tbuckley/cabot-search huggingface dataset:
Abstract 5520: CCN5/WISP-2 is a negative regulator of epithelial to mesenchymal transition and stemness in breast cancer
Authors: Gargi Maity, Amlan Das, Sandipto Sarkar, Snigdha Banerjee, Sushanta K. Banerjee
Journal: Cancer Research (2017)

Abstract Background and Objective: Breast cancer is the most common cancer in women and a leading cause of cancer mortality in western countries. CCN5 (also known as Wnt-1-induced signaling protein-2 or WISP-2) is a 29-31-kDa matricellular protein that plays as a negative regulator of breast carcinoma. Our previous studies had shown the importance of CCN5/ WISP-2 in the suppression of breast and pancreatic cancer progression through the regulation of the invasive phenotypes. Considering the previous report, our aim is to investigate whether human recombinant CCN5 inhibit pathobiological events like epithelial to mesenchymal transition (EMT), migration and stemness in triple negative breast cancer cells. Methods: To investigate the negative impact of CCN5 on EMT and stemness of TNBC, we performed several techniques like western blot, clonoogenic assay, soft agar assay, sphere formation assay etc. Results and Conclusions: The exposure of triple negative human breast cancer cells (TNBC), MDA-MB-231 and HCC-70, to recombinant CCN5 (hrCCN5), resulted in a dose-dependent inhibition of cell-proliferation through the induction of apoptotic cell death. The treatment of hrCCN5 regulates various pathobiological events in breast cancer cells, such as reprogramming the mesenchymal to epithelial transition (MET) followed by reduction of stemness features as confirmed by sphere formation assay and delaying in vitro migration. Finally, treatment with hrCCN5 in TNBC cells significantly inhibited anchorage-dependent and independent growth of TNBC. Collectively, CCN5’s control of cancer cell physiology indicates that hrCCN5 has the potential of being used as a major therapeutic agent against triple negative breast cancer. Citation Format: Gargi Maity, Amlan Das, Sandipto Sarkar, Snigdha Banerjee, Sushanta K. Banerjee. CCN5/WISP-2 is a negative regulator of epithelial to mesenchymal transition and stemness in 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 5520. doi:10.1158/1538-7445.AM2017-5520
Abstract 1650: Targeting CD47- SIRPα interaction by novel peptide-based antagonists
Authors: Pottayil G. Sasikumar, Chennakrishnareddy Gundala, Nagaraj M. Gowda, Sudarshan S. Naremaddepalli, Archana Bhumireddy, Rashmi Nair, Wesley Roy Balasubramanian, Anirudha Lakshminarasimhan, Samiulla S. Dodheri, Kiran Aithal, Raghuveer K. Ramachandra, Girish Daginakatte, Murali Ramachandra
Journal: Cancer Research (2017)

