bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4832: Overcoming breast cancer chemoresistance and blocking metastasis by targeting RNA-binding protein HuR
Authors: Wu Xiaoqing , Marquez Rebecca T. , Han Shuang , Li Ke , Lan Lan , Guo Yuxiao , Dixon Dan A. , Aubé Jeffrey , Welch Danny R. , Xu Liang 
Published: July 2016

Abstract
Patients with metastatic breast cancer have a dismal 5-year survival rate of only 24%. Chemoresistance is another contributor to the high mortality of advanced breast cancer. The RNA-binding protein, Hu antigen R (HuR), is overexpressed at all stages of breast cancer development. 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. HuR also modulates sensitivity of breast cancer cells to chemotherapy. Taken together, HuR is an emerging target for breast cancer therapy, especially metastatic breast cancer. Using shRNA and CRISPR technologies to modulate HuR expression in breast cancer cells, we found that cells with HuR KD/KO were less invasive and more sensitive to chemotherapy. In an effort to discover small molecules that disrupt the HuR-mRNA interaction and block HuR functions in breast cancer progression, metastasis and chemoresistance, high throughput screening (HTS) was carried out using several chemical libraries (∼23,000 compounds) using fluorescence polarization (FP) assay and identified several initial hits with sub-micromolar inhibitory constants (Ki). Those potential disruptors were then validated by ALPHA assay (Amplified Luminescent Proximity Homogeneous Assay), confirmed by Surface Plasmon Resonance (SPR). In cell-based assays, top hit KH-3 and its optimized analogs, specifically shortened HuR target mRNA half-lifes and decreased the level of the encoded proteins. Moreover, those compounds inhibited invasion and restored chemosensitivity. qPCR arrays focusing on specific pathways revealed that HuR inhibitors potently upregulated metastatic suppressors and downregulated genes frequently overexpressed in lung metastases. In animal studies, KH-3 not only powerfully exhibited antitumor efficacy in orthotopic xenografts, but also efficiently blocked experimental metastasis. In conclusion, we identified potent and specific small molecule disrupters of HuR-mRNA interaction for potential anti-metastatic therapy for breast cancer with HuR overexpression.
Citation Format: Xiaoqing Wu, Rebecca T. Marquez, Shuang Han, Ke Li, Lan Lan, Yuxiao Guo, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu. Overcoming breast cancer chemoresistance and blocking metastasis by targeting RNA-binding protein HuR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4832.
Abstract 4848: Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma
Authors: Qinghui Wang , Kinsie Arnst E. , Miller Duane D. , Li Wei 
Published: July 2016

Abstract
We previously discovered a novel 2-aryl-4-benzoyl-imidazole (ABI) scaffold exerts its potent anti-proliferative effects through interacting with the colchicine binding site in tubulin. Extensive structure-activity relationship (SAR) studies of this novel scaffold showed that the best analog in this series, ABI-231, has an average IC50 = 5.2 nM against panels of melanoma and prostate cancer cell lines, is orally bioavailable, and strongly suppress melanoma tumors in vivo. Analyses of the potential binding pose of ABI-231 at the colchicine binding pocket suggested small substitutions to the indole moiety in ABI-231 could further increase its interactions to tubulin.
Based this hypothesis, we have established an efficient synthetic method for the synthesis of ABI-231 analogs by either rotating the indole ring or introducing substituents on the indole of ABI-231. Using this method, we synthesized and tested 27 analogs of ABI-231. Several of the compounds show excellent potency against a panel of melanoma cancer cell lines with a diverse genomic background (mutations in BRAF, TP53, CDKN2A and PTEN) that are frequently encountered in clinical metastatic melanoma tumors. Additionally, they are not substrates for the P-glycoprotein (Pgp) efflux pump and therefore strongly inhibited the multidrug resistant cell lines. The potency of the compounds was further verified by their potent growth inhibition of cancer cell colonies. Results from cell cycle analysis, apoptosis evaluation and tubulin polymerization inhibition are consistent with their expected mechanisms of action. Potential off-target analyses performed by Eurofins Cerep-Panlabs SafetyScreen 44 indicated that they are clean and does not inihibt any of the tested off-targets at 100 fold of its IC50 value in melanoma cells, suggesting the good safety profile for this compound and the probably these scaffold in general. We are currently performing in vivo efficacy studies for the most potent analogs. These compounds hold great promise as a new generation of orally available tubulin inhibitors.
Citation Format: Wang Qinghui, Arnst E. Kinsie, Duane D. Miller, Wei Li. Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4848.
Abstract 485: Blood-based profiling of patients with NSCLC using CLIA certified cell-free DNA tests for EGFR, KRAS and BRAF point mutations and test use in clinical practice
Authors: Mellert Hestia , Thurston Scott , Foreman Trudi , Hahn Westen , Dupuis Nicholas , Pestano Gary 
Published: July 2016

