bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 74: Targeting nuclear export for triple-negative breast cancer therapy
Authors: Petrocca Fabio 
Published: July 2016

Abstract
Triple-negative breast cancers (TNBC) comprise the most aggressive subtype of breast cancer. They rapidly acquire resistance to chemotherapy and are also refractory to endocrine therapy and HER2 inhibitors. In fact, no targeted therapies are currently available against these tumors. Genome sequencing studies have shown that TNBCs are exceedingly heterogeneous in genetic mutations as well as copy number variations. Yet, TNBC almost invariably harbor inactivating mutations in TP53, which seems to be a crucial event in the pathogenesis of these tumors. We recently performed a series of siRNA lethality screens in vitro (N = 11 cell lines) to identify, in an unbiased way, recurrent vulnerabilities that could be harnessed as novel targets for TNBC therapy. Hits were genes whose silencing triggered massive cell death in ≥ 30% of TNBC lines tested. The screens re-discovered mitosis as a frequent Achilles’ heel of these tumors (antimitotic drugs are currently a mainstay of TNBC therapy), supporting the validity of the approach. The nuclear transport gene RAN also scored among the most frequent TNBC selective dependencies. Moreover, TNBC cell lines were exquisitely sensitive to selinexor (KPT-330), a first-in-class inhibitor of exportin 1 (XPO-1) currently in phase 2 trials, both in vitro and in vivo. TNBC cells treated with selinexor died of apoptosis. In contrast, normal human primary breast epithelial progenitors (BPE) underwent cell cycle arrest (but not death) upon selinexor treatment, and were able to resume proliferation upon drug removal. The efficacy of selinexor across different TNBC models varied, suggesting that additional factors, beside the TNBC status, are at play. Preliminary data based on a genome-wide CRISPR screen for genes and networks conferring sensitivity to selinexor using a p53-mutant TNBC cell line (MDA-MB-231) implicated a number of TP53-related genes as key mediators of response. Together, these data support the notion that p53-mutant TNBC coopt nuclear export function to silence TP53-associated networks and that XPO-1 inhibitors could be a viable strategy to tackle TNBC in the clinic.
Citation Format: Fabio Petrocca. Targeting nuclear export for triple-negative breast cancer therapy. [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 74.
Abstract 743: Tyrosine kinase discoidin domain receptor-1 (DDR1) regulates cytotoxicity of recombinant immunotoxin for cancer therapy
Authors: Ali-Rahmani Fatima , Fitzgerald David , Martin Scott , Patel Paresma , Prunotto Marco , Ormanoglu Pinar , Thomas Craig , Pastan Ira 
Published: July 2016

Abstract
Discoidin domain receptor 1 (DDR1) is a collagen-activated tyrosine kinase that facilitates cell adhesion, migration, proliferation and matrix remodeling. The collagen/DDR1 axis is also thought to modulate tumor-stromal interaction and potentially affects tumor response to therapy. Mesothelin is a cell-surface protein over-expressed in several human cancers including mesothelioma, ovarian, lung, breast, and pancreatic cancers with limited expression on normal cells. RG7787 is a clinically optimized recombinant immunotoxin (RIT) consisting of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A in which immunogenic B cell epitopes are silenced. To enhance therapeutic efficacy of RITs we conducted a kinome RNAi sensitization screen which identified DDR1 as a potential target. We hypothesized that DDR1 regulates RIT activity and its inhibition might enhance cell killing by RG7787. Knockdown of DDR1 by siRNA or treatment with inhibitor, ‘7rh’, greatly enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed DDR1 silencing was associated with a decrease in several ribosomal proteins and enhanced inhibition of protein synthesis. Induction of DDR1 expression or stimulation of DDR1 activity by collagen protected cancer cells from RG7787 killing, while DDR1 inhibition enhanced killing by RG7787. Moreover, the combination of immunotoxin and DDR1 inhibitor caused significantly more shrinkage of epithelial A431/H9 and pancreatic KLM1 tumor xenografts than either agent alone. These data demonstrate that DDR1 has a critical role in modulating immunotoxin activity. Inhibition of DDR1 represents a novel strategy to enhance therapeutic efficacy of RITs targeting mesothelin-expressing cancers.
Citation Format: Fatima Ali-Rahmani, David Fitzgerald, Scott Martin, Paresma Patel, Marco Prunotto, Pinar Ormanoglu, Craig Thomas, Ira Pastan. Tyrosine kinase discoidin domain receptor-1 (DDR1) regulates cytotoxicity of recombinant immunotoxin for cancer therapy. [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 743.
Abstract 756: Myo-inositol modulates the tumor microenvironment in a mouse model of lung cancer chemoprevention
Authors: Unver Nese , Zeleke Kirubel T. , Tang Ximing , Holt Samantha , Moghaddam Seyed Javad M. , Wang Hong , Wistuba Ignacio I. , Hanash Samir M. , Ostrin Edwin J. 
Published: July 2016

