bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3437: Genomic alterations, mutation burden, and microsatellite instability status of Chinese intrahepatic cholangiocarcinoma
Authors: Cao Jingyu , Jiang Bo , Liu Zimin , Shu Weibin , Li Lei , Yang Han , Li Hua , Xiao Zhiyu , Yan Maolin , Lin Jie , Liu Siqin , Zhang Peng , Javle Milind , Yao Ming , Wang Kai , Zhao Haitao 
Published: August 2018

Abstract
Background: Intrahepatic cholangiocarcinoma (ICC) is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis. Targeted and immune-therapy have yielded promising therapeutic effects in various solid tumor patients (pts). Thus the understanding of ICC genomic profiling, especially which of Chinese pts, seems to be necessary for the treatment strategy for ICC.
Methods: Comprehensive genomic profiling of molecular alterations and predictive biomarkers to personalized treatment genes were performed on Formalin Fixed Paraffin Embedded (FFPE) samples and matched blood samples of 69 Chinese ICC pts. Genomic alterations (GAs) including substitutions, short and long insertion/deletions (indels), copy number variations and gene rearrangements were assessed. Tumor mutation burden (TMB) of total somatic substitutions and indels per megabase after filtering known driver mutations was calculated. Microsatellite instability (MSI) status was determined by identifying and scoring multiple mono-nucleotide repeats loci.
Results: Median age of the 69 ICC pts was 58 years (range: 38-88), and male vs female was approximately 3:1. Average of 3.7 GAs /sample and 0.9 actionable GAs/sample were detected. The most widespread genomic alterations among the pts were revealed as TP53 (44.9%), ARIDIA (23.2%), KRAS (18.8%), BAP1 (14.5%), IDH1/2 (14.5%), PIK3CA (11.6%), FGFR2/3 (10.1%), MLC1 (8.7%), CDKN2A/B (8.7%), BRAF (7.2%), TERT (7.2%), PBRM1 (7.2%). The actionable mutations of the PI3K/mTOR pathway were found in 18.8% of the pts. In total, pts with one or more actionable GAs were 62.3%. Pts presented MSI-high were 7.2% of the total. Proportion was 10.1% for the pts with TMB value higher than 20 mut/Mb, and 32.8% for those higher than 10 mut/Mb. The TMB range of the 69 pts was 1.1 to 58.4 mut/Mb, and median was 7.4 mut/Mb.
Conclusions: In our study, 62.3% of Chinese ICC pts were detected to have actionable GAs which could potentially guide and influence their personalized treatments. The identification of more frequent high TMB level than the published western populations indicated that Chinese ICC pts may more likely derive therapeutic benefits from immune checkpoint inhibitors.
Citation Format: Jingyu Cao, Bo Jiang, Zimin Liu, Weibin Shu, Lei Li, Han Yang, Hua Li, Zhiyu Xiao, Maolin Yan, Jie Lin, Siqin Liu, Peng Zhang, Milind Javle, Ming Yao, Kai Wang, Haitao Zhao. Genomic alterations, mutation burden, and microsatellite instability status of Chinese intrahepatic cholangiocarcinoma [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 3437.
Abstract 3490: Mechanism of action for antioxidant Twendee X on hepatic cancer cell line HepG2
Authors: Inufusa Haruhiko 
Published: August 2018

Abstract
[Purposes of the study] Reactive oxygen species (ROS) are associated with clinical condition of cancer patient, and closely involved in cancer growth and metastasis. Twendee X (TWX) is a composition consisting of Vitamin C, Glutamine, Cystine, Riboflavin, Succinic acid, Fumaric acid, Coenzyme Q10, and Niacin. TWX strongly reduces oxygen radicals or ROS in vitro and in vivo (World Intellectual Property Organization WO2013/072441 A1 COMPOSITION FOR PROTECTION AGAINST CELL-DAMAGING EFFECTS). TWX has significant effects of reducing tumor growth and inhibition metastasis. Hydrogen peroxide level (d-ROMs test) of tumor bearing nude mouse in serum was significantly reduced and increased NK-activity (2016 AACR meeting). Mechanism of action was examined for TWX using hepatic cancer cell line HepG2.
