bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 846: Co-targeting of Axl and MerTK improves radiation response in HNSCC
Authors: Abbariki Mahyar , Toulany Mahmoud , Iida Mari , Morgan Alecia , Nickel Kwang , McDaniel Nellie , Kang Grace , Li Chunrong , Harari Paul , Wheeler Deric 
Published: August 2018

Abstract
Axl and MerTK are members of the TAM family (Tyro, Axl and MerTK) of receptor tyrosine kinases and have been reported to be altered in several types of cancer including Head and Neck Squamous Carcinoma (HNSCC). It is well known that aberrant expression or activity of Axl is associated with resistance to various therapies. Therefore, the translational potential of targeting AXL in HNSCC is worthy, however poorly defined. We recently identified an adaptive feedback mechanism of resistance to AXL-targeting agents mediated by upregulation of MerTK that reveals a direct role for MerTK in resistance to Axl inhibition. In this study, we investigated potential radiosensitization by dual targeting of Axl and MerTK in combination with radiation in human HNSCC cell lines and xenografts (SCC47 and TU138). Immunoblot analysis demonstrated that endogenous levels of Axl or MerTK expression were distinct between these two cell lines. SCC47 cells expressed higher endogenous levels of Axl compared to Tu138. Tu138 expressed higher levels of MerTK compared to SCC47 cells. Radiation induced Axl phosphorylation in SCC47 cells but not in Tu138 cells in vitro. Next, inhibitors of Axl (R428) and/or MerTK (UNC2025) were utilized in combination with single dose radiation in vitro. Clonogenic assays showed that the Axl inhibitor alone acted as a potent radiosensitizer in SCC47 cells. To better define Axl's role in radiation response in HNSCC, we developed HN30-Vector and HN30-Axl stable cells and exposed them to radiation. Phosphorylation of Axl was increased 1 hour post-radiation in Axl overexpressed HN30 compared to parental HN30-Vector which expresses low endogenous levels of Axl. We also found that the HN30-Axl cell line was associated with radioresistance by clonogenic assays. Tumor xenograft studies demonstrated that the combination of R428 and UNC2025 inhibitors improved the efficacy of radiation in Tu138 but not in SCC47. Interestingly, radiation therapy alone was more effective in SCC47 tumors than TU138 tumors. These results reveal that the co-targeting of Axl and MerTK enhanced tumor growth delay in TU138 xenograft mouse models in vivo. Mechanisms of radiosensitization are currently under investigation.
Citation Format: Mahyar Abbariki, Mahmoud Toulany, Mari Iida, Alecia Morgan, Kwang Nickel, Nellie McDaniel, Grace Kang, Chunrong Li, Paul Harari, Deric Wheeler. Co-targeting of Axl and MerTK improves radiation response in HNSCC [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 846.
Abstract 847: Optimization of radiation regimen in a carcinogen-induced mouse model for lung cancer
Authors: Bhayana Sagar , Liu Joseph , Chakravarti Arnab , Jacob Naduparambil K. 
Published: August 2018

