bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1792: Immune system pathway activation for prediction of the response to neoadjuvant chemotherapy in triple-negative breast cancer
Authors: Sawada Takeshi , Hilhorst Riet , Rangarajan Savithri , Yoshida Masayuki , Tamura Kenji , Beuningen Rinie van , Ruijtenbeek Rob , Tsuda Hitoshi , Koizumi Fumiaki 
Published: July 2017

Abstract
Background: Triple-negative breast cancer patients (TNBCs) who receive neoadjuvant chemotherapy (NAC) generally show a response to NAC, but about 5% experience progressive disease (PD). Although TNBCs that respond to NAC have been well-studied, reports about TNBCs with PD during NAC are absent. We aimed to compare kinase activity profiles of TNBCs of both groups to identify a biological predictor of NAC non-responders.
Methods: Tyrosine kinase activity profiles of lysates of fresh frozen cancer tissues from NAC non-responders and responders, the latter represented by TNBCs who did not receive NAC, were determined with a peptide microarray system (Cancer Res. 2009; 69(14):5987-95). Tumor infiltrating lymphocytes (TILs) were counted in these tissues.
Results: Among 740 TNBCs, 20 NAC non-responders were identified. For the 7 samples from PD confirmed patients and 10 TNBCs not receiving NAC, no correlation was observed between NAC response and age, menopausal status, tumor size or axillary lymph node status. Kinase activity measurements showed large differences in overall tyrosine kinase activity between responders and non-responders. 35 peptides had significantly (p &lt; 0.05) higher phosphorylation in the responder group. Kinases that phosphorylate these peptides (upstream kinases) were identified from literature. Among others, the immune related kinases Zap70, Syk and JAK2 were identified as upstream kinases. Pathway analysis yielded evidence for increased activity in the responder group in immune-related pathways and in pathways involved in development and signal transduction. Responders had a significantly higher (p = 0.0053) TILs count.
Conclusion: Kinases related to the immune system are less activated in NAC non-responders. The low TILs count in the non-responders confirmed that activation of the immune system in non-responders is lower than in NAC responders. These data merit a further investigation of the use of kinase activity profiling either alone or in combination with TIL scoring for the prediction of the response to NAC in TNBC with a larger patient cohort.
Citation Format: Takeshi Sawada, Riet Hilhorst, Savithri Rangarajan, Masayuki Yoshida, Kenji Tamura, Rinie van Beuningen, Rob Ruijtenbeek, Hitoshi Tsuda, Fumiaki Koizumi. Immune system pathway activation for prediction of the response to neoadjuvant chemotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1792. doi:10.1158/1538-7445.AM2017-1792
Abstract 1799: CRM1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity
Authors: Saulino David M. , Younes Pamela S. , Bailey Jennifer M. , Younes Mamoun 
Published: July 2017

Abstract
Introduction: CRM1 is a nuclear export chaperone that mediates the export of proteins essential to growth regulation and tumor suppression. Its overexpression in tumors was found to be associated with poor prognosis. Selective inhibitors of nuclear export are in phase I and II clinical trials for several tumor types. The expression of CRM1 in human pancreatic adenocarcinoma (PAC) and its relation to survivin expression and tumor proliferative activity is largely unknown.
Experimental procedures: Sections of tissue microarray containing 77 formalin fixed and paraffin embedded PAC were stained by immunohistochemistry (IHC) for CRM1, survivin, and Cyclin A. Expression levels of CRM1 and survivin in tumor cells was determined using a quantitative digital image analysis solution (OTMIAS). The tumor proliferative activity was determined by measuring the S-phase fraction (SPF) in sections stained for Cyclin A, also using OTMIAS.
Summary: Sixty-six of the 77 (86%) PAC showed at least some positive staining for CRM1, and 11 (14%) were completely negative. The mean CRM1 expression levels ranged from 0.3 to 53 units and the median from 0.3 to 45 units. There was significant positive correlation between the mean and median expression levels of CRM1 in tumor cells with the mean and median levels of survivin (p&lt;0.001). Moreover, there was positive correlation between the mean and median CRM1 levels in tumor cells the SPF (p=0.005).
