bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 103: Blockage of Cdc7/CDK9 signaling sensitizes triple negative breast cancer to EGFR-targeted therapy
Authors: McLaughlin Ronan P. , He Jichao , Noord Vera van der , Redel Jevin , Smid Marcel , Dorssers Lambert , Martens John , Foekens John , Zhang Yinghui , Water Bob van de 
Published: July 2017

Abstract
The treatment of Triple-Negative Breast Cancer (TNBC) still represents a profound clinical challenge, the disease being disproportionately responsible for breast cancer-associated deaths. As a consequence, the identification of targeted agents, which synergize with current therapeutic options, is paramount. Resistance to EGFR-tyrosine kinase inhibitors (TKIs), despite frequent EGFR overexpression and reliance on downstream signalling pathways in TNBC, remains endemic. Recent data has also suggested that kinase-inhibition of EGFR in itself is insufficient, given the kinase-independent functions of the protein in transcriptional regulation and DNA-repair may permit prolonged EGFR-mediated signalling in the presence of inhibitors. We performed a kinase inhibitor drug screen (378 kinase inhibitors targeting ~40 different cancer-related kinases) to identify synergistic activity with EGFR inhibition in TNBC. We demonstrate that the dual cdc7/CDK9 inhibitor PHA-767491 synergizes with multiple EGFR-TKIs (Erlotinib, Gefitinib and Lapatinib) in vitro to overcome resistance to EGFR-targeted therapy in various TNBC cell lines. Combined inhibition of EGFR and cdc7/CDK9 resulted in reduced cell proliferation, accompanied by induction of apoptosis and G2-M cell cycle-arrest. Combination therapy inhibited crucial components of the DNA-replicative machinery and also proteins involved in CDK9-mediated transcriptional elongation. Moreover, higher expression of cdc7 and POLR2A was found to be significantly correlated with poorer survival rates in breast cancer patients. Additionally, this synergistic combination effectively inhibited the growth of cells isolated from patient-derived TNBC xenografts under ex vivo culture conditions, highlighting the utility of targeting common transcriptional nodes in cancers addicted to growth factor-mediated signalling pathways.
Citation Format: Ronan P. McLaughlin, Jichao He, Vera van der Noord, Jevin Redel, Marcel Smid, Lambert Dorssers, John Martens, John Foekens, Yinghui Zhang, Bob van de Water. Blockage of Cdc7/CDK9 signaling sensitizes triple negative breast cancer to EGFR-targeted therapy [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 103. doi:10.1158/1538-7445.AM2017-103
Abstract 1040: LIN28B-mediated let-7 independent activation of AKT promotes neuroblastoma pathogenesis
Authors: Tao Ting , Powers John T. , Shi Hui , Missios Pavlos , Perez-Atayde Antonio R. , Zhu Shizhen , Daley George Q. , Look Thomas A. 
Published: July 2017

