bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A119: Inhibition of IRE1-mediated pro-tumorigenic responses enhances the sensitivity of MDA-MB-231 cells to the novel arylurea-fatty acid CTU
Authors: Rahman Md Khalilur , Rawling Tristan , Al-Zubaidi Yassir , Choucair Hassan , Umashankar Bala , Chen Yongjuan , Bourget Kirsi , Tam Stanton , Smith Charlotte , Murray Michael 
Published: March 2020

Abstract
There is an unmet need for new agents with low toxicity for treatment of triple-negative breast cancer (TNBC) because current approaches are limited to toxic drug combinations of low efficacy. We recently identified an aryl-substituted fatty acid analogue, termed CTU, that effectively killed TNBC cells in vitro and in mouse xenograft models in vivo without producing toxicity (Rawling et al., 2017). However, there was a residual cell population that survived CTU. The present study evaluated the mechanism underlying residual cell survival. From RNA-seq profiling, a major regulated process in CTU-treated cells was activation of the unfolded response and endoplasmic reticulum (ER)-stress. The ER transmembrane protein inositol-requiring enzyme 1 (IRE1) is a central mediator of the unfolded response and ER-stress that was activated by CTU. IRE1 is also implicated as a pro-tumorigenic factor that can activate the expansion of tumor-initiating cells. From RNA-seq several pro-tumorigenic factors, including cyclooxygenase-2 and the cytokines IL6, IL8 and GM-CSF, were strongly activated in CTU-treated cells; this was confirmed by real-time RT-PCR and Western blot analysis. Using the non-adherent, in vitro colony-forming mammosphere assay, that enables the quantification of cell self-renewal, it was found that CTU expanded tumor-initiating cells. Co-treatment with an inhibitor of IRE1 impaired IRE1 kinase and IRE1 RNase activities, as reflected by decreases in phospho-p65 and XBP1s expression. IRE1 inhibition also prevented the activation of pro-tumorigenic factors and self-renewal by CTU. Taken together, the present findings suggest that inhibition of IRE1 may be a novel approach to optimise the activity of CTU in TNBC.
Citation Format: Md Khalilur Rahman, Tristan Rawling, Yassir Al-Zubaidi, Hassan Choucair, Bala Umashankar, Yongjuan Chen, Kirsi Bourget, Stanton Tam, Charlotte Smith, Michael Murray. Inhibition of IRE1-mediated pro-tumorigenic responses enhances the sensitivity of MDA-MB-231 cells to the novel arylurea-fatty acid CTU [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A119. doi:10.1158/1535-7163.TARG-19-A119
Abstract A135: Discovery of BGS1954, a covalent small molecule ligand of FABP5 using IMTACTM platform
Authors: Chen Hang , Ha Heather , Stanley Robert , Huang Cindy , Cai Qian , Yuan Irene , Cao Ping 
Published: March 2020

Abstract
Fatty acid-binding protein-5 (FABP5) or epidermal FABP belongs to a low molecular weight lipid binding protein family. FABP5 is involved in binding, storing, and transporting hydrophobic ligands to the proper cellar compartment. Recent studies have suggested that FABP5 play important roles in regulation of gene expression associated with with cell growth and differentiation. FABP5 expression level was closely related to malignency in several types of cancers. The functions of FABP5 in modulation of cellular signaling have been studies and suggested that FABP5 is involved in EGFR, NFkB and PPAR pathways. Using IMTACTM (Isobaric Mass Tagged Affinity Characterization) to screen small molecule library in live cancer cells, ligands covalently bound to FABP5 were identified. Our initial characterization of compounds showed that they specifically bind to FABP5 and inhibit cancer cell growth. These FABP5-specific covalent small molecule ligands will provide a valuable pharmacological tool to dissect FABP5 functions and shed light on the therapeutic potential of targeting FABP5 for the treatment of cancer and metabolic disorders.
Citation Format: Hang Chen, Heather Ha, Robert Stanley, Cindy Huang, Qian Cai, Irene Yuan, Ping Cao. Discovery of BGS1954, a covalent small molecule ligand of FABP5 using IMTACTM platform [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A135. doi:10.1158/1535-7163.TARG-19-A135
Abstract B002: Discovery of selective and potent EGFR kinase inhibitors for exon20 insertion mutations
Authors: Kim Sunghwan , Lee Younho , Kim Hwan , Kang Juhee , Seok Jiyoon , Seo Kyung-Ah , Ahn Jaeyoung , Kang Hee-Bum , Lee Sun-Hwa , Son Jung Beom , Choi Hwan Geun , Kim Nam Doo 
Published: March 2020