[Experimental procedures] Human hepatic cancer cell line HepG2 was used in this study. Cell proliferation experiments of antioxidant by ICDD (France). Metabolome analysis was by Human Metabolome Technologies (Tokyo). In both experiments, HepG2 cell line treated one hour with TWX (60ug/ml). [Data] TWX inhibits the RAF-MEK-ERK pathway starting from ERK. Metabolome analysis shows total shift of metabolism, and especially increase mitochondrial metabolism and ATP production. [Conclusion] Effects of TWX on cancer cell line are not only increase immune activity, but also inhibit proliferation pathway, and mitochondrial metabolism change. Several publications using Vitamin-E or Cysteine as anti-oxidant showed cancer progression or increase metastasis. However, Vitamin-E or Cysteine has limited anti-oxidant effects and hydrogen peroxide level (d-ROMS test) dose not change. On the other hand, TWX has significant effects reduce hydrogen peroxide level, and Japanese Association for Dementia Prevention already started clinical trial for MCI and after stroke patients. For the cancer patients, clinical trial using TWX combination with standard therapy will be start soon.
Citation Format: Haruhiko Inufusa. Mechanism of action for antioxidant Twendee X on hepatic cancer cell line HepG2 [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 3490.
Abstract 3514: Differential metabolic targeting of PDAC cells with Zaprinast
Authors: Rao Yi , Gammon Seth , Piwnica-Worms David 
Published: August 2018

Abstract
Many pancreatic cancers consume excessive glutamine as a preferable source for anaplerosis, maintenance of proper redox state, and synthesis of intermediates for cancer cell growth and proliferation. Abrogating glutamine metabolism is under investigation to inhibit the proliferation/ growth of glutamine-addicted cancers. In addition, inhibition of the mitochondrial pyruvate carrier (MPC1) can potentially induce cancer cells to become more dependent on glutaminolysis. In this regard, Zaprinast, originally developed as a phosphodiesterase 5 (PDE5) inhibitor, has recently been identified as an inhibitor of both glutaminase as well as MPC1. We compared the growth inhibition effect of Zaprinast against BPTES, a targeted glutaminase inhibitor, and UK5099, a targeted MPC1 inhibitor, as well as the combination of BPTES and UK5099. Using pancreatic ductal adenocarcinoma (PDAC) cells, KRAS mutant (Mia Paca2) and KRAS wildtype (Panc03.27), KRAS mutant neuroendocrine (QGP1), and normal pancreatic epithelial cells (HPNE), Zaprinast alone showed more potent growth inhibition in all tested cells lines than single agent treatment with BPTES or UK5099. Further, Zaprinast effectively depleted mitochondrial reserve respiratory capacity similar to UK5099, rendering mitochondria more vulnerable to oxidative stress or pharmacological inhibitors targeting the electron transport chain. In addition, Zaprinast treatment of cancer cells differentially elevated ROS levels greater than 10-fold compared to normal HPNE cells (ROS levels: Mia Paca2 ~ Panc03.27 &gt; QGP1 &gt; HPNE). However, the increase in ROS levels did not correlate with Zaprinast-induced growth inhibition (IC50: Mia Paca2=300 µM, Panc03.27=110 µM, HPNE=650 µM, QGP1 &gt;1 mM). Although Zaprinast-induced growth inhibition was selective toward adenocarcinoma cells but not the neuroendocrine subtype, the selective Zaprinast-induced elevation of ROS levels toward all cancer subtypes renders possibilities for potential synthetic lethality when combined with other metabolic inhibitors.
Citation Format: Yi Rao, Seth Gammon, David Piwnica-Worms. Differential metabolic targeting of PDAC cells with Zaprinast [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 3514.
