bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1674: Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism
Authors: Chen Xi , Xie Chun , Fan Xing Xing , Jiang Ze Bo , Wong Vincent , Xu Jia Hui , Yao Xiao Jun , Liu Liang , Leung Elaine L. 
Published: August 2018

Abstract
Lung cancer is the leading cause of cancer mortality. While non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer and dominates almost 85% of all lung cancer cases. Conventional therapy, such as surgery, chemotherapy, or radiotherapy, scarify normal cells during the curing progress are becoming unfavorable. To avoid harmful side-effect on normal cell, target-based therapy is the mainstream of modern cancer therapy. For example, gefitinib is a clinically-marketed drug which acts as tyrosine kinase inhibitor to inhibit epidermal growth factor receptor (EGFR) activating signaling pathway. For the NSCLC patients who harbor activating substitution from leucine to arginine at amino acid 858 (L858R) point mutation and in-frame exon 19 deletion on EGFR, response well to gefitinib and these two common mutation are used a biomarkers for gefitinib prescription. However, gefitinib-resistance commonly happens due to further substitution mutation from threonine to methionine at amino acid position 790 (T790M) occurred after one year or less gefitinib treatment. Therefore, developing new treatment strategy to tackle gefitinib-resistance is urgently. Abnormal energy metabolism is accepted as new cancer hallmark. Recently, a metabolism rate-limiting enzyme 5'-adenosine menophosphate-activated protein kinase (AMPK) has become a promising anti-cancer target. In this study, we have applied computational docking to perform in silico virtual screening, and we have identified a novel direct AMPK agonist, D561-0775 from a compound library. Using enzyme activation assay, we demonstrated that D561-0775 activates directly on AMPK α subunit. In addition, D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines but is less cytotoxicity on normal lung fibroblast cells. D561-0775 also activates AMPK/mTOR signaling pathway, resulting in induction of apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis in gefitinib-resistant H1975 lung cancer cells. Taken together, D561-0775 has provided clue on a new chemical structure that could be developed as cancer drug for gefitinib-resistant NSCLC patients through inhibition lipid metabolism by directly targeting at AMPK directly. Acknowledgments: This work was supported by Macau Science and Technology Development Fund (Project No: 021/2013/A1, 074/2011/A3 & 082/2013/A3)
Citation Format: Xi Chen, Chun Xie, Xing Xing Fan, Ze Bo Jiang, Vincent Wong, Jia Hui Xu, Xiao Jun Yao, Liang Liu, Elaine L. Leung. Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid 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 1674.
Abstract 168: Cancer stem-like properties and drug resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2
Authors: Gotoh Noriko , Nishimura Tatsunori , Nakata Asuka , Horike Shin-ichi , Kohno Susumu , Takahashi Chiaki , Soga Tomoyoshi , Tojo Arinobu 
Published: August 2018

Abstract
Tumor recurrence is attributable to cancer stem-like cells (CSCs), the metabolic mechanisms of which currently remain obscure. Here, we uncovered the critical role of folate-mediated one-carbon (1C) metabolism involving mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and its downstream purine synthesis pathway. MTHFD2 knockdown greatly reduced tumorigenesis and stem-like properties, which were associated with purine nucleotide deficiency, and caused marked accumulation of 5-aminoimidazole carboxamide ribonucleotide (AICAR)—the final intermediate of the purine synthesis pathway. Lung cancer cells with acquired resistance to the targeted drug gefitinib exhibited increased stem-like properties and enhanced expression of MTHFD2. MTHFD2 knockdown or treatment with AICAR reduced the stem-like properties and restored gefitinib sensitivity in gefitinib-resistant cancer cells. Thus, MTHFD2-mediated mitochondrial 1C metabolism appears critical for cancer stem-like properties and resistance to drugs including gefitinib through consumption of AICAR, leading to depletion of the intracellular pool of AICAR. Because CSCs are dependent on MTHFD2, therapies targeting MTHFD2 may eradicate tumors and prevent recurrence.
Citation Format: Noriko Gotoh, Tatsunori Nishimura, Asuka Nakata, Shin-ichi Horike, Susumu Kohno, Chiaki Takahashi, Tomoyoshi Soga, Arinobu Tojo. Cancer stem-like properties and drug resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2 [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 168.
Abstract 1682: Combined treatment of aldose reductase inhibitor, fidarestat, and anti-PD1 antibodies synergistically prevents T cell- and NK cell-mediated colon cancer growth in murine models
Authors: Saxena Ashish , Sonowal Himangshu , Srivastava Satish K. , Ramana Kota V. 
Published: August 2018