Abstract
Purpose: Lung cancer remains the most common cause of cancer-related mortality in United States and worldwide. The major cause of lung cancer is attributed to carcinogens present in tobacco smoke, air pollution, diet and food supplements, occupational and other environmental exposures. Lung Cancer Mutation Consortium has identified many recognized “driver mutations” in nearly two-thirds of the patients who developed advanced form of lung cancer. Our primary goal is to understand the mechanism underlying the variations in radiation sensitivity with driver mutations and optimize radiation dose and treatment regimen. A better understanding of the most frequent driving mutations is required for progression towards personalized therapy. Methods: Urethane, a carcinogen injected via intraperitoneal route into A/J mice induced multiple lung tumors by week 25 that resembled non-small cell lung carcinoma. These lung tumors were assessed via MRI and each tumor was longitudinally tracked via surface rendered 3D imaging following X-ray exposure using small animal radiation research platform (SARRP). We employed acute high single dose (12 Gy) and clinically relevant fractionated dose (3 X 5 Gy). Individual lung tumor was also dissected from non-irradiated and irradiated mice followed by collagenase digestion and then cultured in a specific media for in-vitro mutational analysis. Results: Urethane induced multiple lung tumors (20-25 tumors with 1mg/kg urethane) of varying size (0.5 - 2mm) were detectable by MRI at 25 week following injection. Longitudinal MRI performed on irradiated tumor bearing mice showed significant regression after radiation with commitment survival benefit. Mice performed better when exposed to fractionated regimen than high single dose with relatively low level radiation toxicity. Primary lung cancer cells were prepared from the explanted tumors for prospectively examining relevant driver mutations and studying the genetic determinants of resistance and to identify novel targets. We also have collected body fluids for investigating changes in molecular profile of exosomes at time points after irradiation. Conclusions: Our study thus far set up a platform for longitudinal 3D tracking of individual lung tumors following treatment and recurrence. Tumor regression was evident after a week of radiation exposure. Primary lung tumor cell cultures were successfully established for molecular analysis and mechanistic studies
Citation Format: Sagar Bhayana, Joseph Liu, Arnab Chakravarti, Naduparambil K. Jacob. Optimization of radiation regimen in a carcinogen-induced mouse model for 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 847.
Abstract 865: Small molecule-mediated modulation of Ras elicits inhibition of phospho ERK signaling through negative feedback on SOS1
Authors: Howes Jennifer E. , Akan Denis T. , Burns Michael C. , Sun Qi , Little Andrew J. , Camper DeMarco V. , Abbott Jason R. , Phan Jason , Lee Taekyu , Rossanese Olivia W. , Waterson Alex G. , Fesik Stephen W. 
Published: August 2018

Abstract
Oncogenic mutation of Ras is responsible for more than 30% of all human tumors. Therefore, pharmacological modulation of Ras has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on Ras and paradoxically inhibit downstream signaling. Here we describe how pharmacologically targeting SOS1 induces biphasic modulation of Ras-GTP and downstream ERK levels. We consistently observed this phenotype in a variety of cell lines expressing different Ras mutant isoforms, and using multiple chemotypes of compound. In elucidating the molecular mechanism, we observed that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant, or after pre-treatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of a S1178A SOS1 mutant. Pre-treatment with an ERK inhibitor prevented compound-induced inhibition of the association between SOS1 and GRB2. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated Ras-GTP levels over time in response to compound, as compared to the biphasic changes in Ras-GTP exhibited in cells expressing wild-type SOS1. These results show that small molecule agonists of SOS1 cause paradoxical inhibition of Ras-GTP and MAPK signaling in Ras mutant cancer cells, through negative feedback on SOS1. Overall, these compounds provide us with the unique opportunity to better understand the biological functions of SOS and Ras in cancer cells, and may aid in the discovery of small molecules to treat Ras-driven tumors.
Citation Format: Jennifer E. Howes, Denis T. Akan, Michael C. Burns, Qi Sun, Andrew J. Little, DeMarco V. Camper, Jason R. Abbott, Jason Phan, Taekyu Lee, Olivia W. Rossanese, Alex G. Waterson, Stephen W. Fesik. Small molecule-mediated modulation of Ras elicits inhibition of phospho ERK signaling through negative feedback on SOS1 [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 865.
Abstract 867: Blocking breast cancer metastasis by targeting HuR-FOXQ1 signaling axis
Authors: Wu Xiaoqing , Gardashova Gulhumay , Lan Lan , Zhan Yu , Liu Jiajun , Dixon Dan A. , Aubé Jeffrey , Welch Danny R. , Xu Liang 
Published: August 2018

