bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2083: WNT5a/ROR1 axis in triple-negative breast cancer progression and potential therapy
Authors: Borcherding Nicholas , Ameka Magdalene , Kolb Ryan , Xie Qing , Zhang Weizhou 
Published: May 2015

Abstract
Triple negative breast cancer (TNBC) accounts for 15-20% of total invasive breast cancer. These tumors are more aggressive and have a worse prognosis relative to other types of breast cancer, partially due to the lack of FDA-approved targeted therapy. Utilizing the RNA-seq data for invasive breast cancer specimens deposited in the Cancer Genome Atlas (TCGA), we found that the mRNA expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) decreased in the luminal A (n=231), luminal B (n=128) and Her2+ (n=58) subtypes relative to their corresponding normal controls. In contrast, ROR1 expression increased in all the pathologic stages of TNBC samples relative to normal specimens and ROR1 expression correlates positively with progression of TNBC (n=78). ROR1 is a receptor tyrosine kinase that is involved in embryonic patterning, but lacks expression in adult tissues. We undertook a series of mechanistic studies to understand the role of ROR1 in TNBC and evaluate ROR1 as a potential target for TNBC therapy. Using complex bioinformatics analysis, we found that ROR1 expression correlates with signature genes of TNBC, cancer stem cells, and TGFβ/SMAD pathways, which, in addition to recent observation of potential crosstalk between WNT5A/ROR1 signaling with TGFβ/SMAD, prompted us to examine if this crosstalk contributes to TNBC. Indeed, we found that WNT5a promotes SMAD2/3 activation in a ROR1- and TGFβR1-dependent manner. Inhibiting ROR1 by neutralizing antibody shifted cancer stem cells of TNBC to a more luminal-type, indicating a critical of ROR1 in self-renewal of cancer stem cells. SNAI1/2, master regulators of epithelial to mesenchymal transition (EMT), are potentially involved in the WNT5a/ROR1-mediated self-renewal of cancer stem cells. In agreement with these findings, TNBC cell lines with the highest surface expression of ROR1 had a greater cancer stem cell (CSC) population (CD24-CD44high). In collaboration with Speed Biosystems LLC, we developed an anti-ROR1 immunotoxin that specifically kills ROR1-high TNBC cells but not ROR1-low breast cancer cells or normal epithelial cells. Our findings suggest a role of WNT5a/ROR1 signaling in the progression of TNBC, through its role in potentiating TGFβ/SMAD/SNAI1/2 pathway thus promoting EMT and stem-like phenotype. ROR1 represents a novel therapeutic target for TNBC, especially for late-stage diseases.
Citation Format: Nicholas Borcherding, Magdalene Ameka, Ryan Kolb, Qing Xie, Weizhou Zhang. WNT5a/ROR1 axis in triple-negative breast cancer progression and potential therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2083. doi:10.1158/1538-7445.AM2014-2083
Abstract 2510: A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase
Authors: Yip Kenneth W. , Zhang Zhan , Sakemura-Nakatsugawa Noriko , Huang Jui-Wen , Yue Shijun , Jitkova Yulia , To Terence , Pai Emil , Schimmer Aaron , Lovell Jonathan , Sessler Jonathan , Liu Fei-Fei 
Published: May 2015

Abstract
Uroporphyrinogen decarboxylase (UROD), a heme biosynthetic pathway enzyme that converts uroporphyrinogen to coproporphyrinogen, was recently identified as a potential anticancer target. UROD inhibition leads to an increase in reactive oxygen species (ROS), likely mediated by the Fenton reaction, which decreases cancer cell viability and sensitizes cells to cisplatin and radiation. Because there is no known chemical UROD inhibitor suitable for translational research, we aimed to design, synthesize, and characterize such a compound. In silico design and docking was used to identify a potential porphyrin analogue. Subsequent synthesis produced a porphodimethene (named PI-16) that inhibited UROD in an enzymatic assay (IC50 = 9.9 µM). PI-16 did not affect porphobilinogen deaminase (at 62.5 µM), thereby exhibiting some specificity. In cellular assays, PI-16 reduced FaDu and ME-180 cancer cell viability with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, whereas normal oral epithelial (NOE) cells were only minimally affected. PI-16 combined effectively with cisplatin and radiation, with potent synergy being observed with cisplatin (Chou-Talalay combination index &lt; 1). This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective compounds.
Citation Format: Kenneth W. Yip, Zhan Zhang, Noriko Sakemura-Nakatsugawa, Jui-Wen Huang, Shijun Yue, Yulia Jitkova, Terence To, Emil Pai, Aaron Schimmer, Jonathan Lovell, Jonathan Sessler, Fei-Fei Liu. A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2510. doi:10.1158/1538-7445.AM2014-2510
Abstract 2515: Synthesis of substituted chromone-2-phenylcarboxamides as anti-breast cancer agents
Authors: Redda Kinfe Ken , Gangapuram Madhavi , Ghaffari Mohammad A. , Eyunni Suresh 
Published: May 2015