Abstract
Immune checkpoint inhibitors such as anti-programmed death 1 (PD1) and anti-PD-L1 monoclonal antibodies though have great potential for cancer immunotherapy, the acquired drug resistance and unwanted immune side effects limit their use. However, the combination therapy using conventional drugs and immune checkpoint inhibitors not only synergistically increase anti-tumor responses but it also reduces immune-associated adverse events. In our earlier studies, we have shown that inhibition of polyol pathway enzyme, aldose reductase (AR) prevents colon cancer growth and metastasis in culture as well as in mouse models. In this study, we investigated whether fidarestat, a potent AR inhibitor that has already gone through Phase-III clinical trial for diabetic neuropathy and found to safe for human use, can synergize with anti PD-1 to increase antitumor activity and decrease immune-associated adverse effects. Mice bearing syngeneic CT26 colon carcinoma tumors were treated with anti PD-1 alone or in combination with fidarestat, and the tumor growth was monitored. Our results indicate that fidarestat in combination with anti-PD1 synergistically increases tumor regression within 28 days of treatment. Further, a combination of fidarestat and anti-PD1 significantly increased the CD8+ T cells and natural killer (NK) cells and decreased the Myeloid-derived suppressor cells (MDSCs) at tumor milieu. Fidarestat plus anti-PD1 also increased CD8+ T cell and NK cell effector functions as determined by IFNg and granzyme B. Systemically, combination therapy also increased the number of CD8+ T cells and NK cells and decreased MDSCs in the mouse spleens. Further, the effector functions of CD8+ T cells and NK cells were increased with the combination treatment in mice spleens. Moreover, the levels of various inflammatory cytokines and chemokines in the serum and liver were significantly less in fidarestat plus anti-PD1 -treated mice as compared to anti-PD1 alone -treated mice indicating that fidarestat rescues immune-mediated adverse events in various organs. Thus, our results suggest that by regulating the number as well as effector function of CD8+ T cells, NK cells and MDSCs, AR inhibitor in combination with anti-PD1 would not only regress the tumor growth but would also provide a long-lasting specific immunity against colon cancer, which would decrease the chances of tumor recurrence.
Citation Format: Ashish Saxena, Himangshu Sonowal, Satish K. Srivastava, Kota V. Ramana. Combined treatment of aldose reductase inhibitor, fidarestat, and anti-PD1 antibodies synergistically prevents T cell- and NK cell-mediated colon cancer growth in murine models [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 1682.
Abstract 1685: Genomics based studies of gastric tumors identify ICOS as potential target for therapeutic intervention
Authors: Hirsch Heather A. , Reeves Jason , Zi Tong , Needham Alexander , Stack Edward , Lee David , Lees Emma , Law Deborah A. , Trehu Elizabeth 
Published: August 2018