Abstract
The third generation EGFR tyrosine kinase inhibitors (TKIs), like Osimertinib, target classical activating EGFR mutations containing T790M resistance mutation. However, the exon 20 insertion (Ex20Ins), the third most common EGFR mutations in entire NSCLC, still lacks its therapeutic option. Recently, Robichaux JP et al., showed that Poziotinib, which had been developed as a second-generation EGFR TKI, had efficacy for the EGFR and Her2 Ex20Ins compared to EGFR T790M. Here, we developed inhibitors, structurally distinct from both Poziotinib and Osimertinib, targeting for the EGFR Ex20Ins mutations as well as EGFR T790M. According to kinase profiling, the inhibitors are highly selective to EGFR, ERBB2 and ERBB4 family. The candidate inhibitors demonstrated great activity (GI50 &lt; 20 nM) in cell growth inhibition of Ba/F3 cells containing EGFR Ex20Ins (D770_N771insSVD, V769_D770insASV, D770_N771insNPG, A763_Y764insFQEA, and H773_V774insNPH), Her2 Ex20Ins (A775_G776insYVMA), or cancer cells containing activating EGFR mutations and T790M resistance mutation (L858R/T790M and Del19/T790M). Finally, in several Ex20Ins patient-derived xenograft models, the candidate inhibitors induced tumor regression as strong as Poziotinib and increased survival rates along with minimal weight loss. These novel small molecule compounds inhibiting EGFR exon 20 insertion mutations will provide future therapeutic options for patients with this molecular subtype of NSCLC.
Citation Format: Sunghwan Kim, Younho Lee, Hwan Kim, Juhee Kang, Jiyoon Seok, Kyung-Ah Seo, Jaeyoung Ahn, Hee-Bum Kang, Sun-Hwa Lee, Jung Beom Son, Hwan Geun Choi, Nam Doo Kim. Discovery of selective and potent EGFR kinase inhibitors for exon20 insertion mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B002. doi:10.1158/1535-7163.TARG-19-B002
Abstract B006: Targeting EZH2 increases therapeutic efficacy of PD-1 blockade in models of prostate cancer
Authors: Sheahan Anjali , Morel Katherine , Burkhart Deborah , Baca Sylvan , Labbè David , Roehle Keven , Calagua Carla , Ye Huihui , Galbo Phillip , Panja Sukanya , Mitrofanova Antonina , Hamid Anis , Kibel Adam , Choudhury Atish , Pomerantz Mark , Freedman Matthew , Sweeney Christopher , Dougan Stephanie , Sowalsky Adam , Olson Brian , Loda Massimo , Ellis Leigh 
Published: March 2020

Abstract
Prostate cancers are considered immunologically ‘cold’ tumors as they have demonstrated poor response to check-point inhibitor therapy (CPI). Recently, enrichment of interferon response genes suggests a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models increases expression of double-strand RNA (dsRNA), that is associated with upregulation of genes connected with antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response genes, including PD-L1. Likewise, application of a novel EZH2 derived gene signature and TMA analysis indicated an inverse correlation between tumor EZH2 activity/expression with, T-cell inflamed and IFN gene signatures, and PD-L1 expression in human prostate cancer samples. EZH2 inhibition combined with PD-1 CPI significantly enhances anti-tumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI.
Citation Format: Anjali Sheahan, Katherine Morel, Deborah Burkhart, Sylvan Baca, David Labbè, Keven Roehle, Carla Calagua, Huihui Ye, Phillip Galbo, Sukanya Panja, Antonina Mitrofanova, Anis Hamid, Adam Kibel, Atish Choudhury, Mark Pomerantz, Matthew Freedman, Christopher Sweeney, Stephanie Dougan, Adam Sowalsky, Brian Olson, Massimo Loda, Leigh Ellis. Targeting EZH2 increases therapeutic efficacy of PD-1 blockade in models of prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B006. doi:10.1158/1535-7163.TARG-19-B006
Abstract B015: Targeting histone demethylase KDM4 for cancers driven by chimeric transcription factors
Authors: Yang Jun , Singh Shivendra , Abu-Zaid Ahmed , Fang Jie , Davidoff Andrew 
Published: March 2020