Abstract
As most of treatment options do not work very well for metastatic cancer. Patients with metastatic cancer have a greatly lower survival rate compared with patients with local cancer. Metastasis remains a life-threat to cancer patients and an unmet medical need. The RBP Hu antigen R (HuR) is overexpressed in virtually all malignancies tested, including breast cancer. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by promoting mRNA stability and translation of proteins implicated in proliferation, survival, angiogenesis, invasion, and metastasis. We found that silencing of HuR inhibited cell invasion in vitro in breast cancer. Using RIP-seq (ribonucleoprotein immunoprecipitation-sequencing), a transcription factor FOXQ1, which is recently revealed to implicate in breast cancer invasion and metastasis processes, is found to be a direct HuR target. Furthermore, exogenous introduction of FOXQ1 can rescue cell invasive ability inhibited by HuR knockout. Taken together, HuR-FOXQ1 signaling axis is a potential target for blocking breast cancer metastasis. RNA-binding proteins had previously been considered “undruggable” due to lack of a well-defined binding pocket for target RNAs. Using high throughput screening followed by structure-based rational design and lead optimization, we have identified small molecules that inhibit HuR-mRNA interaction at nM to sub-µM potency. Our lead compound, KH-3, potently inhibits breast cancer cell growth and decreases cell invasion in vitro similar to HuR knockout, as well as increasing the expression of epithelial marker E-cadherin. FOXQ1 overexpression abolishes the effect of KH-3 on blocking metastasis in breast cancer cells, demonstrating that the HuR inhibitor KH-3 inhibits cell metastasis by blocking FOXQ1 function. Moreover, KH-3 treatment disrupts HuR-FOXQ1 interaction in RNP-IP and FOXQ1 3′-UTR luciferase reporter assays. In vivo efficacy studies show that KH-3 not only exhibits potent antitumor efficacy in orthotopic xenograft models of breast cancer, but also efficiently blocks lung metastasis in experimental metastatic cancer model. In conclusion, we identified a potent and specific small molecule disrupter of HuR-FOXQ1 interaction for potential novel anti-metastatic therapy of breast cancer with HuR overexpression.
Citation Format: Xiaoqing Wu, Gulhumay Gardashova, Lan Lan, Yu Zhan, Jiajun Liu, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu. Blocking breast cancer metastasis by targeting HuR-FOXQ1 signaling axis [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 867.
Abstract 872: IDH1-mutated cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity
Authors: Khurshed Mohammed , Molenaar Remco J. , Wilmink Johanna W. , Laarhoven Hanneke W. van , Noorden Cornelis J. van 
Published: August 2018

Abstract
Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer and predicts improved response to treatment with irradiation or chemotherapy. Mutated IDH1 enzymes catalyze neomorphic conversion of α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG) with concomitant consumption of NADPH, resulting in decreased reducing power needed for detoxification of e.g. reactive oxygen species (ROS). We report that a small-molecule inhibitor of IDH1-mutation (IDH1MUT) that is being investigated for cancer therapy may limit efficacy of treatment when co-administered with cisplatin.
In the present study, we investigated whether the efficacy of treatment with cisplatin, which is a widely-used chemotherapeutic agent, induces DNA strand breaks and oxidative damage in IDH1MUT cancer cells. We found that exposure to cisplatin induced higher levels of ROS, DNA double-strand breaks, and cell death in IDH1MUT cancer cells as compared to IDH1 wild-type (IDH1WT) cancer cells. Besides these cytotoxic effects, mechanistic investigations revealed that cisplatin treatment causes dose-dependent reduction of oxygen consumption and thus the oxidative respiration in lDH1MUT cells and not in lDH1WT cells, which was accompanied by disturbed mitochondrial proteostasis and impaired mitochondrial activity. These effects were abolished by the IDH1MUT inhibitor AGI-5198 and were recapitulated by treatment with D-2HG. Thus, our study shows that altered oxidative stress responses due to a vulnerable oxidative metabolism underlie the sensitivity of IDH1MUT cancer cells to cisplatin. Furthermore, our data offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and imply that administration of IDH1MUT inhibitors in these patients limit efficacy of cisplatin treatment.
Citation Format: Mohammed Khurshed, Remco J. Molenaar, Johanna W. Wilmink, Hanneke W. van Laarhoven, Cornelis J. van Noorden. IDH1-mutated cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity [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 872.
Abstract 881: Identifying the context of vulnerability to MLN4924 in glioblastoma (GBM)
Authors: Chaudhuri Leena , Bybee Rita L. , Hartman Lauren K. , Peng Sen , Finlay Darren , Vuori Kristiina , Berens Michael E. , Dhruv Harshil D. 
Published: August 2018