Abstract
Nearly 80% of patients will not have mutation results available at their initial oncology consult and as many as 1 in 4 patients will begin treatment in advance of receiving their tumor mutation results. These factors hinder diagnosis at the molecular level, which is an important component in the decision to commence treatment with specific targeted therapies. The goal of this study was to measure the utility of a CLIA-certified Laboratory Developed Test (LDT) in the absence of a tissue diagnosis. EGFR, KRAS and BRAF point mutations within the cell-free DNA (cfDNA) isolated from the plasma of patients with advanced stages of cancer were analyzed using Droplet Digital™ PCR (ddPCR) technology. The specific tests detected the EGFR sensitizing mutations L858R and exon 19 deletion (E746 - A750) and EGFR resistance mutation, T790M, the KRAS mutations G12C, G12V and G12D, as well as the BRAF V600E mutation. The tests were comprised of three components: (i) a whole-blood collection kit that ships at ambient temperature, (ii) cfDNA isolated from plasma for analysis using ddPCR, and (iii) a secure laboratory information management system (LIMS) for sample accessioning and report generation. Test mutation status results were reported within 72 hours of blood shipment from the physicians’ office. To date we have processed greater than 2000 individual variant tests for patients with NSCLC. The predominant tumor type for EGFR sensitizing mutations requested was NSCLC (95%). Interestingly, even BRAF test orders were &gt; 90% from NSCLC patients. Additionally, the percentage of tests requested that were positive for each mutation category were 12% for EGFR sensitizing, 20% for EGFR resistance, 14% for KRAS and 1.8% for BRAF. Significantly, T790M test orders were observed to have increased five-fold over the last three months of testing. We have developed highly sensitive, 72 hour test to results blood-based assays as a part of the GeneStratTM panel, that expand the utility of laboratory testing for patients previously diagnosed with cancer.
Citation Format: Hestia Mellert, Scott Thurston, Trudi Foreman, Westen Hahn, Nicholas Dupuis, Gary Pestano. Blood-based profiling of patients with NSCLC using CLIA certified cell-free DNA tests for EGFR, KRAS and BRAF point mutations and test use in clinical practice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 485.
Abstract 4852: Multivalent peptoid conjugates suppress enzalutamide-resistant prostate cancer cellular proliferation
Authors: Wang Yu , Levine Paul , Dehigaspitiya Dilani , Profit Adam , Logan Susan , Imberg-Kazdan Keren , Kirshenbaum Kent , Garabedian Michael 
Published: July 2016

Abstract
Development of resistance to latest anti-androgens treatment for advanced prostate cancer is a growing concern. New strategies to block androgen receptor (AR) function in castration resistant prostate cancer are therefore required. Here we report the characterization of a multivalent conjugate presenting two spatially defined bioactive ethisterone ligands as spatially defined pendant groups on a peptoid oligomer. The conjugate, termed Multivalent Peptoid Conjugate 6 (MPC6), suppressed the proliferation of multiple AR-expressing prostate cancer cell lines including those that failed to respond to enzalutamide and ARN509. The structure-activity relationships of MPC6 variants were evaluated, revealing that increased spacing between ethisterone moieties and changes in peptoid topology eliminated its anti-proliferative effect. Mechanistically, MPC6 blocked AR coactivator-peptide interaction, and decreased AR protein half-life. Pharmacological studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Importantly, MPC6 treatment reduced tumor growth and decreased Ki67 and AR expression in mouse xenograft models of enzalutamide-resistant LNCaP-abl cells. Thus, MPC6 represents a new class of compounds with the potential to combat treatment-resistant prostate cancer.
Citation Format: Yu Wang, Paul Levine, Dilani Dehigaspitiya, Adam Profit, Susan Logan, Keren Imberg-Kazdan, Kent Kirshenbaum, Michael Garabedian. Multivalent peptoid conjugates suppress enzalutamide-resistant prostate cancer cellular proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4852.
Abstract 4856: Selective human estrogen receptor partial agonist (ShERPAs) for treatment of tamoxifen-resistant ER+ breast cancer
Authors: Delgado-Rivera Loruhama M. 
Published: July 2016