Abstract
LIN28 is well known as a RNA-binding protein and a suppressor of microRNA biogenesis, by selectively blocking the processing of let-7 precursors. It plays diverse functions in cellular reprogramming, development, metabolism and tumorigenesis. Many of these functions are executed through its ability to inhibit let-7 maturation. However, little is known about its function independent of let-7. Here we made zebrafish transgenic lines expressing high levels of either wild-type or mutant LIN28B (does not block the maturation of let-7) in the peripheral sympathetic nervous system driven by the dopamine beta-hydroxylase promoter. We bred these lines with a transgenic zebrafish line overexpressing the MYCN oncogene in these cells. Either wild-type or mutant LIN28B overexpression accelerated the onset and increased the penetrance of MYCN-induced neuroblastoma, despite the fact that only wild-type LIN28B blocked let-7 maturation compared to MYCN-only tumors. Mechanistically, both wild-type and mutant LIN28B overexpression enhanced MYCN-induced hyperplasia by increasing cell proliferation in the sympathoadrenal lineage. Further studies revealed that overexpression of either wild-type or mutant LIN28B resulted in hyperphosphorylation of AKT on both Ser473 and Thr308 in zebrafish tumors and also serum-deprived human neuroblastoma cell lines. Both wild-type and mutant LIN28B interacted with IGF2BP1, a known interactor that increases stability and translation of a subset of RNAs. We found IGF2 RNA levels to be increased in response to either form of LIN28B. Coincident with IGF2 overexpression, IGF1R was phosphorylated, providing an explanation for PI3K-AKT activation in LIN28B overexpressing cells. Finally, overexpression of a constitutively active, myristoylated murine Akt2 (myr-mAkt2) alone in zebrafish induced ganglioneuroma in the interregnal gland (the zebrafish equivalent of the human adrenal medulla), without a requirement for MCYN overexpression. Thus, our studies indicate that overexpression of LIN28B leads to AKT activation mediated through its interaction with IGF2BP1 and subsequent upregulation of IGF2. This pathway provides a mechanism underlying enhanced transformation in LIN28B overexpressing neuroblastomas, which is independent of the inhibitory activity of LIN28B on let-7 maturation.
Citation Format: Ting Tao, John T. Powers, Hui Shi, Pavlos Missios, Antonio R. Perez-Atayde, Shizhen Zhu, George Q. Daley, Thomas A. Look. LIN28B-mediated let-7 independent activation of AKT promotes neuroblastoma pathogenesis [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 1040. doi:10.1158/1538-7445.AM2017-1040
Abstract 1044: Development of a miRNA-based signature to predict human cancer metastasis
Authors: Willetts Lian , Stoletov Konstantin , Jovel Juan , Woolner Emma , Lewis John D. 
Published: July 2017

Abstract
Metastasis is the primary cause of death for cancer patients, and invasive cancer cell migration is required at multiple steps during metastasis (e.g. intravasation and extravasation). Since microRNAs (miRNAs) have been implicated as key regulators of metastatic spread of cancer cells, we sought to develop a miRNA signature that can be used to predict cancer metastasis. We hypothesized that the miRNAs that are functionally required for invasive cell migration could serve as biomarkers to predict human cancer metastasis.
We developed an intravital imaging-based approach combined with NGS to screen for miRNAs that are required for invasive cell migration of human HT1080 fibrosarcoma cells. The screen-identified miRNAs were validated in a panel of in vitro and in vivo assays for invasive migration. Microarray analysis identified genes downregulated in transfected HT1080 cells. Publically available databases were used to correlate the expression of screen-identified miRNAs and the progression of multiple human cancers. We used a qRT-PCR approach combined with machine learning to develop a miRNA signature to predict metastasis in a 66-patient cohort of prostate cancer.
We identified over twenty novel miRNAs that regulate directional cancer invasion. Microarray analysis in HT1080 cells revealed that the altered expression of metastasis-regulating miRNAs is associated with 50% reduction in gene expression of migration and adhesion gene network components such as integrin a4, CDC42, and transgelin).
We evaluated the potential of screen-identified miRNAs to serve as biomarkers to predict cancer metastasis. Using publically available databases, we found that majority of screen-identified miRNAs are dysregulated in multiple human cancer types (e.g. prostate, breast, ovarian and lung) and the expression of these miRNAs correlate directly with patient disease progression. We analyzed the expression of the top two screen-identified miRNAs in plasma samples from the PCa patient cohort. A signature was generated using a weighted K-nearest neighbor algorithm that provided a ROC area under the curve of 0.79 for predicting metastatic disease.
We identified a panel of novel metastasis-regulating miRNAs that is functionally involved in human cancer metastasis. These miRNAs have the potential to serve as both biomarkers to predict metastasis and potentially as therapeutic targets to block metastasis.
Citation Format: Lian Willetts, Konstantin Stoletov, Juan Jovel, Emma Woolner, John D. Lewis. Development of a miRNA-based signature to predict human 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 1044. doi:10.1158/1538-7445.AM2017-1044
Abstract 1052: Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiomyopathy
Authors: Sonowal Himangshu , Pal Pabitra B. , Srivastava Satish K. , Ramana Kota V. 
Published: July 2017