Abstract
JTX-2011, an ICOS agonist antibody, is the first clinical program to emerge from Jounce's Translational Science Platform, which couples the choice of target mechanism to potential predictive biomarkers of response. ICOS (Inducible T cell CO-Stimulator), a co-stimulatory molecule expressed primarily on T lymphocytes, was prioritized as a target based on preclinical and clinical data suggesting that it plays an important role in the immune response to cancer. Fundamental data from our preclinical studies shows that tumor reduction occurs only in animals when a certain percentage of ICOS positive immune cells are resident within the tumor or in combination with a PD-1 inhibitor. Thus ICOS expression is a key element of our biomarker-driven approach in the ICONIC clinical trial. Based on this biomarker approach, we have identified gastric cancer as a cancer of potential interest for an ICOS-targeted immunotherapy approach.
Gastric adenocarcinoma was identified as a tumor of interest based on the integrated analysis of RNA, DNA and clinical data from the Cancer Genome Atlas (TCGA). This analysis was performed within stomach adenocarcinoma (STAD) to understand the context in which ICOS is expressed. ICOS levels were correlated to gene signatures of immune infiltrate as well as other clinical attributes and molecular markers. ICOS and PD-L1 levels were assessed by IHC in human tumor samples and in biopsies from ICONIC participants.IHC and RNA analyses reveals a dynamic range of ICOS expression across gastric adenocarcinoma tumors, with high prevalence in both EBV+ and MSI-H tumors as well as a subset of EBV-/MSS tumors. While there is a correlation between ICOS, ICOS signature, PD-L1 and IFNγ signatures, RNA analysis indicates that a subpopulation of gastric tumors with lower levels of PD-L1 expression may be ICOS positive. Integrative analysis of tumors identifies gastric cancer as an attractive indication for exploration of JTX-2011 plus a PD-1 inhibitor based on the relatively high frequency of ICOS expression within this tumor type. Since ICOS expression has a dynamic range of expression, an ICOS IHC biomarker is being used to enrich for patients in a gastric cancer cohort, as well as other tumor-specific cohorts in the Phase 2 portion of the ICONIC clinical study.
Citation Format: Heather A. Hirsch, Jason Reeves, Tong Zi, Alexander Needham, Edward Stack, David Lee, Emma Lees, Deborah A. Law, Elizabeth Trehu. Genomics based studies of gastric tumors identify ICOS as potential target for therapeutic intervention [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 1685.
Abstract 1696: Glycogen synthase kinase (GSK-3) inactivation downregulates PD-1 and synergizes with PD-1/PL1 and CTLA-4 blockade in cancer immunotherapy
Authors: Rudd Christopher E. 
Published: August 2018

Abstract
Immune checkpoint blockade (ICB) of negative co-receptors on T-cells such as cytotoxic T-cell antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) is a promising approach for the treatment of cancer. Despite this success, the poor prognosis for most patients continues to highlight a need for developing novel clinical interventions. In this context, we identified the enzyme glycogen synthase kinase-3 (GSK-3) as the major regulator of PD-1 expression on T-cells (Taylor et al., 2016 Immunity). We have shown that small molecule inhibitors (SMIs) of GSK-3 are as effective as anti-PD-1 in controlling the growth of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings (Taylor et al., 2017 Can Res; Krueger and Rudd, Immunity 2017). At the same time, the fact that GSK-3 inactivation up-regulates transcription factor T-bet which upregulates interferon gamma (IFNγ) and granzyme B (GZMB) suggested that GSK-3 inactivation might provide extra value beyond of its down-regulation of PD-1. Here, we show that GSK-3 SMIs can synergize with anti-PD-1 and anti-CTLA-4 to eliminate B16 solid tumors that are otherwise resistant to anti-PD-1, or anti-CTLA-4 inhibition alone. At a cellular level, GSK-3 inactivation preferentially down-regulated PD-1 on CD8+ tumor infiltrating T-cells, while at a molecular level, GSK-3 SMIs inhibited PD-1 transcription, increased granzyme B (GZMB)/ interferon-gamma1 (IFNγ) transcription and directly acted upon glycogen synthase to skew metabolism towards greater glycolysis. We further showed that the inactivation of GSK-3α/β through siRNA or by SMIs substituted for CD28 co-stimulation in the potentiation of cytotoxic CD8+ CTL function. This data supports a model where GSK-3 mediates the dependency of anti-PD-1 immunotherapy on the expression of CD28. Overall, our data show that GSK-3 inactivation is an immune-sensitizer which assists the immune system to overcome tumor resistance to immune check-point blockade.
Citation Format: Christopher E. Rudd. Glycogen synthase kinase (GSK-3) inactivation downregulates PD-1 and synergizes with PD-1/PL1 and CTLA-4 blockade in cancer immunotherapy [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 1696.
Abstract 1698: Loss of MHC-I expression is associated with altered immune microenvironment and decreased response to PD-1 checkpoint inhibition
Authors: Gstalder Cecile , Pancholi Priya , Sadowicz Dorota , Haq Rizwan 
Published: August 2018