Abstract
Background: Myo-inositol is a nutritional supplement that has been investigated as a chemopreventive agent for lung cancer. We have investigated the effect of myo-inositol in a CC-LR (CCSPCre/LSL-K-rasG12D) mouse lung cancer model. Blood, broncho-alveolar lavage fluid (BALF), and lungs were collected from CC-LR and LR littermate control mice at 14 weeks of age, when mice had a large number of premalignant lesions with only small foci of adenocarcinoma.
Methods: Lesion burden and stage was quantified using macroscopically evident lung surface tumor counts as well as histology from paraffin sections. Serial paraffin sections were also used for immunohistochemistry. Plasma was analyzed using high-sensitivity liquid-chromatography coupled tandem mass spectrometry. Cytokine and chemokine concentrations in BALF were quantitated using multiplex immunobead assays.
Results: Myo-inositol treated mice (n = 20) had fewer tumors (p &lt; 0.0001) than mice raised on control diet (n = 23). Additionally, lesions were shifted towards lower grade, from adenomas and adenomatous alveolar hyperplasia to bronchial hyperplasia. Several host factors including cytokines and proteins produced by myeloid derived suppressor cells and macrophages were significantly impacted by myo-inositol treatment. In addition to changes in metabolic inflammation derived factors, proteins which are associated with both chronic inflammation and lung tumorigenesis were altered as well.
Conclusions: Myo-inositol treatment both reduced tumor burden and lesion grade in a KRAS model of lung cancer. Our findings of a substantial impact of myo-inositol treatment on the host response suggests novel mechanisms for its chemopreventive activitiy.
Citation Format: Nese Unver, Kirubel T. Zeleke, Ximing Tang, Samantha Holt, Seyed Javad M. Moghaddam, Hong Wang, Ignacio I. Wistuba, Samir M. Hanash, Edwin J. Ostrin. Myo-inositol modulates the tumor microenvironment in a mouse model of lung cancer chemoprevention. [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 756.
Abstract 760: Identifying candidate genes that regulate tumor cell dormancy
Authors: Nini Ryan J. , El Touny Lara H. , Murgai Meera , Kaplan Rosandra N. , Green Jeffrey E. 
Published: July 2016