Abstract Background: Cluster of differentiation (CD47) is a trans-membrane glycosylated protein which is upregulated in several cancers. Increased expression of CD47 on tumor cells is associated with immune evasion and cancer progression. CD47 through its interaction with signal regulatory protein alpha (SIRPα), a cell-surface molecule on macrophages inhibits phagocytosis of tumor cells. Disrupting CD47-SIRPα interactions by monoclonal antibodies targeting CD47 and recombinant SIRPα proteins have been used as therapeutic strategies for treating cancer. Our objective was to discover and develop peptide/peptidomimetic based CD47 antagonists for disrupting CD47-SIRPα interactions. Methods: Through rational design based on crystal structure of CD47/SIRPα interacting interface, we designed peptides having potential to disrupt CD47-SIRPα interactions. FACS based cellular binding assay was developed to assess the binding affinity of CD47 antagonists. SIRPα protein labelled with fluorescent dye was incubated with Jurkat T cells expressing high levels of CD47 in the presence/absence of peptides. Binding affinity was measured by decrease in fluorescence. Functional activity of the peptides was evaluated in a FACS-based phagocytosis assays, in which tumor cells were incubated with human/mouse macrophages in the presence/absence of CD47 antagonists. Results: We identified CD47 antagonists demonstrating disruption of CD47-SIRPα interaction in a cellular binding assay. These peptides significantly inhibited phagocytosis of different tumor cells by macrophages. The lead CD47 antagonist displaying good ADME properties including moderate oral bioavailability was evaluated in a B16F10 syngeneic mouse tumor model. The lead CD47 antagonist inhibited primary tumor growth as well tumor metastasis to lungs. Biomarker characterization and efficacy studies in additional tumor models are ongoing. Citation Format: Pottayil G. Sasikumar, Chennakrishnareddy Gundala, Nagaraj M. Gowda, Sudarshan S. Naremaddepalli, Archana Bhumireddy, Rashmi Nair, Wesley Roy Balasubramanian, Anirudha Lakshminarasimhan, Samiulla S. Dodheri, Kiran Aithal, Raghuveer K. Ramachandra, Girish Daginakatte, Murali Ramachandra. Targeting CD47- SIRPα interaction by novel peptide-based antagonists [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 1650. doi:10.1158/1538-7445.AM2017-1650
Abstract 444: Monocarboxylate transporter 1 inhibition with AZD3965 increases cancer cell dependence on bioenergetic metabolism predicating combination therapy with mitochondrial inhibitors
Authors: Mounia Beloueche-Babari, Teresa Casals Galobart, Slawomir Wantuch, Paul D. Smith, Martin O. Leach
Journal: Cancer Research (2017)

Abstract Monocarboxylate transporters (MCTs) are key mediators of lactate transport that have emerged as promising targets for anti-cancer therapy. The MCT1 inhibitor AZD3965 (AstraZeneca) has shown promising activity in various pre-clinical models and is currently in phase I/II clinical testing. Understanding the impact of this drug on tumour cell metabolism may unravel dependencies that could be exploited for combination therapy. Here we investigate changes in glucose metabolism induced by AZD3965 treatment using 13C NMR isotopomer analysis, and examine their significance for cell survival using mitochondrial metabolism inhibitors. Exposure of Raji human lymphoma cells to AZD3965 in media supplemented with [1-13C]glucose led to a marked reduction in glucose uptake and lactate production in the cellular growth media alongside a build-up in intracellular [3- 13C]lactate and [1-13C]glucose levels, indicative of blockade of lactate excretion and inhibition of overall glycolytic activity. These effects were concomitant with increased [4-13C]glutamate levels, consistent with re-routing of pyruvate towards mitochondrial metabolism and enhanced flux through oxidative pyruvate dehydrogenase. Further, AZD3965 treatment was paralleled with a significant increase in levels of steady state Krebs cycle-related metabolites (including succinate, fumarate, acetate and NAD+/NADH) and cellular ATP, as revealed by bioluminescent and 1H NMR analyses, indicating improved mitochondrial metabolism and cellular re-energization. Co-administration of the mitochondrial complex I inhibitor metformin or the mitochondrial pyruvate carrier inhibitor UK5099 markedly potentiated the anti-proliferative effects of AZD3965 and led to significantly increased cell death, indicating that the observed upregulation in mitochondrial metabolism was necessary to maintain cell survival under MCT1 inhibitor-induced metabolic stress. Similar effects were observed with a second human lymphoma cell line, Hut78. Our findings show that MCT1 inhibition leads to a shift in cellular metabolism towards mitochondrial bioenergetic metabolism, creating a metabolic vulnerability that could be exploited for combinatorial therapy to increase the efficacy of AZD3965. Citation Format: Mounia Beloueche-Babari, Teresa Casals Galobart, Slawomir Wantuch, Paul D. Smith, Martin O. Leach. Monocarboxylate transporter 1 inhibition with AZD3965 increases cancer cell dependence on bioenergetic metabolism predicating combination therapy with mitochondrial inhibitors [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 444. doi:10.1158/1538-7445.AM2017-444
Abstract 3169: SerpinB2 enhances invadopodia-like structure protrusions and is down-regulated in acquired gefitinib-resistant non-small cell lung cancer cells
Authors: Song Yi Bae, Donghwa Kim, Hyen Joo Park, Woong Sub Byun, Ji-Young Hong, Hye-Jung Lee, Sang Kook Lee
Journal: Cancer Research (2017)