Abstract
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target for cancer therapy as they usually do not bear druggable pockets. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3-FOXO1 or its variant PAX7-FOXO1 fusion oncoprotein. Even with intensive chemotherapy and radiotherapy, the 5-year survival for fusion positive aRMS is poor with no significant improvement in over recent decades. Here we show that PAX3-FOXO1 function is dependent on histone demethylase KDM4B, a potential therapeutic vulnerability for aRMS. KDM4B is highly expressed in PAX3-FOXO1-positive aRMS and is associated with late stage disease. KDM4B physically interacts with PAX3-FOXO1 via its JmjN and TUDOR domains. Genetic depletion and pharmacologic inhibition of KDM4B with a novel inhibitor QC6352 significantly delay tumor growth, impact the expression of FAX3-FOXO1 targets such as MYOD1 and FGFR4, and reduce chromatin accessibility of PAX3-FOXO1 target genes in accordance with the changes of KDM4B substrates such as H3K9me3. Combination of QC6352 with chemotherapy lead to significant xenograft regression and extended mouse survival in cell line- and PDX- based preclinical aRMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3-FOXO-driven aRMS, providing pre-clinical data for a clinal trial combining the KDM4 inhibitor with standard chemotherapy for high-risk aRMS.
Citation Format: Jun Yang, Shivendra Singh, Ahmed Abu-Zaid, Jie Fang, Andrew Davidoff. Targeting histone demethylase KDM4 for cancers driven by chimeric transcription factors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B015. doi:10.1158/1535-7163.TARG-19-B015
Abstract B079: Inhibitory role of NFE2L2/NRF2-silencing in hypoxia-induced metabolic adaptation of cancer cells
Authors: Kwak Mi-Kyoung , Lee Sujin , Hallis Steffanus Pranoto 
Published: March 2020

Abstract
The nuclear factor erythroid 2-like-2 (NFE2L2/NRF2) pathway contributes to the environmental resistance of cancers by enhancing the antioxidant capacity. Hypoxia, a common element in the tumor environment, leads to hypoxia-inducible factor-1α (HIF-1α) stabilization to induce the adaptive response to hypoxic condition, including metabolic reprogramming and blood vessel formation. Our global miRNA expression analysis of HT29 and HCT116 human colon cancer cells identified that NRF2 silencing upregulated miR-181c, and this increase was associated with the reduction in mitochondria-encoded cytochrome c oxidase subunit-1 (MT-CO1), a catalytic core subunit of the complex IV of the electron transport chain. Therefore, NRF2-silenced cancer cells exhibited the decreases in the mitochondrial membrane potential, oxygen consumption rate, and cellular ATP contents. Notably, as a result of low oxygen consumption rate, NRF2-inhibited cancer cells failed to accumulate HIF-1a protein under hypoxic conditions. This phenomenon led to differential responses of NRF2-inhibted cancer cells to hypoxic condition when compared to control cells. First, stable knockdown of NRF2 in human colon cancer cells suppressed tumor growth in mouse xenograft settings with a concomitant reduction in blood vessel formation and vascular endothelial growth factor expression. Second, NRF2-silencing in breast cancer cells inhibited metabolic adaptation upon hypoxia, and hypoxic-inducible levels of metabolites involved in glycolysis and pentose phosphate pathway were reduced. Collectively, targeting NRF2/miR-181c could be an effective strategy to counteract HIF-1α-orchestrated adaptation of cancer cells to hypoxic microenvironment.
Citation Format: Mi-Kyoung Kwak, Sujin Lee, Steffanus Pranoto Hallis. Inhibitory role of NFE2L2/NRF2-silencing in hypoxia-induced metabolic adaptation of cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B079. doi:10.1158/1535-7163.TARG-19-B079
Abstract B110: Assessments of ameliorative effect of Forsythia Fructus on chemotherapy-induced neuropathic pain and its genotoxic potential
Authors: Shin Sarah , Kim Jinhee , Yi Jin-Mu , Kim No Soo , Bang Ok-Sun 
Published: March 2020