Conclusions: CRM1 is expressed in a significant proportion of PAC, and increased CRM1 expression correlates with increased survivin expression and increased proliferative activity, suggesting that selective inhibitors of nuclear export may be effective against PAC.
Note: This abstract was not presented at the meeting.
Citation Format: David M. Saulino, Pamela S. Younes, Jennifer M. Bailey, Mamoun Younes. CRM1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1799. doi:10.1158/1538-7445.AM2017-1799
Abstract 181: Discovery of novel targeted therapeutics for metastatic breast cancer
Authors: Valle Cristina Del , Hernández Eliud , Vlaar Cornelis P. , Cubano Luis A. , Dharmawardhane Suranganie , Castillo-Pichardo Linette 
Published: July 2017

Abstract
Metastatic disease is the primary cause of breast cancer mortality, due to the lack of effective therapy. The Rho GTPase Rac is integral for the promotion of cancer cell migration/invasion, proliferation, and survival. Since metastatic breast cancers often overexpress or exhibit high Rac activity, inhibition of Rac is a viable strategy against metastatic cancer. Recently, we characterized EHop-016, a small molecule that inhibits Rac activity of metastatic breast cancer cells with an IC50 of 1 µM. EHop-016 is 10-100 times more active than previously available Rac inhibitors, and is the first compound shown to inhibit the activation of Rac by the oncogenic GEF Vav. EHop-016 inhibits the activity of the Rac downstream effector p21 activated kinase (PAK), lamellipodia extension, and cell migration of metastatic breast cancer cells. We also reported that EHop-016 at ≥ 25 mg/kg Body Weight (BW) significantly reduced tumor growth, metastasis, and angiogenesis in a mouse model. However, our recent pharmacokinetic study of EHop-016 in a mouse model demonstrated that the bioavailability of Ehop-016 needs to be improved for further pharmacological development. Therefore our hypothesis is that improvement of the EHop-016 structure will provide probes with increased potency against Rac and, therefore, increased bioavailability. Herein we have tested several Ehop-016 derivatives for their effects on breast cancer cell viability and Rac activation. Using MTT assays we found that the Ehop-016 derivatives, HV-107 and HV-118, significantly inhibit the viability of metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-435. The effects of HV-107 and HV-118 on the inhibition of Rac activation were tested by ELISA-based Rac activity assays and pulldown assays. Results show that at 250nM, HV-107 inhibits Rac activation by 55%, whereas HV-118 has a similar effect at 100nM in MDA-MB-231 and MDA-MB-435 cells. Taken together, our findings suggest HV-107 and HV-118 as promising Ehop-016 derivatives with potential as anti-metastatic agents, which should be further characterized.
This study was supported by awards from the Susan Komen for the Cure, NIH/NIMHHD U54MD008149, and the Puerto Rico Science and Technology Trust to SD; NIH/NCRR R25GM061838 to UPR MSC; NIH/NIMHHD RCMI 8G12MD007583RCMI, Title V PPOHA 031M10505 and Title V Cooperative P031S130068 from U.S. Department of Education to UCC; and PRINBRE (NIH/NIGMS P20GM103475-13) Pilot Project to LCP.
Citation Format: Cristina Del Valle, Eliud Hernández, Cornelis P. Vlaar, Luis A. Cubano, Suranganie Dharmawardhane, Linette Castillo-Pichardo. Discovery of novel targeted therapeutics for metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 181. doi:10.1158/1538-7445.AM2017-181
Abstract 1816: Endogenous ADAMTS-13 regulates angiogenesis in cultured human endothelial cells
Authors: Tang Huiyuan , Lee Manfai , Kim Eun Ho , Bishop Daniel , Rodgers George M. 