Abstract
Neddylation is a post-translational mechanism that marks proteins for degradation through activity of NEDD8 Activating Enzyme (NAE). NAE activates cullin-RING ligases (CRL), which ubiquitylate selected substrates and mark them for proteosomal degradation. MLN4924, or Pevonedistat, targets NAE and inhibits Neddylation and induces apoptosis in sensitive cells. To assess the preferential sensitivity of cell lines to MLN4924, we performed a 10-point drug dose response (DDR) assay on long-term established GBM cell lines. Efficacy of MLN4924 in glioma cell lines was evaluated by measuring cell viability (CellTiterGlo®) and cell cycle progression (flow cytometry with propidium iodide staining). To identify mechanism of differential response to MLN4924 treatment, cell cycle regulatory pathway and DNA damage were also examined by Western blotting. GB1 (IC50 = 0.28 μM) & LN18 (IC50 = 0.19 μM) were established as sensitive and M059K (IC50 = 5.5 μM) & SNU1105 (IC50 = 20.9 μM) as non-sensitive cell lines based on the IC50 values. Flow cytometry analysis of DNA content revealed significant arrest of cells in G2/M even at low doses of 100 nM of MLN4924 preferentially in GB1 and LN18. This was consistent with an increase in CRL substrates p21, p27 and WEE1 in GB1 and LN18 possibly contributing to the G2/M arrest. While CDT1 accumulation was observed starting at 2h post MLN4924 treatment in sensitive cell lines, it took upto 8h for CDT1 accumulation in the non-sensitive cell lines. Increases in CDT1 induced re-replication causing massive arrest in G2/M phase lead to increased DNA damage, validated by higher expression of γH2AX in the sensitive cell lines. Additionally, we also investigated the efficacy of MLN4924 against orthotopic glioma PDX models in vitro and in vivo to validate our findings. In a cohort of glioblastoma PDX models we discovered that GBM PDX models with lower Neddylation gene set enrichment score (GBM116, GBM59, SF7300) were markedly more vulnerable to MLN4924 than GBM PDX models with higher Neddylation gene set enrichment score (GBM91 and GBM102) in vitro and in vivo. Orthotopic PDX models of selected GBM revealed survival prolongation of GBM116, but minimal survival benefit to GBM102 tumors. Validation of the predictive markers of vulnerability to MLN4924 in additional PDX models will set the stage for prospective clinical trials of MLN4924 in glioblastoma patients.
Citation Format: Leena Chaudhuri, Rita L. Bybee, Lauren K. Hartman, Sen Peng, Darren Finlay, Kristiina Vuori, Michael E. Berens, Harshil D. Dhruv. Identifying the context of vulnerability to MLN4924 in glioblastoma (GBM) [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 881.
Abstract 894: Overexpression and extended degradation rate of Axl in acquired gefitinib-resistant non-small cell lung cancer cells
Authors: Kim Donghwa , Bach Duc-Hiep , Hong Ji-Young , Park Hyen Joo , Lee Sang Kook 
Published: August 2018

Abstract
Non-small cell lung cancer (NSCLC) is a major type of lung cancer which accounts for approximately 80-85% of all lung cancers. Epidermal growth factor receptor (EGFR)- targeted tyrosine kinase inhibitors (TKIs), such as gefitinib have improved the survival of NSCLC patients with activating mutations in EGFR. However, the drug responses are only transient because tumors acquire resistance via secondary mutations in EGFR (T790M) or amplification of other receptor tyrosine kinases (RTKs) including MET or AXL. Therefore, the precise mechanisms of chemoresistance and finding the novel ways of targeting cancer cells are needed to be identified. AXL, a TAM (Tyro3, AXL, Mer) family member, has been studied as a tumorigenesis, chemoresistance, and EMT marker. Also, we found that AXL is overexpressed in EGFR mutated gefitinib-resistant non-small lung cancer cells (PC9-gef) compared to its parent cells (PC9). Moreover, the AXL degradation rate was found to be suppressed. These findings suggest that the modulation of AXL turnover can be a therapeutic target to overcome gefitinib-resistance. In this study, we confirmed the possibilities of overcoming gefitinib-resistance through the down-regulation and turnover acceleration of AXL by employing yuanhadine, an anti-tumor agent derived from Daphne Genkwa. Yuanhuadine was also effectively suppressed the tumor growth in nude mouse xenograft models implanted with PC9 or PC9-gef cells. Therefore, regulation of AXL expression by modulating its degradation rate can be a therapeutic strategy to overcome acquired gefitinib-resistance in NSCLC.
Citation Format: Donghwa Kim, Duc-Hiep Bach, Ji-Young Hong, Hyen Joo Park, Sang Kook Lee. Overexpression and extended degradation rate of Axl in acquired gefitinib-resistant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 894.
Abstract 897: A novel fusion gene responsible for colon cancer drug resistance
Authors: Xie Jingwu , Gu Dongsheng , Song Ruolan 
Published: August 2018