Abstract
Chemotherapy is one of the most common option for colorectal cancer (CRC), specifically at the advanced stages and after surgical resection of the tumor. Anthracycline drugs such as doxorubicin, daunorubicin are the most commonly used for the therapy of leukemia, lymphoma and breast cancer. However, doxorubicin is not a very effective drug to kill CRC cells since a high amount of doxorubicin is required for colon cancer therapy, which leads to unwanted side effects like cardiac toxicity and cardiomyopathy. Therefore, better adjuvant therapies are required to increase sensitivity of CRC to doxorubicin as well as to decrease the associated cardiomyopathy. Our recent studies indicate that aldose reductase (AR; AKR1B1) inhibitors such as fidarestat prevent CRC growth as well as metastasis in nude mice xenograft models. We now examined our hypothesis that AR inhibition increases the sensitivity of CRC to doxorubicin and decreases its cardiotoxicity by modulating oxidative stress-mediated signaling pathways. We have investigated the effect of co-administration of doxorubicin along with AR inhibitor fidarestat in in vitro and in vivo CRC cells growth and toxicity. Our results suggest that treatment of CRC cells with fidarestat increases the efficacy of doxorubicin-induced death of HT-29 and SW-480 colon cancer cells. Flow cytometric analysis indicates that in fidarestat + doxorubicin -treated CRC cells, the intracellular accumulation of doxorubicin is increased as compared to doxorubicin alone-treated cells. Further, AR inhibition prevents doxorubicin-induced increase in the expression of drug transporter proteins such as MRP-1 and ABCG-2 in CRC cells. In addition, combination of fidarestat with doxorubicin significantly prevented the growth of CRC cells in nude mice xenografts as compared to doxorubicin alone. Fidarestat also prevented the doxorubicin-induced cardiac toxicity as measured by serum troponin-I levels and inflammatory cytokines and chemokines in the serum and heart of doxorubicin-treated mice in combination with fidarestat. Most importantly, fidarestat protects the cardiac damage and dysfunction in doxorubicin-treated mice. Thus, our results suggest that fidarestat could be used as a novel adjuvant therapy in enhancing doxorubicin sensitivity of CRC cells and to reduce the doxorubicin-associated cardiotoxicity.
Citation Format: Himangshu Sonowal, Pabitra B. Pal, Satish K. Srivastava, Kota V. Ramana. Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiomyopathy [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 1052. doi:10.1158/1538-7445.AM2017-1052
Abstract 106: Traditional medicinal plants effect on five cancer cell lines
Authors: Myles Elbert L. 
Published: July 2017

Abstract
Cancer refers to as a group of numerous diseases that can originate in various parts of the body. From the beginning of human history natural compounds have been used for medical purposes. Many of the most frequently used natural compounds have their origin from plants. Plants are very diverse and responsible for the synthesis of a number different secondary compounds. Scientist and non-scientist have taken advantage of these secondary compounds treatment of a variety of diseases. In the current study, we are investigating the viability of specific cancer cell lines after exposure to methanolic extracts from each of the following plants. The plants are Costus, Fenugreek, and Rhamnus. The cell lines used in this investigation are lung cancer (A549), colon cancer, (SW620 and Colo320), breast cancer (BT549), and cervical cancer (HeLa). The determination of cell viability found inhibition. The three test compounds were methanolic extracts from the plants Costus, Fenugreek, and Rhamnus. All showed different levels of viability and was dependent on the specific cell line.
Citation Format: Elbert L. Myles. Traditional medicinal plants effect on five cancer cell lines [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 106. doi:10.1158/1538-7445.AM2017-106
Abstract 1068: Driver pathway blockage synergizes with PLK1 inhibition in anaplastic thyroid cancer
Authors: Martino Daniela De , Yilmaz Emrullah , Orlacchio Arturo , Cristofano Antonio Di 
Published: July 2017