Published: July 2017

Abstract
ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a zinc-containing metalloprotease that cleaves von Willebrand factor (vWf). Previous publications by our laboratory have shown that ADAMTS-13 may also be involved in angiogenesis; for example; addition of exogenous ADAMTS-13 enhances endothelial cell (Lee et al. Microvascular Res 2012; 84:109) and glioblastoma cell (Lee et al. Blood 2013; 122:#2306) migration and proliferation. For this study, we report the successful transient knockdown of endogenous ADAMTS-13 in human umbilical vein endothelial cells (HUVEC) via siRNA. 30pmols of ADAMTS-13 siRNA in a six-well plate inhibited HUVEC ADAMTS-13 expression levels by 90% after 24hr incubation, whereas control siRNA did not affect endogenous ADAMTS-13 levels. The knockdown effect was decreased over time: 72hr after the initial knockdown, ADAMTS-13 expression was reduced by only 50%. The effects of reduced endogenous ADAMTS-13 on HUVEC angiogenesis functions were studied. Transfection of HUVEC with 10pmols of ADAMTS-13 siRNA in a 24-well plate resulted in a 21% and 22% decrease in proliferation after 24hr and 48hr incubation, respectively. The effects of ADAMTS-13 knockdown on migration of HUVEC across a scratch wound were also evaluated. 24hr after transfection with control siRNA, there was robust cell migration across the scratch wound. This dramatic migration did not occur with ADAMTS-13 knockdown cells. Decreased expression of endogenous ADAMTS-13 also affected angiogenesis as measured by endothelial cell tube formation using a Matrigel matrix method. The tube lengths, sizes and junction numbers of the ADAMTS-13 knockdown cells were all significantly lower compared to control cells by about 40%. Activity of the AKT pathway, one of the angiogenesis downstream signaling pathways was down-regulated by ADAMTS-13 siRNA while ERK, a component of the MAP kinase pathway was not affected upon knockdown of ADAMTS-13. These data indicate that in cultured endothelial cells, one role of endogenous ADAMTS-13 is regulation of angiogenesis, mediated through the AKT signaling pathway. Overall, our data suggest an additional model of endogenous ADAMTS-13 functionality, beyond that of cleaving von Willebrand factor.
Citation Format: Huiyuan Tang, Manfai Lee, Eun Ho Kim, Daniel Bishop, George M. Rodgers. Endogenous ADAMTS-13 regulates angiogenesis in cultured human endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1816. doi:10.1158/1538-7445.AM2017-1816
Abstract 1817: Resistin induces angiogenesis and lymphangiogenesis in human chondrosarcoma
Authors: Chi Meng-Ju , Lin Chih-Yang , Tang Chih-Hsin 
Published: July 2017

Abstract
Chondrosarcoma is a common kind of bone cancers, and it may develop distant metastasis, followed by a significant decline in overall survival. However, there are still no specific therapeutic methods for it today. For tumors to metastasis, angiogenesis and lymphangiogenesis are both important in the early processes. Therefore, inhibiting the development of angiogenesis and lymphangiogenesis could be a method to decline tumor metastasis. Resistin was discovered as an adipocyte-secreting adipokine, which may play a critical role in modulating cancer pathogenesis. In our lab, we previously found that resistin appears to increase MMP-2 expression and then promotes metastasis in human chondrosarcoma cells. Nevertheless, the role of resistin in angiogenesis and lymphangiogenesis of human chondrosarcoma is still unknown. To examine angiogenetic and lymphangiogenetic effects of resistin, we used human endothelial progenitor cells (EPCs) and lymphatic endothelial cells (LECs) to mimic capillary and lymphatic vessels formation. The results indicated that resistin-treated chondrosarcoma cell lines promoted EPCs VEGF-A-dependent as well as LECs VEGF-C-dependent tube formation and cell migration. Then we confirmed that treating cells with resistin increased VEGF-A and VEGF-C expression in human chondrosarcoma cell lines. Moreover, we found resistin-induced VEGF-A and VEGF-C expressions are mediated by PI3K/AKT signaling and by the activation of c-Src separately. In addition, resistin decreased the expression of miR-16-5p via PI3K/AKT pathway, and so of miR-186 via c-Src. We also demonstrated that miR-186 directly targeted on VEGF-C 3’ untranslated region, and regulated the VEGF-C production. Besides, we found the expressions of resistin, VEGF-A and VEGF-C was higher in human chondrosarcoma biopsy tissues than those in normal cartilage. Taken together, resistin not only promotes human chondrosarcoma angiogenesis through the activation of PI3K/AKT signaling pathway and down-regulating miR-16-5p expression, but also promotes human chondrosarcoma lymphangiogenesis through the activation of c-Src and down-regulating miR-186. Consequently, resistin may represent a potential novel molecular therapeutic target for human chondrosarcoma therapeutic treatment.