Abstract
Estrogen receptor positive (ER+) breast cancer represents a significant cause of death among women in the US, which is exacerbated by resistance to 1st line endocrine therapies, notably tamoxifen, which occurs in 50% of patients. Estrogen fuels growth of endocrine-dependent cancers and yet estradiol (E2) and ERá agonist, diethylstilbestrol, were used successfully in the clinic in greats cancer therapy in the 20th century. The side effects associated with these treatments are considered unacceptable, spurring the pursuit of safer, alternative therapeutic agents and the model systems to develop and optimize these agents. Three breast cancer cell lines that demonstrate resistance to tamoxifen and endocrine independence in 2D (MCF-7:5C), or 3D (T-47D:PKCá and T-47D:TAM1) cell cultures; and comparison to the parent endocrine-dependent cell lines provides a set of model systems able to test the hypothesis that a selective estrogen mimic (SEM) will provide a safe, therapeutic approach to ER+ endocrine-independent breast cancer overexpressing the PKCá biomarker. A partial agonist at ERá was selected as such a therapeutic approach: The use of partial agonists will allow us to retain the beneficial properties of E2, while attenuating the unwanted side effects. Selective human Estrogen Receptor Partial Agonists (ShERPAs) were designed, synthesized, and validated, using a combination of time-resolved FRET (TR-FRET) on ERá/SRC3 recruitment, isolated ERá affinity, and cell-based assays. ShERPAs were identified containing novel structures derived from the selective estrogen receptor modulators (SERMs) bazedoxifene and raloxifene, and their scaffolds, 3-methylindole and benzothiophene, respectively. Examples with favorable pharmacokinetic properties were validated in xenograft models of tamoxifen-resistant breast cancer.
Citation Format: Loruhama M. Delgado-Rivera. Selective human estrogen receptor partial agonist (ShERPAs) for treatment of tamoxifen-resistant ER+ breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4856.
Abstract 4859: Identifying high quality, potent and selective inhibitors of ATM kinase: Discovery of AZD0156
Authors: Pike Kurt G. 
Published: July 2016

Abstract
Ataxia telangiectasia mutant (ATM) is a serine/threonine protein kinase from the phosphatidylinositol 3-kinase-related kinase (PIKK) family of protein kinases (also comprising ATR, DNA-PKcs, mTOR etc.) and plays a crucial role in the cellular DNA damage response signalling activated by DNA double strand breaks (DSB). Activated ATM promotes DNA repair and S/G1-cell cycle checkpoints to prevent premature mitosis, maintain genomic integrity and promote appropriate cell survival or death pathways. DSBs arise intrinsically through the collapse of stalled replication forks, which are induced by a wide range of chemotherapies, or extrinsically through exposure to ionizing radiation. Therefore, ATM inhibition represents an exciting clinical opportunity as a target to hyper-sensitize tumors to chemo/radiotherapy.
Herein, we describe our efforts to identify multiple, novel series of ATM inhibitors. We will describe our optimization efforts with particular attention given to improving the potency of the compounds in cellular systems and the selectivity of the compounds over other closely related proteins (e.g. ATR, mTOR etc.). We will also describe our efforts to optimize both the physicochemical properties of the molecules as well as the pharmacokinetic profile to enable low dose, oral administration in the clinic. These efforts culminated in the discovery of the clinical candidate AZD0156, a first in class orally available ATM inhibitor. AZD0156 shows sub-nanomolar potency in cell based assays of ATM inhibition with selectivities of greater than 1000 fold over other members of the PIKK family of enzymes. AZD0156 is a permeable, highly soluble compound with excellent preclinical pharmacokinetic properties including oral bioavailability. AZD0156 shows robust efficacy in mouse xenograft models after oral administration when combined with DSB inducing agents. AZD0156 is currently undergoing early clinical assessment.
Citation Format: Kurt G. Pike. Identifying high quality, potent and selective inhibitors of ATM kinase: Discovery of AZD0156. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4859.
Abstract 4862: AGI-134: a fully synthetic alpha-Gal glycolipid that prevents the development of distal lesions and is synergistic with an anti-PD-1 antibody in a mouse melanoma model
Authors: Shaw Stephen , Kristian Sascha , Wigglesworth Kim , Middleton Jenny , Glossop Mel , Whalen Giles , Old Robert , Westby Mike , Pickford Chris 
Published: July 2016

