advanced HCC.
Methods: This study had 2 patient cohorts. The exploration cohort consisted of patients who were previously enrolled in a phase 2 clinical trial that examined sorafenib with tegafur/uracil as first-line therapy for advanced HCC. The validation cohort consisted of patients who received sorafenib alone as first-line therapy for advanced HCC under reimbursement of National Health Insurance of Taiwan. Pretreatment plasma IL-6 levels were determined. We used the receiver operating characteristic (ROC) curve in the exploration cohort to determine the best cut point for IL-6 levels to predict overall survival (OS). We then confirmed the cut point in the validation cohort.
Results: There were 55 and 73 patients in the exploration and validation cohort, respectively. In the exploration cohort, there was no complete response but 3 (6%) partial response. The median OS was 8.1 months. In the validation cohort, there was no complete response but 7 (10%) partial response. The median OS was 10.3 months. In the exploration cohort, we found 4.28 pg/ml was the best cut point in defining high and low IL-6 levels because it could differentiate OS (p = 0.042) with the best sensitivity and specificity. Applying the cut point on the validation cohort, patients with high pretreatment plasma IL-6 levels, compared with patients with low IL-6 levels, exhibited significantly poorer OS (median, 8.0 vs. 13.9 months, p = 0.031). After adjusting for age, gender, hepatitis etiology, tumor characteristics, α-fetoprotein level, performance status, and prior treatment, a high plasma IL-6 level remained an independent predictor for poor OS (hazard ratio 2.594, p = 0.005). By contrast, the plasma IL-6 level was not associated with progression-free survival, treatment response, disease control, or other patient characteristics.
Conclusion: High pretreatment plasma IL-6 level predicted prognosis of patients who received sorafenib as first-line therapy for advanced HCC.
Citation Format: Yu-Yun Shao, Hang Lin, Yong-Shi Li, Ying-Hui Lee, Ho-Min Chen, Ann-Lii Cheng, Chih-Hung Hsu. Plasma interleukin-6 level predicts prognosis of patients who received sorafenib for advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4728. doi:10.1158/1538-7445.AM2017-4728
Abstract 4747: Subcutaneous fat predict outcome in head and neck cancer
Authors: Tsang Ngan M. 
Published: July 2017

Abstract
Background: Previous studies have shown that body mass index (BMI) is linked to survival in cancer patients. Our objective was to analyze whether body composition before treatment can predict outcomes in patients with head-and neck cancer.
Methods: All 881 patients with loco-regional head-and -neck cancer treated with curative-intent RT during 2005 to 2012 were retrospectively studied. Body composition analyses by using pre-RT CT images acquired for RT simulation. We compared subcutaneous adipose tissue (SAT) index and muscle index by measuring cross-sectional area of tissues at level of the third thoracic vertebrae (T3) in both genders. Overall survival (OS), loco-regional control (LRC), and distant metastasis-free survival (DFS) were analyzed by body composition index that divided into two groups based on values higher and lower than the median. The median follow-up was 4.68 years.
Results: SAT index in female patients was significantly higher than that in male (p &lt;0.001). The median SAT index and muscle index for female were 15.25 cm2/m2 (range, 0.93-88.09 cm2/m2) and 34.3 cm2/m2 (range, 14.78-73.05 cm2/m2), and for male were 6.19 cm2/m2 (range, 0.21-40.48 cm2/m2) and 51.74 cm2/m2 (range, 8.03-89.06 cm2/m2). The 5-year and 10-year OS, LRC and DFS were 66.3%, 57.6%, 73.4%, 71.4%, 83%, and 82.1%. Higher pre-treatment SAT index was associated with longer OS (HR = 0.616; P = 0.001) and DFS (HR = 0.649; P = 0.015) and a trend towards longer LRC (HR = 0.772; P = 0.066). Pre-treatment muscle index was also a significant predictor of OS (HR = 0.662; P = 0.006) and LRC (HR = 0.684; P = 0.029).
Conclusion: SAT index and muscle index of T3 level obtained from CT images appear to predict outcomes in patients with curative head-and-neck cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Ngan M. Tsang. Subcutaneous fat predict outcome in head and neck 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 4747. doi:10.1158/1538-7445.AM2017-4747