Abstract Non-small cell lung cancer (NSCLC) is a major type of lung cancer which accounts for approximately 80-85% of all lung cancers. The targeted therapies have significantly improved the survival of advanced NSCLC patients, but the failure of targeted therapy due to the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is now considered a major problem. SerpinB2 is a component of the urokinase plasminogen activator (uPA) system and has been recognized as a biomarker for the progression and metastasis of lung cancer. We found that SerpinB2 is down-regulated in gefitinib-resistant (H292-Gef) cells compared to gefitinib-sensitive (H292) cells. The low SerpinB2 levels in H292-Gef cells were also associated with an enhancement in invasiveness and increase in the length of invadopodia-like structures in the cells. The effect on invasiveness and gefitinib sensitivity was confirmed by knockdown and overexpression of SerpinB2. In addition, an antitumor agent yuanhuadine (YD) was used to test the possibility to overcome the resistance through the up-regulation of SerpinB2. YD effectively elevated SerpinB2 levels and suppressed invasive properties in H292-Gef cells. Collectively, these findings demonstrate the prospective role of SerpinB2 as a novel biomarker for acquired gefitinib resistance and a potential target for NSCLC treatment. Acknowledgement This study was funded by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A02062012). Citation Format: Song Yi Bae, Donghwa Kim, Hyen Joo Park, Woong Sub Byun, Ji-Young Hong, Hye-Jung Lee, Sang Kook Lee. SerpinB2 enhances invadopodia-like structure protrusions and is down-regulated in acquired gefitinib-resistant non-small cell lung cancer 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 3169. doi:10.1158/1538-7445.AM2017-3169
Abstract 5266: The mechanisms of apoptosis induction by deubiquitylatinase inhibitor b-ap15 in esophageal squamous cell carcinoma cells
Authors: Pei Li, Ping Chen, Xiao-Yu Chen, Jing-Yang Zhang, Bei-Bei Sha, Tao Hu, Yi-Lin Zhang, Ying Du, Zi-Ming Dong
Journal: Cancer Research (2017)

Abstract Deubiquitinases (DUBs) act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties which can reverse the process of protein degradation, and further affect or regulate cell metabolism, proliferation and differentiation. As a novel small molecular inhibitor, b-AP15 can specifically inhibit the deubiquitinating activity of 19S regulatory subunit UCHL5(ubiquitin C-terminal hydrolase 5) and USP14(ubiquitin-specific peptidase 14) in cancer cells. In this study, we aimed to check whether b-AP15 have anti-tumor activity in esophageal cancer cells in vitro and try to explore the underling mechanisms. Results: CCK-8 assay, colony formation assay and morphological observation results indicate that b-AP15 can significantly inhibit the proliferation activity of EC1 and Kyse 450 esophageal cancer(EC) cell lines in a concentration-dependent manner in vitro studies. Flow cytometry results show cells were arrested in G2/M phase after being treated with b-AP15. Western blot results show that the expression of G2/M phase related proteins p21, p27 and pWee1 significantly increased while the expression of the G1/S phase marker proteins including cyclinA, cyclinD show no significant change after being treated with b-AP15. FITC annexin V Apoptosis detection kit with PI and Caspase 3 Assay kit results show that b-AP15 treatment can significantly induce apoptosis in two EC cell lines. The results from western blot show that the expression of apoptotic protein c-PARP and c-caspase 3 significantly increased and was dose-dependent. JC-1 flow cytometry analysis show that b-AP15 treatment can significantly decrease mitochondrial membrane potential. All these results suggest that b-AP15 can induce EC cells apoptosis and may play certain role in mitochondrial control of apoptosis signaling pathway. Conclusion: b-AP15 shows a significantly anti-tumor activity in vitro models of ESCC and the results confirm that b-AP15 can inhibit proliferation of EC cell lines by inducing cell-cycle arrest and promoting cell apoptosis. Key words: b-AP15;esophageal cancer;deubiquitylatinase(DUBs);apoptosis; Citation Format: Pei Li, Ping Chen, Xiao-Yu Chen, Jing-Yang Zhang, Bei-Bei Sha, Tao Hu, Yi-Lin Zhang, Ying Du, Zi-Ming Dong. The mechanisms of apoptosis induction by deubiquitylatinase inhibitor b-ap15 in esophageal squamous cell carcinoma 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 5266. doi:10.1158/1538-7445.AM2017-5266
Identification of circulating tumor cells with EML4-ALK translocation using fluorescence in situ hybridization in advanced ALK-positive lung cancer patients.
Authors: Myoung Shin Kim, Eun Joo Hwang, Sung Ho Choi, Chan Kwon Park, Byung Hee Jeon
Journal: Journal of Clinical Oncology (2016)