Abstract
Tumor cells disseminate from the primary tumor site early in the disease process. These disseminated tumor cells may remain dormant for years and later become proliferative to cause clinical recurrence and morbidity. The goal of this study is to better understand the biological and genetic mechanisms driving this dormant to proliferative switch. We have developed a 3D culture system using the dormant murine mammary tumor cell line, D2.0R. D2.0R cells remain dormant when cultured on basement membrane extract (BME), and exit dormancy when supplemented with collagen-1 (col-1). We have characterized the gene expression profile of these cells exiting dormancy in 3D through microarray analysis, and developed a fourteen-gene dormancy signature by profile cross-referencing this expression profile to a tumor cell dormancy signature developed by Kim, R.S. et al (PLOS ONE 2012). We hypothesize that knocking down expression of genes upregulated in proliferative cells will hinder the ability of D2.0R cells to break dormancy in 3D culture supplemented with collagen-1. We have validated three genes by qPCR and are screening these upregulated genes for biological effects on proliferation by short-hairpin RNA or molecular inhibition of D2.0R cells in our 3D model. We conclude that this signature will provide useful insight into genetic drivers of the dormant to proliferative switch and potential candidates as therapeutic targets in recurrent disease.
Citation Format: Ryan J. Nini, Lara H. El Touny, Meera Murgai, Rosandra N. Kaplan, Jeffrey E. Green. Identifying candidate genes that regulate tumor cell dormancy. [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 760.
Abstract 779: The role of exosome-mediated cell-cell communication in inducing phenotypic changes
Authors: Lu Mingyang , Capello Michela , Tripathi Satyendra C. , Levine Herbert , Ben-Jacob Eshel , Hanash Samir M. , Onuchic José 
Published: July 2016

Abstract
A new class of intercellular communication has recently emerged that involves transfer of exosomes, especially during the interactions between tumor and the immune system. However, the advantage of exosome-mediated cell-cell communication over direct cell to cell communication mechanisms or through soluble factors is unclear. We have performed mass spectrometry based proteomic profiling of exosomes isolated from pancreatic cancer cell lines, for the exosome cell surface and for the protein cargo. The resulting profiles were compared with proteomic profiles of corresponding cell lysates. We uncovered substantial enrichment in protein pairs in exosomes across cell lines but not in cell lysates, suggestive of a mechanism of exosome-based protein sorting and packaging that favor specific protein combinations. Stochastic simulations and analytical analysis provide supportive evidence that exosomes enable recipient cells to rewire gene regulatory networks to induce robust phenotypic transitions among different gene states. Moreover, from the simulation of two-way exosome-mediated communication of two cell types, we show that cells could achieve synchronized decision making through exosomes. Our integrative approach provides new insights into unique features of exosome-mediated cell-cell communication.
Citation Format: Mingyang Lu, Michela Capello, Satyendra C. Tripathi, Herbert Levine, Eshel Ben-Jacob, Samir M. Hanash, José Onuchic. The role of exosome-mediated cell-cell communication in inducing phenotypic changes. [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 779.
Abstract 828: α-Lipoic acid inhibits human hepatoma cell proliferation by Grb2-mediated downregulation of EGFR activity
Authors: Yang Lan , Lin Yuntao , Wen Ya , Sun XiaoJuan 
Published: July 2016

Abstract
Background: It has been reported that α-Lipoic acid (α-LA) as a naturally occurring anti-oxidant, suppresses the growth of hepatoma cells, but the mechanisms remains unclear.
Aims: To investigated whether α-LA inhibited hepatoma cells proliferation through EGFR-Grb2.
Methods and Results: The results showed that Hu7, Bel7402 and HepG2 proliferation were dramatically decreased after α-LA (2 mM) treatment for 24 and 48 hours, which were measured by CCK8 assay. Moreover, phosphorylation levels of EGFR was decreased by α-LA treatment, and its associated with an inhibition in cell-cycle transition. Next, we found that growth factor receptor bound protein 2 (Grb2), which is adaptor protein, was also significantly reduced by RT-PCR and western blot after α-LA treatment at 24 and 48 hours. Consistent with previous report, silenced of Grb2 dramatically blocked cell proliferation. To test whether the downregulation of Grb2 mediates α-LA induced proliferation inhibition, Grb2 was transfected into hepatoma cells to recover the reduction of Grb2 induced by α-LA. It was showed that overexpression of Grb2 also successfully inhibited α-LA induced decrease of cell proliferation. In addition, the data showed that phosphorylation levels of ERK1/2 was decreased by cell treated with α-LA. These results suggested that the Grb2 through binds to phosphorylated site in EGFR medicated α-LA suppress cell proliferation.
Conclusion: Our study showed α-LA inhibited cell proliferation through Grb2 suppressed phosphorylation levels of EGFR, ERK1/2 was involved in this pathway.
Citation Format: Lan Yang, Yuntao Lin, Ya Wen, XiaoJuan Sun. α-Lipoic acid inhibits human hepatoma cell proliferation by Grb2-mediated downregulation of EGFR activity. [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 828.
Abstract 833: Benzyl isothiocyanate mediates glucose uptake through AKT activation in breast cancer cells
Authors: Roy Ruchi , Singh Shivendra V. 
Published: July 2016