Abstract
Background: AGI-134 is a fully synthetic glycolipid, composed of an alpha-Gal (Galá1-3Galâ1-4GlcNAc-R) sugar epitope attached via a linker to a lipid tail. Natural antibodies to the alpha-Gal epitope are responsible for the hyperacute rejection of xenografts in humans. It is proposed that intratumorally administered AGI-134 will incorporate into the cell membranes of the tumor cells, presenting the alpha-Gal epitope for binding of anti-Gal antibodies to the tumor cells. This will initiate an immune response that attacks the injected tumor and, through uptake of immune-complexed tumor antigens by antigen presenting cells, will create a patient-specific, systemic anti-tumor response against distant metastases.
Results: We demonstrate that AGI-134 incorporates into tumor cell membranes in vitro and that the exposed alpha-Gal epitope binds anti-Gal IgG and IgM antibodies from human serum to the tumor cell surface. Using flow cytometry and a complement-dependent cytotoxicity assay we show that tumor cell opsonization with anti-Gal antibodies leads to deposition of complement proteins C3b and C5b-9, which ultimately leads to tumor cell lysis. Furthermore, we demonstrate that AGI-134-labeled tumor cells opsonized with human serum proteins are phagocytosed by professional APCs.
Using the B16-F10 melanoma model in anti-Gal producing á1,3-galactosyltransferase knockout (GT KO) mice we present data to demonstrate that AGI-134 injection into a primary tumor provides significant dose-dependent protection from the development of established distant lesions. Using GT KO mouse serum we demonstrate in vitro that deposition of complement on AGI-134-labeled mouse tumor cells is both alpha-Gal and anti-Gal dependent. In vivo, we demonstrate that the effect of AGI-134 is due to the alpha-Gal moiety by replacing it with human blood group antigens. The protection from secondary lesions conferred by AGI-134 is long lasting in the GT KO mouse melanoma model (monitored up to 90 days). Importantly, when sub-optimal concentrations of AGI-134 were tested in vivo in combination with an anti-PD-1 antibody (RMP1-14), a significant enhancement in efficacy over either of the agents administered alone was observed.
Citation Format: Stephen Shaw, Sascha Kristian, Kim Wigglesworth, Jenny Middleton, Mel Glossop, Giles Whalen, Robert Old, Mike Westby, Chris Pickford. AGI-134: a fully synthetic alpha-Gal glycolipid that prevents the development of distal lesions and is synergistic with an anti-PD-1 antibody in a mouse melanoma model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4862.
Abstract 4867: The CD40 agonistic antibody APX005M ‘licenses’ antigen presenting cells to promote tumor-specific T-cell responses
Authors: Filbert Erin L. , Björck Pia , Yang Xiaodong , Trifan Ovidiu C. 
Published: July 2016