Citation Format: Meng-Ju Chi, Chih-Yang Lin, Chih-Hsin Tang. Resistin induces angiogenesis and lymphangiogenesis in human chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1817. doi:10.1158/1538-7445.AM2017-1817
Abstract 1832: Bioluminescent pharmacokinetics of luciferin in preclinical brain metastases of breast cancer models
Authors: Shah Neal , Adkins Chris E. , Mohammad Afroz S. , Lockman Paul R. 
Published: July 2017

Abstract
Background: Approximately 20% of breast cancer patients with disseminated disease will develop brain metastases. Preclinical models of brain metastases of breast cancer rely on ex-vivo histology to evaluate drug efficacy. However, bioluminescence imaging allows more precise quantification of tumor burden and progression through counting photons per second without requiring animal sacrifice. This methodology has not readily been applied to hematogenously derived brain metastases models given the heterogeneity of tumor burden and growth. Herein we demonstrate repeatable methodology to quantify brain metastases of breast cancer progression which is verified with histology.
Methods: Approximately 1.75 x 105 JIMT-1 (n=3) and 231-BrLuc (n=4) brain seeking subclones were injected intracardially to produce metastatic brain lesions. Mice were given 150 mg/kg of luciferin IP and luminescence was captured every 2-minutes for 60 minutes starting 24 hours after cell implantation. Radiance (photons per second per square centimeter per steridian) was plotted to observe peak luminescence. Imaging was repeated twice weekly to evaluate progression until euthanasia.
Results: Following intracardiac injection, both brain seeking metastatic models produced a maximum luminescence signal between 14-20 minutes after luciferin injection. For all subsequent imaging, 5 minute imaging between 15-20 minutes after luciferin injection was used. Longitudinally, both tumor cell lines produce bioluminescence 24 hours after cell injection, which is used to ensure tumor implantation and randomization. The BLI signal decreases to undetectable limits in both models between 3-7 days after cell implantation. Re-emergence of signal occurs on day 14 for the JIMT-1 line and day 21 for 231-Br line. JIMT-1 bioluminescence on day 14 begins at ~105 photons/sec/cm2/sr and then over time signal increases with an ~slope of 5.6x105 until reaching a maximum of 107 units on day 28. 231-Br bioluminescence on day 21 begins at ~104 photons/sec/cm2/sr and then over time signal increases with an ~ slope of 1.1x106 until reaching a maximum of ~107 on day 53.
Conclusion: To accurately measure bioluminescence as a surrogate for tumor burden in hematogenously implanted metastases, the optimal circulation time is approximately 15 minutes with a 5 minute imaging period. Bioluminescence of the 231Br line initially starts at a lower magnitude and later in time than the JIMT-1 line, but slopes of both intracardiac models are similar and result in similar bioluminescent curves.