Abstract
The Forsythia Fructus (FF) have been prescribed in traditional medicine to relive clinical symptoms such as fever, pain, wound healing, vomiting, and nausea. The present study was performed to evaluate the neuroprotective effect of aqueous extract of FF on oxaliplatin-induced peripheral neuropathic pain; the in vivo neuroprotection activity was evaluated by von Frey test in murine models and in vitro protective effect was measured using PC12 cells. FF significantly alleviated oxaliplatin-induced mechanical hypersensitivity in rat model. In addition, FF exerted the neuroprotection effects against oxaliplatin-induced neurotoxicity as well as -inhibited neurite outgrowths in PC12 cells and dorsal root ganglion cells. In order to assess the safety of FF, we next evaluated genotoxic potential using a standard battery of in vitro and in vivo test system: the bacterial reverse mutation (Ames) test, the chromosomal aberration test, and the micronucleus test with bone marrow cells derived from male ICR mice in accordance with OECD guidelines. The results showed that aqueous extract of FF had not any genotoxic potential under the conditions tested. Taken together, these results indicated that FF will be useful for relieving oxaliplatin-induced peripheral neuropathic pain in cancer patients undergoing chemotherapy without genotoxic potential at least in our experimental condition.
Citation Format: Sarah Shin, Jinhee Kim, Jin-Mu Yi, No Soo Kim, Ok-Sun Bang. Assessments of ameliorative effect of Forsythia Fructus on chemotherapy-induced neuropathic pain and its genotoxic potential [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B110. doi:10.1158/1535-7163.TARG-19-B110
Abstract B111: A herbal formula BP10A enhanced anticancer effect of chemotherapeutic agents in the colon cancer PDTX model
Authors: Kim Jinhee , Shin Sarah , Kim No Soo , Bang Ok-Sun 
Published: March 2020

Abstract
BP10A is a novel two-herb medicine formula, consisting of Descurainiae sophia Semen and Peucedani praeruptorum Radix. This study was done to evaluate the antitumor efficacy of BP10A and its effect on the efficacy of the anticancer drugs oxaliplatin and irinotecan (CPT-11) in a colon tumor xenograft model. Chemical constituents from the ethanol extracts of BP10A were characterized with the ultra-performance liquid chromatography (UPLC) and each constituent was quantified with the UPLC-diode array detector method. Our study showed that BP10A exerted the cytotoxic effects in two colorectal cancer cell lines and its combination treatments with oxaliplatin or CPT-11 remarkably increased the in vitro cytotoxicity of each cancer drug assessed by the Ez-cytox assay. The in vivo antitumor activity of BP10A was evaluated in three colon cancer patient-derived tumor xenograft (PDTX) models with different genetic backgrounds. Oral administration with BP10A (250 and 500 mg/kg, daily) delayed tumor growth by 34-70% in the all PDTX models. Similarly, intraperitoneal injection of oxaliplatin (6 mg/kg) or CPT-11 (20 mg/kg) also suppressed tumor growth by 31.8-60.5% or by 24.3-50.4%, respectively. Furthermore, the combination treatment of BP10A with oxaliplatin or CPT-11 remarkably enhanced the antitumor activity of each anti-cancer drug and delayed tumor growth by 47.1-74.6% or by 74.4-82.9%, respectively. In accordance with the antitumor activity, the Ki-67 expression for tumor cell proliferation and the CD31 for angiogenesis were decreased, and TUNEL staining for tumor cell apoptosis was remarkably increased by the co-treatment of BP10A and the anticancer drugs as well as by each treatment of BP10A, oxaliplatin or CPT-11. Conclusively, BP10A has a strong tumor inhibitory effect against colon cancer and a synergistic effect with anticancer drugs, suggesting that BP10A could be considered as a good therapeutic candidate for the treatment of colon cancer. Funding source: This research was supported by a grant from Korea Institute of Oriental Medicine (K1515294).
Citation Format: Jinhee Kim, Sarah Shin, No Soo Kim, Ok-Sun Bang. A herbal formula BP10A enhanced anticancer effect of chemotherapeutic agents in the colon cancer PDTX model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B111. doi:10.1158/1535-7163.TARG-19-B111
Abstract B112: Obtusaquinone is a cysteine-modifying compound that targets Keap1 for degradation
Authors: Hora Cintia Carla da , Tabet Elie , Badr Christian Elias , Tannous Bakhos 
Published: March 2020