Abstract
Cancer immunotherapies, such as PD-1 inhibitors, achieve durable responses in a subset of cancer patients, however, a significant proportion of patients fail to respond to treatment. Defects in antigen presentation, such as the loss of MHC-I expression, are a major mechanism of resistance to PD-1 inhibitors. Developing new therapeutic strategies that overcome the lack of antigen presentation will improve cancer treatment and patient survival. To develop a pre-clinical model to evaluate therapies that could overcome resistance, we have generated a unique PD-1 blockade sensitive, syngeneic immunocompetent melanoma mouse model. We generated defects in antigen presentation using the CRISPR/Cas9 system, creating B2m-deficient melanoma cell lines. We demonstrated that B2m is necessary for IFN-gamma induced MHC-I surface expression. Unlike control tumors, we found that B2m-deficient tumors were resistant to PD-1 blockade, leading to decreased mouse overall survival. Using multi-parameter flow cytometry, we showed an increase in NK cell, regulatory T cell and dendritic cell infiltration in B2m-deficient tumors compared to controls, while the other immune cell population were unchanged. Since NK cell activity is negatively regulated by MHC-I, our findings suggest that additional factors are required to further invigorate infiltrating NK cells and to trigger a NK cell-mediated anti-tumor response. We are currently evaluating new approaches targeting NK cells and regulatory T cells on B2m-deficient tumors. This pre-clinical model could enable the development of a therapeutic strategy serving to improve the treatment of tumors lacking antigen presentation.
Citation Format: Cecile Gstalder, Priya Pancholi, Dorota Sadowicz, Rizwan Haq. Loss of MHC-I expression is associated with altered immune microenvironment and decreased response to PD-1 checkpoint inhibition [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 1698.
Abstract 170: Targeting colorectal cancer stem cells with the anticancer molecule thymoquinone
Authors: Ballout Farah R. , Fatfat Maamoun , Abdel-Samad Rana , Darwiche Nadine , Schneider-Stock Regine , Abou-Kheir Wassim , Muhtasib Hala-Gali 
Published: August 2018

Abstract
Introduction: 5-fluorouracil (5-Fu) remains the standard chemotherapy for metastatic colorectal cancer (CRC), but drug resistance and unpredictable cardiotoxicity limit its effectiveness. The high recurrence rates and the common resistance are thought to be due to a population of self-renewing cancer stem cells (CSCs). The black seed extract Thymoquinone (TQ) is a promising anticancer molecule known to inhibit cancer cell growth and progression in numerous cancer systems both in vitro and in vivo. This project aims to investigate the effect and mechanism of action of TQ on colon cancer stem/progenitor cells using two isogenic HCT116 colon cancer cell lines that differ in their 5-Fu drug sensitivity.
Methods: Sphere-formation and propagation assays were used to assess the efficacy of TQ on targeting self-renewal capacity of colon CSCs enriched from the sensitive and resistant cell lines in 3D cultures over several generations in comparison to 2D monolayers. In addition, xenotransplantation experiments were used to assess for the tumor initiation of 2D vs. 3D cells.
Results: Our results of TQ efficacy in 2D cell culture system showed that it reduced the viability of both cell lines. Importantly, our 3D results showed that TQ inhibits HCT116 colonosphere growth at 10-fold lower concentrations than those required to inhibit the growth of 2D monolayer cells. Interestingly, the injection of 100 spheres derived from HCT116 sensitive cell line and not the 2D equivalent cell density into NOD-SCID immunocompromised mice resulted in tumor development, suggesting that spheres are rich in cells with stem-like properties.
Conclusion: In summary, our data suggests that TQ might be an effective treatment strategy and may prevent colorectal cancer recurrence by targeting CSCs.
Citation Format: Farah R. Ballout, Maamoun Fatfat, Rana Abdel-Samad, Nadine Darwiche, Regine Schneider-Stock, Wassim Abou-Kheir, Hala-Gali Muhtasib. Targeting colorectal cancer stem cells with the anticancer molecule thymoquinone [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 170.
Abstract 1708: Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer
Authors: Chua Corrine Ying Xuan , Jain Priya , Folci Marco , Ballerini Andrea , Rhudy Jessica , Gilbert April , Shaibala Shail , Bruno Giacomo , Filgueira Carly S. , Yee Cassian , Butler E. Brian , Grattoni Alessandro 
Published: August 2018