Citation Format: Neal Shah, Chris E. Adkins, Afroz S. Mohammad, Paul R. Lockman. Bioluminescent pharmacokinetics of luciferin in preclinical brain metastases of breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1832. doi:10.1158/1538-7445.AM2017-1832
Abstract 1834: Constitutive Nedd9 null genotype promotes lung cancer aggressiveness
Authors: Deneka Alexander , Kopp Meghan , Nikonova Anna S. , Gaponova Anna , Nagele Alexandra , Hensley Harvey , Golemis Erica 
Published: July 2017

Abstract
Non-small cell lung cancer (NSCLC) has a low survival rate, with metastasis contributing to the vast majority of deaths. The NEDD9 (HEF1/Cas-L) protein has been reported to be elevated in expression and to promote metastasis in a large subset of lung cancers and in other malignancies. NEDD9 functions as a scaffold for multiple critical effectors in integrin/FAK/SRC and receptor tyrosine kinase signaling cascades, as well as for the mitotic kinase Aurora-A, with overexpression thought to sustain signaling by these pro-oncogenic proteins. Previous studies demonstrated depletion of NEDD9 by RNAi reduced the growth and invasion of established lung cell lines and tumors, based on cell culture and xenograft assays. We have now investigated the consequences of a null genotype for Nedd9 from the earliest stages of tumor formation, crossing Nedd9 null mice to a 129S/Sv-Krastm3Tyj/Trp53tm1Brn (KP) model in which Kras mutation is induced specifically in lung tissue by inhalation of adenovirus bearing the Cre gene. Unexpectedly, based on in vivo imaging, the Nedd9 null genotype significantly accelerated tumor growth in KP mice. Pathological examination of tissues indicated Nedd9 null genotype also was associated with higher invasive capacity in vivo, including direct invasion to the heart, as well as elevated proliferation rate, decreased apoptotic activity, and changes in the expression of proteins such as vimentin, associated with mesenchymal status. Although Nedd9 function has been implicated in immune cell activity, we found minimal differences in tumor infiltration of myeloid cells or macrophages based on Nedd9 genotype. Rather, use of Reverse Phase Protein Array (RPPA) analysis to characterize signaling in isolated tumors suggested tumor intrinsic changes in glycolytic and proliferative signaling pathways, which were subsequently validated using direct functional assays. These results for the first time imply that NSCLC tumor progression beyond early stages in the absence of Nedd9 requires reprogramming of intrinsic tumor signaling to compensate for the absence of this protein, emphasizing activities distinct from those associated with elevated Nedd9 in late stage tumors.
Citation Format: Alexander Deneka, Meghan Kopp, Anna S. Nikonova, Anna Gaponova, Alexandra Nagele, Harvey Hensley, Erica Golemis. Constitutive Nedd9 null genotype promotes lung cancer aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1834. doi:10.1158/1538-7445.AM2017-1834
Abstract 1846: Immunocompetent mouse allograft models for development of therapies to target breast cancer metastasis therapies to target breast cancer metastasis
Authors: Yang Yu-an , Yang Howard , Hu Ying , Watson Peter , Liu Huaitian , Geiger Thomas R. , Anver Miriam R. , Haines Diana , Martin Philip , Lee Maxwell P. , Hunter Kent W. , Wakefield Lalage M. 
Published: July 2017

Abstract
Effective drug development to combat metastatic disease in breast cancer would be aided by the availability of well-characterized preclinical animal models that (a) metastasize with high efficiency, (b) metastasize in a reasonable time-frame, (c) have an intact immune system, and (d) capture some of the heterogeneity of the human disease. To address these issues, we have assembled a panel of twelve mouse mammary cancer cell lines that can metastasize efficiently on implantation into syngeneic immunocompetent hosts. Genomic characterization shows that more than half of the 30 most commonly mutated genes in human breast cancer are represented within the panel. Transcriptomically, most of the models fall into the luminal A or B intrinsic molecular subtypes, despite the predominance of an aggressive, poorly-differentiated or spindled histopathology in all models. Patterns of immune cell infiltration, proliferation rates, apoptosis and angiogenesis differed significantly among models. Inherent within-model variability of the metastatic phenotype mandates large cohort sizes for intervention studies but may also capture some relevant non-genetic sources of variability. The varied molecular and phenotypic characteristics of this expanded panel of models should aid in model selection for development of anti-metastatic therapies in vivo, and serve as a useful platform for predictive biomarker identification.
Citation Format: Yu-an Yang, Howard Yang, Ying Hu, Peter Watson, Huaitian Liu, Thomas R. Geiger, Miriam R. Anver, Diana Haines, Philip Martin, Maxwell P. Lee, Kent W. Hunter, Lalage M. Wakefield. Immunocompetent mouse allograft models for development of therapies to target breast cancer metastasis therapies to target breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1846. doi:10.1158/1538-7445.AM2017-1846