Abstract
Breast cancer is one of the most commonly diagnosed cancers and causes the second leading cancer deaths in women. The overall survival rate of breast cancer patients has substantially increased during the last decades due to early tumor detection. Unfortunately, the recovery rate of advanced breast cancer by current available drug treatment is still unacceptably low. Although chemotherapy is the main stay of cancer treatment at present, most of the drugs cause general toxicity to any proliferating cells and tend to severely limit the therapeutic values of these drugs. In an attempt to overcome these problems, the synthesis of new anti-breast cancer agents with unique mechanisms of action was developed. Chromones are benzannulated oxygen containing heterocyclic compounds widely distributed in nature that have a -pyrone ring. The chemical core of chromone has been classifies as a privileged structures in drug discovery, due to its uses in a wide variety of pharmacologically active compounds such as anti cancer, anti-HIV, antibacterial and anti-inflammatory agents. Based on these considerations, we attempted the synthesis of novel substituted chromone-2-phenylcarboxamides as anti-breast cancer agents. The starting material chromones-2-carboxylic acid was obtained by the hydrolysis reaction of ethyl esters with the mixture of glacial acetic acid and concentrated HCl (2:1v/v) and the mixture was heated to reflux for 12 h. The acids were obtained in 70-80% yields. A suspension of substituted chromone-2-carboxylic acid in DMF was added to substituted anilines, in the presence of diphenylphosphorylazide and triethylamine. The reaction mixture was stirred at room temperature for 24 h, which furnished the target compounds i.e., substituted chromone-2-phenylcarboxamides. These compounds were evaluated for their cytotoxic effects on MCF-7 ER+ve breast cancer cells, MDA-MB-231 ER-ve breast cancer cell lines and Ishikawa cells using the CellTiter-Glo luminescent cell viability assay. N-(4-hydroxyphenyl)-5,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide showed the most potent cytotoxicity with an IC50 values of 29.5 and 25.7 µM on MCF-7 and Ishikawa cell lines, respectively.
This research was supported by National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 8 G12MD007582-28.
Citation Format: Kinfe Ken Redda, Madhavi Gangapuram, Mohammad A. Ghaffari, Suresh Eyunni. Synthesis of substituted chromone-2-phenylcarboxamides as anti-breast cancer agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2515. doi:10.1158/1538-7445.AM2014-2515
Abstract 2534: High-affinity small molecule inhibitors of the menin-MLL interaction reverse oncogenic transformation mediated by MLL fusion proteins in leukemia
Authors: Grembecka Jolanta E. , He Shihan , Senter Timothy J. , Borkin Dmitry , Pollock Jonathan , Han Changho , Upadhyay Sunil Kumar , Purohit Trupta , Miao Hongzhi , Gogliotti Rocco D. Gogliotti D. , Lindsley Craig W. , Cierpicki Tomasz , Stauffer Shaun R. 
Published: May 2015

Abstract
The protein-protein interaction (PPI) between menin and Mixed Lineage Leukemia (MLL) plays a critical role in acute leukemias with translocations of MLL gene, and inhibition of this interaction with small molecules represents a new potential therapeutic strategy for the MLL leukemia patients. We identified novel small molecule inhibitors of the menin-MLL interaction with distinct molecular scaffolds by performing a High Throughput Screening (HTS) of over 300,000 compounds. Extensive medicinal chemistry efforts performed for two lead classes to improve inhibitory activity of these compounds resulted in menin-MLL inhibitors with low nanomolar binding affinities. The menin-inhibitor co-crystal structures revealed that these compounds directly bind to menin and closely mimic the key interactions of MLL with menin, resulting in their high binding affinity. Interestingly, the hydroxymethylpiperidine class of the menin-MLL inhibitors extends beyond the MLL binding region on menin, providing additional opportunity for their optimization. We combined extensive crystallography studies with structure-based design to perform rational optimization and scaffold modification to rapidly improve activity and modulate physicochemical properties of the menin-MLL inhibitors. Treatment of MLL leukemia cells with the most potent menin-MLL inhibitors we developed resulted in very effective and selective inhibition of cell proliferation, induced apoptosis and differentiation of these cells. These effects were associated with downregulation of Hoxa9 and Meis1 expression, the downstream targets of MLL fusion proteins required for their leukemogenicity, demonstrating a very specific mechanism of action for these newly developed menin-MLL inhibitors. In vivo studies are currently undergoing to assess the effect of these compounds on leukemia progression in animal models of MLL leukemia. Our studies provide a novel and very attractive scaffolds for further development as a new potential therapeutic approach for the MLL leukemia patients.
Citation Format: Jolanta E. Grembecka, Shihan He, Timothy J. Senter, Dmitry Borkin, Jonathan Pollock, Changho Han, Sunil Kumar Upadhyay, Trupta Purohit, Hongzhi Miao, Rocco D. Gogliotti D. Gogliotti, Craig W. Lindsley, Tomasz Cierpicki, Shaun R. Stauffer. High-affinity small molecule inhibitors of the menin-MLL interaction reverse oncogenic transformation mediated by MLL fusion proteins in leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2534. doi:10.1158/1538-7445.AM2014-2534
Abstract 2562: Evaluate in vivo efficacy of anti-tumor immuno-therapeutics using MixenoTM mouse models
Authors: Zhang Juan , Qiu Junzhuan , Sun Ziyong , Dong Xin , Jiping Zha , Shi Qian 
Published: May 2015