Abstract
Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies, with a median survival of less than 6 months from the time of diagnosis. Molecular changes that characterize ATC have been recently well defined and involve most often p53 mutations, and activation of PI3K, RAS and BRAF. PLK1, an essential mitotic regulator, has been found overexpressed in ATC.
Previous data from our lab have shown that PLK1 inhibitors are effective in ATC cell lines. However PLK1 inhibition often results in escape from growth arrest through mitotic slippage. This leads to the generation of polyploid, genetically unstable, cell populations.
We have tested the effect of combining PLK1 and PI3K inhibitors in ATC cell lines. Combined treatment with the PLK1 inhibitor BI6727 and the PI3K inhibitor BKM120 resulted in a significant synergistic effect in ATC cell lines with high levels of AKT activity, but not in those with undetectable pAKT. Combination of the two drugs enhanced the G2/M arrest at doses in which the single drugs showed no effect. In addition, it led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment with BI6727 and BKM120 in PI3Khigh cell lines showed a significant induction of apoptosis in a time- and dose-dependent manner.
Combined inhibition of PI3K and PLK1 was extremely effective in inhibiting tumor growth in vivo, in an immunocompetent allograft model of ATC.
Our results show that combination of PLK1 and PI3K inhibitors is an effective treatment for ATC cells with high levels of PI3K signaling. This combination results in cell cycle arrest, inhibition of of tetraploid cell generation, and induction of apoptosis, suggesting a clear therapeutic potential.
Citation Format: Daniela De Martino, Emrullah Yilmaz, Arturo Orlacchio, Antonio Di Cristofano. Driver pathway blockage synergizes with PLK1 inhibition in anaplastic thyroid 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 1068. doi:10.1158/1538-7445.AM2017-1068
Abstract 1077: Extra-virgin olive oil Met inhibitor oleocanthal-lapatinib: a novel synergistic combination for HER2-dependent breast malignancies
Authors: Siddique Abu Bakar , Ebrahim Hassan Y. , Akl Mohamed R. , Mohyeldin Mohamed M. , Sayed Khalid A. El 
Published: July 2017

Abstract
Breast cancer (BC) is the most commonly diagnosed cancer in women, claiming the lives of hundreds of thousands of women each year. The Mediterranean diet is known to reduce BC and colon cancer incidence. Extra-virgin olive oil (EVOO) represents a main ingredient in this diet. The EVOO-derived (-)-oleocanthal was shown to target the Receptor tyrosine kinases (RTK) c-Met. Oleocanthal exerted potent in-vivo efficacy in an orthotopic athymic nude mouse breast cancer xenograft model much greater than its modest in-vitro potency. Dysregulation of RTKs, specifically EGFR/HER-2 pathways, correlates with poor prognosis and more aggressive breast cancer phenotypes. Dysregulation of hepatocyte growth factor (HGF) and its receptor c Met correlates with aggressive proliferation, invasive character, and pathological motility. c-Met amplification correlates with escape from the anticancer effects of EGFR/HER2 inhibitors and cetuximab. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid from EVOO showed significant in vivo activity against invasive breast cancers through targeting HGF/Met axis. The Dual EGFR/HER-2 inhibitor lapatinib (LP) has already been in clinical practice for HER2-amplified breast cancer, which occasionally develops resistance through c-Met upregulation. Lapatinib’s therapeutic dose induced significant hepatotoxicity. The combined use of OC and LP was hypothesized not only for therapeutic synergy but also to notably reduce LP’s effective doses and therefore minimize its hepatotoxicity. Combined treatment of subeffective doses of lapatinib and OC caused significant in vitro and in vivo synergistic antiproliferative effects against the HER-2-dependent BT-474 and SKBR-3 BC cells. Interestingly, OC induced 4-fold lapatinib dose reduction index with improved potency. Protein microarray and Western blot analyses of OC-LP combination treatments synergistically reduced EGFR, HER-2, FAK, JAK1, MEK, and c-Met activation. These results propose OC use as dietary supplement to synergize the chemotherapeutic effects of LP, reduce its therapeutic dose to ¼ and therefore can minimize its morbidity. Combinatorial inhibition of c-Met-HER-2-EGFR is an effective strategy for the control of HER-2 positive breast cancer. This study was supported by NIH/NCI project 1R15CA167475-01.
Citation Format: Abu Bakar Siddique, Hassan Y. Ebrahim, Mohamed R. Akl, Mohamed M. Mohyeldin, Khalid A. El Sayed. Extra-virgin olive oil Met inhibitor oleocanthal-lapatinib: a novel synergistic combination for HER2-dependent breast malignancies [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 1077. doi:10.1158/1538-7445.AM2017-1077
Abstract 1081: APC regulation of breast cancer therapeutic resistance
Authors: Arnason Anne , VanKlompenberg Monica , Prosperi Jenifer R. 
Published: July 2017