Abstract 382: Inhibition of mitochondrial spare respiratory capacity by new securinine derivatives as a novel differentiation therapy for acute myeloid leukemia
Authors: Karunanithi Sheela , Liu Ruifu , Roe Anne , Moreton Stephen , Hou Yongchun , Oldford Natasha , Goyco Juan Valentin , Wald David 
Published: August 2018

Abstract
Acute myeloid leukemia (AML) is characterized by a differentiation block in myeloid progenitors resulting in aberrant proliferation of immature myeloid cells. Therapeutics that induce differentiation of leukemic cells would overcome the high toxicity and low potency of conventional chemotherapy. Securinine, a plant-derived alkaloid from Securinega suffruticosa, has been shown to be a promising AML differentiation agent through an unclear mechanism, but is limited by its low potency (~20μM) and toxicity. We performed lead optimization chemistry on securinine that led to derivatives 250 and 317, with nanomolar efficacy and reduced toxicity. These derivatives effectively inhibit growth of AML cell lines and patient samples. Treatment of AML cell lines with compounds 250 and 317 induces the expression of differentiation markers CD11b and CD14c. Compounds 250 and 317 significantly reduced leukemic burden in a circulating model of AML in NSG mice. Additionally, these compounds were effective in inhibiting cell growth of HL60 cells that are resistant to a conventional chemotherapeutic, doxorubicin. By using the drug-affinity responsive target sensitivity (DARTS) assay, we identified that the redox mediator thioredoxin reductase (TrxR) is the primary target of these derivatives. 250 and 317 inhibit TrxR activity in vitro and in cells, and the resultant alterations in redox status are overcome by addition of a scavenger of reactive oxygen species (ROS), N-acetylcysteine. The ensuing oxidative metabolic stress rapidly alters the metabolite profile in AML cells including depletion of malate. Securinine derivatives decreased basal oxygen consumption rate and spare respiratory capacity, resulting in differentiation and cell death. Downregulating TrxR1 expression increased the sensitivity of OCI-AML3 cells to compounds 250 and 317. Together, we show here that these new derivatives of securinine exhibit preclinical efficacy in AML by decreasing mitochondrial spare respiratory capacity through the inhibition of TrxR.
Citation Format: Sheela Karunanithi, Ruifu Liu, Anne Roe, Stephen Moreton, Yongchun Hou, Natasha Oldford, Juan Valentin Goyco, David Wald. Inhibition of mitochondrial spare respiratory capacity by new securinine derivatives as a novel differentiation therapy for acute myeloid leukemia [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 382.
Abstract 3833: SEA-BCMA: A highly active enhanced antibody for multiple myeloma
Authors: Epps Heather Van , Anderson Martha , Yu Changpu , Klussman Kerry , Westendorf Lori , Carosino Chris , Manlove Luke , Cochran Julia , Neale Jason , Benjamin Dennis , Ryan Maureen 
Published: August 2018

Abstract
Despite a number of new therapies for multiple myeloma (MM) most patients relapse, require multiple lines of therapy, and ultimately succumb to disease. Therapies that are well tolerated and active remain an unmet need. Currently, successful MM therapies combine agents with different mechanisms of action and safety profiles. Therapeutic antibodies have recently altered the MM treatment paradigm, allowing patients to achieve deeper responses with minimal added toxicity. SEA-BCMA is a humanized afucosylated IgG1 antibody targeting BCMA, which shows preclinical evidence of encouraging activity and tolerability. BCMA is expressed at the surface of plasma cells, and induces proliferative signals through the binding of its ligands APRIL and BAFF. SEA-BCMA acts through three mechanisms of action. One, it engages in increased binding to FcγRIII through SEA technology leading to enhanced antibody dependent cellular cytotoxicity. Two, it mediates antibody dependent cellular phagocytosis. Three, it blocks the proliferative signals from BCMA ligand binding. This antibody shows activity in all seven tumor xenograft models tested, inducing tumor delays at doses as low as 0.1mg/kg, and generating prolonged survival and durable regressions with repeat dosing. SEA-BCMA is active on tumor xenografts expressing as few as 2000 surface copies of BCMA antigen. Both effector function and ligand blocking contribute to overall in vivo activity. In the absence of effector cell recruitment, ligand blocking alone can induce prolonged durable regressions. In addition, SEA-BCMA can target MM cells in the presence of soluble BCMA. SEA-BCMA is tolerated up to 100mg/kg in cynomolgus monkey, reflecting lack of toxicity from cellular interactions with the Fc portion of the Ab, since SEA-BCMA does not bind to the cynomolgus monkey antigen. SEA-BCMA displays a 12-day half-life in these animals. In vitro testing with human PBMCs or bone marrow mononuclear cells induced minimal cytokine production in the presence of BCMA target. In summary, SEA-BCMA is highly active and well tolerated in preclinical models and is a strong candidate for treatment of MM patients.