Abstract
The past few years have witnessed a renaissance in the field of cancer immunotherapy, relating largely to the clinical advances associated with the development of immunomodulatory agents, e.g. monoclonal antibodies targeting the immune inhibitory pathways (CTLA-4 and PD-1/PD-L1). Often, the preclinical efficacy assessments are based on the evaluation of surrogate anti-mouse target antibodies using mouse syngenic tumor models, because of the need for T cell activation in an immune competent system. However, this strategy is limited due to the fact that the immune systems in human and mouse are different, and a surrogate molecule needs to be tested in those syngenic models. Here we set out to validate mouse models that harbor human immune cells by pre-engrafting the immuno-deficient mice with human PBMC (the MixenoTM model), and use them for efficacy evaluation of the humanized anti-PD-1 antibody. PD-L1 high-expression human tumor cell lines are selected for these in vivo models. T cell activation, infiltration and the cytokine production were analyzed to illustrate the immune cell involvement. In conclusion, the MixenoTM models are useful tools in immunotherapeutic antibody development, and may greatly increase the clinical translatability of animal studies.
Citation Format: Juan Zhang, Junzhuan Qiu, Ziyong Sun, Xin Dong, Zha Jiping, Qian Shi. Evaluate in vivo efficacy of anti-tumor immuno-therapeutics using MixenoTM mouse models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2562. doi:10.1158/1538-7445.AM2014-2562
Abstract 2565: Conformation overrides base sequence - insights from a novel class TLR-9 agonists
Authors: Kapp Kerstin , Kleuss Christiane , Schroff Matthias , Wittig Burghardt 
Published: May 2015

Abstract
Introduction
DNA-based TLR-9 agonists are potent activators of immune cell populations and the immune system. Preclinical and ongoing clinical studies support the use of TLR-9 agonists as immunomodulators and/or adjuvants, and proof their anti-tumor effect by enhancing both the humoral and cellular responses. From the 4 classes of known activators with distinct immunomodulation profiles all members except one comprise of linear DNA molecules. The exception is dSLIM®, the active ingredient of MGN1703 in several clinical trials. dSLIM® establishes a new class of TLR-9 agonists, represented by covalently closed dumbbell-like DNA molecules consisting entirely of natural DNA with two single-stranded CG-containing loops separated by a double-stranded stem.
Results
By cytokine secretion and cellular activation of relevant cells in human PBMC we show that CG-motifs - such as in ODN2006, a class B TLR9 agonist - if incorporated in dSLIM® conformation reveal an improved immunomodulatory potential compared to their corresponding linear CpG oligonucleotides. Increased cytokine secretion encompasses the central anti-cancer cytokine IFN-alpha, the potent angiostatic cytokine IP-10, or IFN-gamma the key activator of NK-, NKT-, and cytotoxic T-cell responses. After 24-48h exposure to dSLIM® TLR-9 agonists, also activation surface markers of relevant cell subpopulations of PBMC are up-regulated including CD80 of pDCs, CD86 of B-cells, CD86 and CD169 of monocytes, CD69 of NK, NKT as well as T cells. Consequently, dSLIM® triggers an explicit specific cytotoxicity against Jurkat target cells while ODN2006 is without significant effect in this readout. All these effects are considered important and relevant cancer-fighting features of dSLIM®.
Conclusions
Differences in immunomodulation profiles between classes of TLR-9 agonists appear to be more closely related to their conformation than their individual nucleotide sequences. We show individual loop sequences in dSLIM® that differentiate the immunomodulation profile of molecules only to a moderate extent. Inherent to the dumbbell-like structure of dSLIM® TLR-9 agonists is their potential to dimerize loop-binding TLR-9 molecules in the membrane of immune-competent cells. Thereby, dSLIM® TLR-9 agonists most probably not only bind and activate but also cluster TLR-9 molecules thereby changing the TLR-9 triggered immune response in a qualitative way. Stabilizing chemical modifications in linear CpG ODN also impact the immunomodulatory profile of TLR-9 agonists and are discussed.
Citation Format: Kerstin Kapp, Christiane Kleuss, Matthias Schroff, Burghardt Wittig. Conformation overrides base sequence - insights from a novel class TLR-9 agonists. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2565. doi:10.1158/1538-7445.AM2014-2565
Abstract 258: Characterizing cancer gene mutations in non-small cell lung cancer from African American patients
Authors: Bollig-Fischer Aliccia , Gadgeel Shirish , Chen Wei , Cote Michele , Schwartz Ann G. , Bepler Gerold 
Published: May 2015