e20579 Background: The evaluation of ALK rearrangement in non-small-cell lung cancer (NSCLC) is a useful and significant tool for the decision of crizotinib treatment. However, tumor biopsy in patients with recurrent and/or metastatic disease is not always possible. Here, we suggest isolation and culturing of circulating tumor cells (CTCs) as an alternative to tumor tissue biopsy for the diagnostic test of ALK rearrangement. Methods: The blood samples (10 ml) were collected in ACDA tubes from 21 patients with NSCLC harboring ALK rearrangement. The blood samples were divided into two parts: one for immunofluorescent staining and other for culturing. Both samples were processed by size-base filtration using CTC isolation kit (Cytigen, Inc.). Cultured CTCs were analyzed for EML4-ALK translocation by fluorescence in situ hybridization (FISH) using Vysis ALK break apart FISH probe kit. Results: CTCs were detected in 10 of 22 patients (47.6%, range 1-8). CTC culturing was successful in 18 of 22 cases (81.8%). Among 18 cases of successful CTC cultures, 13 cases showed ALK rearrangement positivity (72.2%). Interestingly, the patients sensitive to crizotinib, did not show ALK rearrangement positivity of cultured CTCs. Conclusions: In this study, we suggest that the isolation and culture of CTCs can be a substitute method for tumor tissue biopsy, and may provide clinical applications, including serial blood samplings for the personalized cancer therapy based on their genomic information.
Abstract 475: Role of microRNA-34a in regulating oncoprotein STMN1
Authors: Balabhadrapatruni V.S.K. Chakravarthi, Rohit Mehra, Rui Wang, Darshan Shimoga Chandrashekar, Sai Akshaya Hodigere Balasubramanya, Irfan A. Asangani, Robert J. Lonigro, Arul M. Chinnaiyan, Sooryanarayana Varambally
Journal: Cancer Research (2017)

Abstract MicroRNAs, as negative regulators of gene expression, play a major role in cellular homeostasis. Downregulation of miRs is common in cancer which results in upregulation of multiple oncogenes in cancer. Here we show that stathmin (STMN1), which is over-expressed and oncogenic in wide variety of cancers, is regulated by microRNA-34 in prostate cancer. Earlier studies suggest that stathmin is involved in vital cellular processes such as cell proliferation, motility and metastasis. In the present study, we show elevated expression of stathmin in metastatic prostate cancer. Functionally, knockdown of stathmin in prostate cancer cells resulted in reduced cell proliferation and invasion in vitro, and tumor growth and metastasis in vivo. We also show that tumor suppressor microRNA miR-34a targets stathmin and mir-34 is regulated by transcriptional corepressor CtBP1 (C-Terminal Binding Protein 1). Further, Microarray analyses using stathmin modulated prostate cancer cell line RNA revealed multiple molecular alterations which may play a critical role in STMN1-mediated oncogenic activity. Thus, our study suggests that CtBP1-regulated miR-34a modulates stathmin expression in prostate cancer. This study therefore demonstrates functional role of CtBP1-miR-34a-Stathmin axis in prostate cancer progression. Citation Format: Balabhadrapatruni V.S.K. Chakravarthi, Rohit Mehra, Rui Wang, Darshan Shimoga Chandrashekar, Sai Akshaya Hodigere Balasubramanya, Irfan A. Asangani, Robert J. Lonigro, Arul M. Chinnaiyan, Sooryanarayana Varambally. Role of microRNA-34a in regulating oncoprotein STMN1 [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 475. doi:10.1158/1538-7445.AM2017-475
Abstract 2919: Quantitative mapping of epidermal growth factor receptor activation in single breast cancer cells treated with targeted therapies
Authors: Phuong Le, Kristopher Kilian, Andrew Smith
Journal: Cancer Research (2017)