Abstract
Colorectal cancer is a leading cause of cancer-related mortality worldwide. Patients with advanced colorectal cancer eventually succumb to the disease, despite the fact that some patients respond initially to therapies (chemotherapy and targeted therapy). Thus, identifying molecular mechanisms responsible for drug resistance will help design novel strategies to treat colorectal cancer. In this study, we identified a novel mechanism by which colorectal cancer cells acquired 5-FU resistance. Through exome sequencing, we discovered a novel fusion gene common in 5-FU-resistant colorectal cancer cells. This fusion gene, once ectopically expressed in the sensitive cancer cells, promotes drug resistance to 5-FU treatment. Further analyses have revealed a signaling network linking this fusion gene to drug resistance. Taken together, we have revealed a novel mechanism for drug resistance in colorectal cancer, which may be a novel target to overcome drug resistance in colorectal cancer.
Citation Format: Jingwu Xie, Dongsheng Gu, Ruolan Song. A novel fusion gene responsible for colon cancer drug resistance [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 897.
Abstract 910: Mechanisms of Ewing sarcoma resistance to LSD1 inhibition
Authors: Pishas Kathleen I. , Sharma Sunil , Lessnick Stephen L. 
Published: August 2018

Abstract
Given the modest efficacy of current sarcoma therapeutic modalities, there is a major unmet clinical need for the translation of novel agents to tackle the burden of Ewing sarcoma (pediatric and young adolescent bone cancer). We have recently shown that therapeutic targeting of LSD1, a highly expressed lysine specific demethylase, with the reversible small molecule inhibitor SP-2509, comprehensively disrupts the global transcriptional function of EWS-FLI, and significantly impairs the growth of Ewing sarcoma cell lines both in vitro and in vivo. Prior to clinical trial evaluation, the goal of this study was to elucidate mechanisms of Ewing sarcoma SP-2509 drug resistance.
In order to investigate SP-2509 resistance, A673 Ewing sarcoma cells were cultured in escalating concentrations of SP-2509 for 8 months. Cell Titer Glo analysis revealed that these SP-2509 drug resistant (DR) cells were 54.9 fold more resistant to SP-2509 compared to parental A673 cells (72hr IC50 0.138μM versus 7.586μM). SP-2509 DR cells also exhibited a significant decrease in their ability to form anchorage-independent colonies in soft agar. Whole exome (250X coverage) and RNA seq analysis of parental and SP-2509 DR A673 cells revealed 25 drug induced mutations, with 88% of the whole cell population harboring a Glu53* stop-gain mutation in MRPL45 (mitochondrial ribosomal protein L45). In addition, SP-2509 DR cells displayed a distinct transcriptomic profile, with 3250/2376 genes significantly up/down regulated (≥1.5 fold) in SP-2509 DR cells compared to parental controls. KEGG Pathway analysis revealed that the genes were highly enriched for hepatic stellate cell activation/interferon signaling and cholesterol biosynthesis respectively. Lastly, SP-2509 DR cells were shown to be equally sensitive to etoposide, resistant to vincristine/doxorubicin and surprisingly more sensitive to the HDAC inhibitors vorinostat and entinostat compared to parental A673 cells.
Together, our preliminary findings provide key insights into the mechanisms of SP-2509 drug resistance, information of which can be used to find combinatorial agents that can potentially be used to circumvent resistant clones to achieve maximal therapeutic effect.
Citation Format: Kathleen I. Pishas, Sunil Sharma, Stephen L. Lessnick. Mechanisms of Ewing sarcoma resistance to LSD1 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 910.