Abstract
Background and Hypothesis: Lung cancer is the leading cause of cancer-related deaths in the United States. The reasons for higher incidence and inferior survival rates among African American lung cancer patients have not been adequately defined. We hypothesized that molecular differences, specifically differential incidence of somatic cancer gene mutations, may be a contributing factor to these population-based disparities. Large-scale, high-throughput genomic studies of the major subtype of lung cancer, non-small cell lung cancer (NSCLC), have so far neglected to adequately represent African American patients. Such information holds potential to transform treatment decisions to improve care for subsets of patients and address disparities.
Methods: We tested our hypothesis using a MALDI-TOF mass spectrometry approach to analyze tumor DNA for 214 coding mutations in 26 cancer genes previously linked to NSCLC, including oncogenes and tumor suppressor genes. The sample sets investigated included NSCLC specimens from 335 patients of European ancestry and 137 African Americans. For 299 of these 472, DNA from normal matched specimens was available and included in the study, thus totaling 771 samples.
Results: There was no significant difference in frequencies for somatic cancer gene coding mutations across populations and gene mutation frequencies were within reported ranges, e.g., KRAS (11%), EGFR (10%) and PIK3CA (2%). However, this study also uncovered a previously unrecognized germ line variant in the DDR2 oncogene. In addition, we found that the frequencies of single nucleotide polymorphisms (SNPs) in STK11, cMet, and NOTCH differ between African American and European ancestry patients.
Conclusion: This body of work is among the largest reported on to date comparing somatic cancer gene mutations in African American and European-ancestry patients. The outcomes show that across a broad spectrum of coding mutations, genomic tumor testing could equally benefit both populations.
Citation Format: Aliccia Bollig-Fischer, Shirish Gadgeel, Wei Chen, Michele Cote, Ann G. Schwartz, Gerold Bepler. Characterizing cancer gene mutations in non-small cell lung cancer from African American patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 258. doi:10.1158/1538-7445.AM2014-258
Abstract 2583: Intratumoral treatment of one tumor lesion with LTX-315 induces complete tumor regression and long-term specific protective immune responses in a metastatic rodent tumor model
Authors: Rekdal Øystein , Nestvold Janne , Wang Meng Y. , Camilio Ketil André , Areffard Ali , Sveinbjørnsson Baldur , Kvalheim Gunnar 
Published: May 2015

Abstract
Host defense peptides are naturally occurring peptides that have an important function in innate immune responses in almost every life form. Recently it has been documented that several host defense peptides have anticancer activity. Based on a naturally occurring host defense peptide we have do novo designed the short chemically modified peptide LTX-315. We have demonstrated that LTX-315 induces an immunogenic type of cell death with subsequent release of danger signals (e.g. HMBG1, ATP and Cytochrome C) and tumor associated antigens (TAA`s). In addition LTX-315 also has the ability to directly modulate immune-responses.
In a novel rat mescenhymal sarcoma model (rTMSC) we demonstrate that LTX-315 induces a complete tumor regression by intratumoral (i.t.) injection. Studies on treated tumor tissue confirmed massive necrosis and infiltration of immune cells. Successfully treated animals were protected against re-challenge with the tumor cell type treated, but not against other types of tumor cells. Moreover, tumor resistance could be adoptively transferred by spleen cells from LTX-315-treated animals. The resistance was abrogated by depletion of T-lymphocytes.
To clarify whether intratumoral injection of LTX-315 in one tumor lesion can have an effect on metastatic disease, intraperitoneal tumor and two subcutaneous tumors were established in the animals. Thereafter, LTX-315 was injected into one of the subcutaneous lesion and tumor growth assessed by living imaging. The results showed that LTX-315 eradicated all three lesions and the animal went into durable complete remission.
We propose that by targeting tumor locally LTX-315 can be used for individualized therapeutic in situ vaccination against cancer.
Citation Format: Øystein Rekdal, Janne Nestvold, Meng Yu Wang, Ketil André Camilio, Ali Areffard, Baldur Sveinbjørnsson, Gunnar Kvalheim. Intratumoral treatment of one tumor lesion with LTX-315 induces complete tumor regression and long-term specific protective immune responses in a metastatic rodent tumor model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2583. doi:10.1158/1538-7445.AM2014-2583