Citation Format: Heather Van Epps, Martha Anderson, Changpu Yu, Kerry Klussman, Lori Westendorf, Chris Carosino, Luke Manlove, Julia Cochran, Jason Neale, Dennis Benjamin, Maureen Ryan. SEA-BCMA: A highly active enhanced antibody for multiple myeloma [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 3833.
Abstract 3946: Androgen receptor drives differential gene expression in KRAS-mediated non-small cell lung cancer
Authors: Wang Albert Roy , Beyer Hope , Brennan Sean , Stiles Shannon , Wiese Dylan , Buehler Darya , Saeed Anwaar , Baschnagel Andrew M. , Iyer Gopal 
Published: August 2018

Abstract
The Cancer Genome Atlas (TCGA) has identified alterations such as amplification, deletion, or mutation of androgen receptor (AR) in about 5% of human lung squamous cell carcinoma and adenocarcinoma. The expression of AR in human lung appears to play a crucial role in lung development and type II pneumocytes (PTII) maturation, but unlike in prostate cancer, the role of AR is not well known in non-small cell lung cancer (NSCLC). In our study, we demonstrated AR in NSCLC cell lines translocated into the nucleus over time when stimulated with synthetic androgen R1881, while addition of enzalutamide (MDV3100) or AR siRNA reduced AR nuclear localization. Using an NSCLC human tissue microarray also revealed that 10 out of 88 patients (11%) have positive AR immunohistochemical staining. Preliminary data from clonogenic assay indicated that enzalutamide might have radiosensitizing effect on certain NSCLC cells at 2 Gy, further suggesting the involvement of AR in lung cancer and its potential therapeutic value as a target. With the induction of R1881 for 30 minutes to 24 hours, certain NSCLC cells display decreased AR mRNA (0.5-0.8 fold), while others show modest increase (up to 1.5 fold), suggesting that AR regulation in these cells might be different due to their mutational landscapes. We then used predesigned 384 well panels from Bio-Rad to survey the effects of R1881, enzalutamide, and AR siRNA on mRNA expression levels of selected NSCLC cells. Distinct expression profiles were observed between cells that have wild-type and mutated KRAS. Taken together, these findings suggest that the AR signaling could be different based on KRAS mutational profiles of NSCLCs, and further work is required to reveal the underlying mechanism. Chromatin immunoprecipitation (ChIP) assay and RNA sequencing will be utilized to investigate AR interactions with androgen response elements and differential expressions in KRAS-driven NSCLC cells, respectively.
Citation Format: Albert Roy Wang, Hope Beyer, Sean Brennan, Shannon Stiles, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer. Androgen receptor drives differential gene expression in KRAS-mediated non-small cell lung 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 3946.
Abstract 3967: Potent treatment combinations with CIB1 depletion in triple-negative breast cancer
Authors: Chung Alexander H. , Leisner Tina M. , Dardis Gabrielle , Bivins Marissa , Parise Leslie V. 
Published: August 2018

Abstract
The current standard of care for triple-negative breast cancer (TNBC) patients is limited to chemotherapy, radiation, and/or surgery. Therefore, there is a pressing need for new targeted therapies to improve clinical efficacy, reduce toxicity, and overcome resistance. We previously found that CIB1 depletion induces cell death selectively in TNBC cells, while sparing normal cells. The purpose of this study was to ask whether depleting CIB1 further enhances tumor-specific killing when combined with either the commonly used chemotherapeutic, docetaxel, or the cell death-inducing ligand, TRAIL. To address this, we targeted CIB1 by RNA interference in MDA-MB-436, MDA-MB-231, MDA-MB-468 TNBC cells and ME16C normal breast epithelial cells alone or combination with docetaxel or TRAIL. Cell death was quantified via trypan blue exclusion using FACS and cell death mechanisms were analyzed by Western blotting. We found that the combination of CIB1 depletion with docetaxel significantly enhanced tumor-specific cell death relative to each treatment alone. The enhanced cell death strongly correlated with caspase-8 activation, a hallmark of death receptor-mediated apoptosis. Because CIB1 depletion also upregulated the death receptor, TRAIL-R2, we tested for sensitization to TRAIL. While TRAIL alone had no effect on cell viability, CIB1 depletion profoundly sensitized tumor cells to TRAIL, resulting in a synergistic increase in cell death. In addition to death receptor-mediated apoptosis, both combination treatments activated a non-apoptotic mechanism, called paraptosis. Interestingly, these combination treatments also induced nearly complete death of docetaxel-resistant MDA-MB-436 cells, again via apoptosis and paraptosis. In contrast, neither combination treatment induced cell death in normal ME16C cells. In conclusion, our results demonstrate that the novel combinations of CIB1 depletion with docetaxel or TRAIL significantly enhance naive and docetaxel-resistant TNBC cell death via increased death receptor-mediated apoptosis and paraptosis, suggesting that targeting CIB1 may also overcome resistance to chemotherapeutics. Taken together, combination therapies that target CIB1 could prove to be a safe and durable strategy for treatment of TNBC and potentially other cancers.