Abstract
In a previous study, we described the antineoplastic properties of the natural compound Obtusaquinone (OBT) against glioblastoma, breast cancer and other cancer types. We have shown that OBT targets cancer cells by increasing the production of reactive oxygen species (ROS) leading to DNA damage and apoptotic cell death. However, the mechanism behind the tumor targeting properties of OBT is not fully elucidated, hampering further preclinical development. In our current study we combined medical chemistry, quantitative mass-spectrometry-based proteomics, functional cancer cell studies, pharmokinetics and in vivo xenograft models to understand the mechanism of action of this compound and develop new OBT analogues with enhanced pharmacokinetic properties. Mechanistically, we now show that OBT binds cysteine residues, and in particular cysteine residues on Keap1. Our data also demonstrates that binding of OBT to Keap1 leads to its ubiquitination and degradation by the ubiquitin proteasome pathway (UPP). Since Keap1 acts as a negative regulator of Nrf2, its degradation following treatment with OBT results in the activation of Nrf2 signaling. Further, our pharmacokinetic studies demonstrate that OBT is able to cross the blood-brain barrier. In a GBM cancer stem cell xenograft model, OBT treatment results in 50% decrease in glucose uptake as detected using FDG-PET imaging. In conclusion, we show here that OBT binding to Keap1 is crucial for its anti-cancer properties, and that this binding leads to ubiquitination and proteasomal degradation of Keap1 and the activation of Nrf2 pathway.
Citation Format: Cintia Carla da Hora, Elie Tabet, Christian Elias Badr, Bakhos Tannous. Obtusaquinone is a cysteine-modifying compound that targets Keap1 for degradation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B112. doi:10.1158/1535-7163.TARG-19-B112
Abstract B130: Elevated cancer-intrinsic type I interferon signaling confers a dependency on the RNA editor ADAR1
Authors: Gardino Alexandra K. , Collins Cindy , Lynes Maureen S. , Boriack-Sjodin P. Ann , Copeland Robert A. , Ribich Scott A. 
Published: March 2020

Abstract
The deamination of adenosine to inosine (known as A-to-I editing) is one of the most prevalent RNA modifications that occurs in metazoans and is mediated by the Adenosine Deaminase Acting on RNA (ADAR) family of enzymes. The enzyme ADAR/ADAR1 catalyzes the majority of A-to-I editing where it has been demonstrated to effect coding sequence, miRNA function and silencing of Alu repetitive elements1. A critical function of ADAR1 is to edit double stranded RNA (dsRNA) structures that can activate the cytoplasmic nucleoside sensors MDA5 and PKR, preventing aberrant activation of an innate immune type I interferon (IFN) response2,3. Consistent with this hypothesis, mutations in ADAR1 and other enzymes involved in nucleoside metabolism and/or sensing are found in Aicardi-Goutiéres Syndrome (AGS), an interferonopathy associated with spontaneous interferon production4. Through analysis of pooled CRISPR and shRNA screening data, we have identified that cancer cell lines with elevated expression of specific type I interferon stimulated genes (ISGs) are dependent on ADAR1 for their survival. Tumor cells can display elevated intrinsic type I interferon signaling and associated dsRNA burden due to multiple factors, including chronic cytoplasmic DNA activation of STING, oncovirus infection and other proinflammatory signals. We have identified a core subset of 26 ISGs that predict a cellular dependency on ADAR1 and demonstrate elevated expression of these ISGs in a diverse range of tumor types including head and neck squamous cell carcinoma, breast cancer, esophageal cancer, and lung cancer. Utilizing an isogenic cell line with low basal type I interferon signaling and knockout of ADAR1, we demonstrate that we can induce cell death through exogenous treatment with the dsRNA mimetic poly-(I:C) or type I interferons (IFNα or IFNβ) but not the type II interferon IFNγ. We believe that chronic ISG expression and dsRNA burden creates a dependency on ADAR1 to prevent activation of MDA5 and PKR. These data suggest an ADAR1 inhibitor could be beneficial for the treatment of tumors with elevated ISG expression.
Eisenberg et al., Nature Review Genetics (2018)
Ahmad et al., Cell (2018)
Chung et al., Cell (2018)
Crow et al., Nature Review Immunology (2015)
Citation Format: Alexandra K. Gardino, Cindy Collins, Maureen S. Lynes, P. Ann Boriack-Sjodin, Robert A. Copeland, Scott A. Ribich. Elevated cancer-intrinsic type I interferon signaling confers a dependency on the RNA editor ADAR1 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B130. doi:10.1158/1535-7163.TARG-19-B130