Abstract
We have shown previously that benzyl isothiocyanate (BITC) administration retards the development of mouse mammary tumors driven by Her-2 oncogene proving in vivo evidence for its chemopreventive efficacy. However, we also observed an increase in glucose uptake by tumor in BITC treatment group compared with control mice. Proteomics using tumors from control and BITC-treated mice revealed changes in proteins related to metabolism. Thus, we studied the mechanism by which BITC increases glucose uptake using four cell lines with different genetic backgrounds (e.g., ER+, ER-, HER-2+, triple negative). Consistent with in vivo findings, BITC treatment enhanced the protein levels of glucose transporters (GLUT1 and GLUT4) regardless of ER, HER-2 or p53 status. On the other hand, lactate dehydrogenase (LDH) was downregulated in response to BITC treatment. Pyruvate kinase (PKM2) as well as tricarboxylic cycle (TCA cycle) related enzymes (IDH1, PDH, MDH) were upregulated in BITC treated cells compared with control. In agreement with these results, BITC treatment increased glucose, pyruvate, and acetyl-CoA levels but decreases lactate level. These results suggested that elevated glucose after BITC treatment was largely utilized through TCA cycle. Because AKT is known to regulate tumor metabolism including glycolysis and oxidative phosphorylation, we explored its involvement in BITC-mediated metabolic alterations. To our surprise, BITC treatment resulted in a marked increase in activation of AKT. Pharmacological inhibition of AKT antagonized BITC-mediated increase in GLUT1 expression as well as increase in glucose and pyruvate levels. In addition, AKT inhibition augmented BITC-mediated inhibition of cell survival (colony formation), induction of apoptosis, and suppression of migration in human breast cancer cells. Based on these findings, we propose that mammary cancer chemopreventive efficacy of BITC may be augmented by a combination regimen involving an AKT inhibitor. This study was supported by the grantCA129347 awarded by the National Cancer Institute.
Citation Format: Ruchi Roy, Shivendra V. Singh. Benzyl isothiocyanate mediates glucose uptake through AKT activation in breast cancer cells. [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 833.
Abstract 841: Effect of equol on hormone-dependent rat mammary carcinoma induced by ethyl methanesulphonate (EMS)
Authors: ONO MISAKI , Higuchi Takako , Takeshima Mikako , Nakano Shuji 
Published: July 2016

Abstract
Soy isoflavones such as daidzein and its bioactive metabolite equol converted from daidzein by human intestinal bacterial flora, have been proposed to reduce the risk of breast cancer incidence in Asian women probably due to higher number of the inhabitants capable of producing equol in these countries. Although several in vitro studies shows the anti-cancer activity of equol against human breast cancer cells, there have been few reports that have directly showed the preventive role of equol in the experimental animal model of mammary carcinoma. We investigated here the effects of equol on the development of breast cancer using the EMS chemically induced rat model of hormone-dependent mammary carcinoma. Female WKA rats (n = 30) were equally divided into 2 groups, subsequently given EMS orally for 12 weeks and fed the CE2 diets with or without 50 mg equol/g diet throughout the experiments. All EMS-treated rats fed either diet developed ER- and/or PgR- positive hormone-dependent mammary carcinoma by 24 weeks. Compared with the equol-free diet, the diet supplemented with equol could not significantly delay the development of mammary carcinoma, showing any preventive activity on the development of EMS-induced hormone-dependent mammary carcinoma. The body weight, total EMS uptakes, and urine estradiol concentrations were not significantly different between these 2 groups. These data indicate that high dose administration of equol alone does not exert clear preventive effects on hormone-dependent EMS-induced mammary carcinogenesis, and may require other soy isoflavone components such as genistein that has previously been shown to exhibit a great synergy when combined with equol. The in vivo combination studies using genistein and equol are underway.
Citation Format: MISAKI ONO, Takako Higuchi, Mikako Takeshima, Shuji Nakano. Effect of equol on hormone-dependent rat mammary carcinoma induced by ethyl methanesulphonate (EMS). [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 841.
Abstract 845A: Novel twin method estimates genetic prevalence of breast cancer
Authors: Baker Stuart G. 
Published: July 2016