Abstract Twenty percent of breast cancers are triple-negative, lacking estrogen receptor, progesterone receptor, and HER2. There is currently no specific FDA-approved targeted therapy for triple-negative breast cancer patients. Approximately half of triple-negative breast cancers overexpress epidermal growth factor receptor (EGFR), however phase II trials have only shown a 5% response rate with targeted inhibition. A quantitative analysis of EGFR signaling pathway dynamics of single cells at the single molecule level has the potential to shed light on the mechanism of lack of response to targeted therapy, as well as the cell-to-cell heterogeneity of response. Here, we combine single-molecule 3D imaging of EGFR using fluorescent quantum dots (QDs) with cell geometry normalization by micro-patterning to quantitatively map EGFR endocytosis in single cancer cells. Triple negative MDA-MB-231 cells conformed to defined geometries (rectangular with different aspect ratios) were grown on soft polyacrylamide gels after micro-contact printing islands of fibronectin. Two color QD conjugates of EGFR and its ligand, EGF, are used to track ligand binding and receptor internalization upon activation in the absence and presence of different families and dosages of pharmaceutical EGFR inhibitors. We demonstrated that microcontact-printing normalizes cell geometry while maintaining EGFR localization so that EGFR signaling response can be quantitatively assessed on a single-cell basis and that QD conjugates can specifically label EGFR and EGF. Quantitative single-molecule imaging at single-cell level revealed high level of heterogeneity in the amount and spatial localization of EGF binding and EGFR endocytosis among the cell population in the presence and absence of EGFR inhibitor, gefitinib. Using this platform, we will investigate if spatial organization of EGFR clusters within individual cells contribute to single-cell heterogeneous response to EGFR inhibitors. We anticipate quantitative mapping of EGFR activity with drug treatment will help to elucidate why EGFR drug treatments fail and provide a means to develop combination therapy to address heterogeneity in triple negative-breast cancer. Citation Format: Phuong Le, Kristopher Kilian, Andrew Smith. Quantitative mapping of epidermal growth factor receptor activation in single breast cancer cells treated with targeted therapies [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 2919. doi:10.1158/1538-7445.AM2017-2919
Abstract 2310: Molecular dynamics simulation of permeation pathway of cytochrome C through Bax pore
Authors: Mingzhen Zhang, Jie Zheng, Ruth Nussinov, Buyong Ma
Journal: Cancer Research (2017)

Abstract How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on the residue-residue distances detected experimentally for Bax and its homologous protein (Bak), we recently computationally solve the first atomic model for Bax oligomeric pores at the membranes. Next, we investigate the mechanism at the microsecond time- and nanometer space- scale using coarse-grained replica exchange and all-atom MD simulations. Our free energy landscape depicts a low barrier for the permeation of cytochrome C into the Bax C-terminal mouth, with the pathway proceeding to the inner cavity and exiting via the N-terminal mouth. Release is guided by organized charged/hydrophilic surfaces. The hydrophilicity and negative charge of the pore surface gradually increase along the release pathway from the pore entry to the exit opening. Rather than inert passing of cytochrome C through a rigid pore, the flexible pore may selectively aid the cytochrome C passage. The energy barrier is under 4 kcal/mol. Thus, once the Bax pore is formed in the membrane, the release of cytochrome C may be readily achieved through energy fluctuations. Collectively, our work provides mechanistic insight and atomic detail into the release of cytochrome C through Bax oligomeric pores. Citation Format: Mingzhen Zhang, Jie Zheng, Ruth Nussinov, Buyong Ma. Molecular dynamics simulation of permeation pathway of cytochrome C through Bax pore [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 2310. doi:10.1158/1538-7445.AM2017-2310