Citation Format: Alexander H. Chung, Tina M. Leisner, Gabrielle Dardis, Marissa Bivins, Leslie V. Parise. Potent treatment combinations with CIB1 depletion 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 3967.
Abstract 4068: Galectin-1 intensifies immunosuppression in head and neck cancer by boosting myeloid-derived suppressive cell (MDSC) expansion
Authors: Nambiar Dhanya K. , Aguilera Todd A. , Bloomstein Joshua Daniel , Jiang Dadi , Cao Hongbin , Koong Albert , Le Quynh Thu 
Published: August 2018

Abstract
Head and neck squamous cell carcinoma (HNSCC), with more than 450,000 newly diagnosed cases annually, is the 6th most common cancer worldwide. Recent literature shows that tumor induced suppression of the host immune system is critical to HNSCC progression and metastases. Tumor secreted factors directly influence the expansion of myeloid-derived suppressor cells (MDSCs), which are considered important contributors for tumor to escape from immune surveillance. The presence of expanded MDSCs peripherally and within the tumor microenvironment is associated with metastasis and recurrence after definitive treatment in HNSCC patients. In this study, we evaluated at the role of tumor secreted Galectin-1 in recruitment of MDSCs in HNSCC. We utilized HPV-negative as well as HPV-positive HNSCC models to test the effect of Galectin-1 knockout (KO) in the tumor microenvironment. CRISPR/Cas9 knock out Galectin-1 in MOC2 and MEERL models resulted in a ~50% reduction in the tumor growth. We further analyzed the tumor microenvironment of these tumors for MDSC recruitment. Both MOC2 and MEERL tumors showed highly inflammatory phenotype, with significant presence of MDSCs (&gt;70% of CD45+ cells were of myeloid origin). Knocking out Galectin-1 led to a significant decrease in CD11b+Gr1+ MDSCs in both MOC2 and MEERL tumors. We also observed high level of MDSCs in both the spleen and the peripheral blood of mice bearing Galectin-1 wildtype (WT) tumors in both models. In contrast, knocking out Galectin-1 from the tumor reduced systemic MDSCs levels. To investigate how Galectin-1 modulates MDSC levels, we compared the secreted cytokine profiles between MOC2 WT and Galectin-1 KO tumors. Galectin-1 null cells secreted significantly lower levels of monocyte and macrophage recruiting chemokines: CCL5, CXCL1, and G-CSF. Analysis of the gene expression signatures of MOC-2 WT and KO tumor cells revealed critical signaling pathways differences, including down-regulation of PI3K-AKT pathway in KO-tumors. In conclusion, the present study reveals that tumor derived Galectin-1 can stimulate the recruitment of MDSCs, thereby potentiating an inflammatory tumor microenvironment which supports HNSCC progression. (Acknowledgements: BMS for Anti-Gal1 Abs. Dr R. Uppaluri, for MOC-2 oral cancer cells, Dr. W. Spanos for MEERL cells)
Citation Format: Dhanya K. Nambiar, Todd A. Aguilera, Joshua Daniel Bloomstein, Dadi Jiang, Hongbin Cao, Albert Koong, Quynh Thu Le. Galectin-1 intensifies immunosuppression in head and neck cancer by boosting myeloid-derived suppressive cell (MDSC) expansion [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 4068.