Abstract
Modulation of co-stimulatory and co-inhibitory molecules on immune cells has become a promising approach for cancer immunotherapy. CD40 engagement on antigen presenting cells (APCs) by its ligand CD154 leads to maturation and expression of co-stimulatory molecules such as CD80, CD86, OX-40L, and 4-1BBL that are requisite for optimal antigen-specific T-cell activation, an essential component of the anti-tumor immune response. To evaluate the therapeutic potential of targeting the CD40-CD154 pathway, Apexigen has developed APX005M - a humanized IgG1 CD40 agonistic antibody that binds with high affinity to human CD40. APX005M mimics CD154, has potent CD40 agonistic activity and promotes activation of APCs. Monocyte-derived dendritic cells treated with APX005M display a mature phenotype characterized by upregulation of CD80, CD86 and HLA-DR and increased secretion of IL-12. In mixed lymphocyte reaction and viral antigen recall assays, APX005M significantly enhances proliferation of and IFN-ã secretion from both naïve and memory T cells. Since CD40-CD154 signaling is involved in the priming phase of T cell activation and acts upstream of many critical costimulatory pathways, CD40 agonistic antibodies may represent an essential component of combination immunotherapy. In support of this, we show that APX005M synergizes with checkpoint inhibitors to promote antigen-specific T-cell responses. Importantly, in an ex vivo tumor assay APX005M induces T-cell proliferation and cytokine secretion. These data demonstrate that APX005M binds to APCs and induces their activation and maturation to ultimately drive a potent tumor-specific T-cell response. T cell activation in cancer patients receiving APX005M will be assessed in current and future clinical studies.
Citation Format: Erin L. Filbert, Pia Björck, Xiaodong Yang, Ovidiu C. Trifan. The CD40 agonistic antibody APX005M ‘licenses’ antigen presenting cells to promote tumor-specific T-cell responses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4867.
Abstract 487: Usefulness of exosome quantification by cholesteryl ester transfer protein activity as a biomarker for human esophageal squamous cell carcinoma (ESCC)
Authors: Matsumoto Yasunori , Kano Masayuki , Akutsu Yasunori , Hanari Naoyuki , Hoshino Isamu , Murakami Kentaro , Usui Akihiro , Suito Hiroshi , Takahashi Masahiko , Otsuka Ryota , Matsubara Hisahiro 
Published: July 2016

Abstract
Exosomes are small membrane vesicles (30-100 nm) and are thought to play an important role in tumor progression, chemoresistance, dormancy etc. However, the exosome dynamics and transportation between cancer cells and the other cells are still unclear. In addition, although it is common method to quantify exosomes using standard protein quantification methods, it is actually incorrect.
In this study, we assessed the exosome dynamics with mouse model and quantify plasma exosome by cholesteryl ester transfer protein activity, which is known to be enriched within exosomes. We analyzed the relationship between exosome quantification and clinical characters in ESCC patients.
In order to image and analyze the movement of cancer cell-derived exosomes, green fluorescent protein (GFP)-tagged CD63, which is a general marker of exosomes, was expressed in human esophageal squamous cancer cell line TE2. Mouse model of human ESCC were then established by s.c. injection of TE2-CD63-GFP or TE2 cell lines. Eight weeks after injection, the tumor, blood and other organs were harvested and imaged with fluorescence. Our data indicates tumor derived exosome can emitted from the tumor and circulate in the blood flow.
Quantification of plasma exosome in ESCC patients (n = 64) and no malignant patient (n = 10) were performed by measurement of cholesteryl ester protein activity, and then analyzed the relationship between the exosome number and the patients’ clinical characteristics, such as age, sex, TNM classification, prognosis, tumor marker. Our data indicates the exosome number was higher in ESCC patients than no malignant patients (P = 0.0014). Althogh there were no difference in tumor depth, lymph node status, distant metastasis, the exosome number can be a prognostic marker for ESCC (P = 0.04).
Citation Format: Yasunori Matsumoto, Masayuki Kano, Yasunori Akutsu, Naoyuki Hanari, Isamu Hoshino, Kentaro Murakami, Akihiro Usui, Hiroshi Suito, Masahiko Takahashi, Ryota Otsuka, Hisahiro Matsubara. Usefulness of exosome quantification by cholesteryl ester transfer protein activity as a biomarker for human esophageal squamous cell carcinoma (ESCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 487.