Abstract
The standard twin method of the last one hundred years uses data from fraternal and identical twins to estimate heritability, which is the fraction of the variance attributed to genetic effects under an additive genetic model. Using the same data, the latent class twin method estimates a more easily interpretable quantity, the genetic prevalence, which is the fraction persons with an outcome who are in a genetic susceptibility latent class. A key assumption is that the genetic susceptibility latent class has relatively large independent probabilities of outcome as compared with an environmental susceptibility latent class with smaller and possibly dependent probabilities of outcome. Unlike the standard twin method which assumes additive genetic inheritance, the latent class twin method also allows for autosomal recessive, autosomal dominant inheritance. The method handles survival data by treating loss-to-follow up and death from competing risk as non-informative censoring. Applying this methodology to registry data from 45,000 pairs of Nordic twins, we estimated a genetic prevalence for breast cancer of only 1%. Because BRCA1 and BRAC2 have a combined prevalence of around 1%, there are likely no other high-penetrance genes contributing to breast cancer
Citation Format: Stuart G. Baker. Novel twin method estimates genetic prevalence of 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 845A.
Abstract 869: Meditope enablement and structural analysis of anti-CD33 antibodies
Authors: Dumitru Calin D. , Matho Michael , Gardiner Elisabeth , Williams John C. , Bzymek Krzysztof 
Published: July 2016

Abstract
Meditope Biosciences’ SnAP (Site-specific novel Antibody Platform) technology provides a novel and specific way to create antibody drug conjugates (ADCs). Cyclic peptides, termed ‘meditopes’, have been designed to selectively bind to a ‘meditope binding site’ engineered into the Fab of an antibody. The process of conferring meditope binding is referred to as “meditope enablement”. Enabling antibodies for meditope binding does not interfere with antigen recognition or antibody integrity due to the unique location of the binding site. Meditope peptide binding can be utilized to attach cytotoxic payloads to an enabled antibody in a specific and consistent manner, and has the potential to dramatically improve the consistency of ADC production. For advanced hematological cancers such as CD33 positive acute myeloid leukemia (AML), using an anti-CD33 monoclonal antibody conjugated to a potent cytotoxic agent may be a useful tumor reduction strategy, especially when patients have failed other treatments. To this end, meditope enablement of lintuzumab and gentuzumab permits a consistent, site-specific attachment of cytotoxins with a highly controllable drug antibody ratio (DAR). Structural and biophysical characterization of the meditope enabled anti CD33 antibodies has provided key insight to the meditope enablement process. Experiments confirm that payload conjugation and meditope peptide binding does not interfere with antibody integrity or antigen recognition. The meditope peptide drug complexes were tested in cell-based assays for CD33-targeted cell killing. Using X-ray crystallographic analysis and guided docking, we propose modifications to further enhance affinity of the meditope peptide conjugate : CD33 antibody interaction.
Citation Format: Calin D. Dumitru, Michael Matho, Elisabeth Gardiner, John C. Williams, Krzysztof Bzymek. Meditope enablement and structural analysis of anti-CD33 antibodies. [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 869.