Abstract
Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit robust anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic drug-eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of intratumoral drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for repeated injections or clinician intervention. In this study, the NDES was utilized to deliver immunotherapeutics intratumorally in the 4T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES-mediated intratumoral release of agonist immunotherapeutic monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti-tumor immune response and significant inhibition of tumor growth compared to control mice. Further, mice treated with NDES-CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors.
Citation Format: Corrine Ying Xuan Chua, Priya Jain, Marco Folci, Andrea Ballerini, Jessica Rhudy, April Gilbert, Shail Shaibala, Giacomo Bruno, Carly S. Filgueira, Cassian Yee, E. Brian Butler, Alessandro Grattoni. Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative 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 1708.
Abstract 1712: Assessing tumor mutation load using an NGS-based, routine-friendly target gene panel
Authors: Costa Jose , Reis Joana , Fernandes Margarida , Silva Rafaela , Cirnes Luis , Chaudhary Ruchi , Carneiro Fatima , Machado Jose C. 
Published: August 2018

Abstract
In several cancer models, it was shown that tumor mutation load correlates with response to immune checkpoint blockade therapy. However, whole exome sequencing of FFPE samples is not ideal for implementation on molecular pathology laboratories. In colorectal cancer (CRC), mutation load is correlated with microsatellite instability (MSI), which can therefore be used as surrogate marker for mutation load. In this study, we aimed at determining whether a target NGS-based mutation panel can be used for routine testing of mutation load in cancer, by assessing its performance in identifying MSI+ and MSI- CRC samples. The Oncomine Tumor Mutation Load Assay, which targets 409 genes corresponding to 1.7Mb of sequencing data, was used. It is a two-pool panel, optimized for FFPE samples, and only requires 20 ng of DNA in total. A cohort of 16 CRC samples was used. These included six cases MSI+, known to present a hypermutable phenotype caused by the loss of DNA mismatch repair activity, and 10 MSI- samples, which typically have a lower rate of somatic mutation. DNA was isolated from 10 uM slide cuts using the MagMAX FFPE DNA/RNA Ultra Kit. A multiplex of eight samples per 540 sequencing chip was sequenced using an Ion S5 XL system. In our data set, we observed an average of 67.2 mutations per Mb for the MSI+ samples and an average of 29.7 mutations per Mb for the MSI- samples (p=0.004). Using a cut-off of 40.0 mutations per Mb, we were able to classify correctly every sample as MSI+ or MSI-. Interestingly, we observed a tri-modal distribution of the samples, suggesting there might be a sub-group of MSI+ CRC cases that show a level of mutation load comparable to that of MSI- CRC cases. It remains to be seen whether these MSI+, low mutation load CRC cases are non-responders to treatment with immunotherapy. A validation cohort of CRC cases is currently being analyzed to validate our findings. In this study, we demonstrate it is viable to use a target and routine-amenable NGS-based sequencing gene panel to identify CRC samples with different levels of mutation load. It remains to be seen whether mutation load is a better predictor of response to immunotherapy than MSI status in CRC. This approach also needs to be validated in different tumor types.
Citation Format: Jose Costa, Joana Reis, Margarida Fernandes, Rafaela Silva, Luis Cirnes, Ruchi Chaudhary, Fatima Carneiro, Jose C. Machado. Assessing tumor mutation load using an NGS-based, routine-friendly target gene panel [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 1712.