Abstract
Resistance to chemotherapy is one of the leading causes of death from breast cancer. Our lab discovered that Adenomatous Polyposis Coli (APC) loss in breast cancer cells results in an elevation of tumor-initiating cells (TICs) and resistance to chemotherapy-induced apoptosis. Given that TICs are often most resistant to standard chemotherapeutic compounds, we sought to understand the mechanism responsible for APC-mediated TIC enhancement. Our hypothesis is that the molecular mechanism involved in chemotherapeutic resistance parallels that promoting the TICs. APC-mutant cells have amplified activation of signal transducer and activator of transcription 3 (STAT3). Interestingly, inhibition of STAT3 with a small molecule inhibitor A69 decreases the TIC population and restores drug sensitivity. Studies are ongoing in the laboratory to investigate other molecular signaling pathways involved in APC-mediated enhanced TIC population and therapy resistance. These data have begun to reveal the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance.
Note: This abstract was not presented at the meeting.
Citation Format: Anne Arnason, Monica VanKlompenberg, Jenifer R. Prosperi. APC regulation of breast cancer therapeutic resistance [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 1081. doi:10.1158/1538-7445.AM2017-1081
Abstract 1083: Synergistic drug combination prediction through drug differential dependency network analysis
Authors: Kim Seungchan , Speyer Gil , Dhruv Harshil , Kiefer Jeff , Berens Michael 
Published: July 2017

Abstract
In an effort to discover strategies which identify effective drug combinations, we analyzed 39 of the 480 compounds screened in the Cancer Therapeutics Response Portal (CTRP) where combinations of two compounds were tested against 860 cancer cell lines; this enabled a comparison of the drug sensitivity of the combinations versus that of the individual compounds. More than half of the drug combinations (n=21) did not significantly improve the drug sensitivity, compared to individual compounds alone. In fact, some of the combinations showed reduced drug sensitivity. In EDDY-CTRP* analysis, the Cancer Cell Line Encyclopedia (CCLE) RNAseq data and CTRP compound response measurements were analyzed to discover both 1) pathways enriched with differential dependencies between sensitive and non-sensitive cell lines for each compound and 2) the mediators of cell line response to a drug. A mediator is a gene in a pathway that plays a significantly different role between sensitive and non-sensitive conditions. The significance is assessed for either essentiality, measured as a node’s centrality change, or specificity, measured as the difference in condition specific edges. These drug-pathway-mediator connections are predicted to reveal crucial molecular determinants of drug sensitivity that otherwise are hidden in the complexities of the molecular networks of the cell (Speyer et al., PSB 22:497-508, 2017). We further investigated whether mediators identified for single compounds could predict sensitivity to drug combinations. This analysis revealed that if two single compounds share the same specificity mediators, i.e. the genes with the most significant re-wiring of gene dependencies between sensitive and non-sensitive cell lines, combination of these two compounds correlate with improved sensitivity. The converse was also found: compounds that do not share mediators rarely show synergy. Further analysis and empirical testing of predicted combinations promises to prioritize synergistic drug combinations. We believe that this methodology may predict synergistic drug combinations from cancer cell line drug screening data. Supported by NIH U01CA168397.
*available at http://biocomputing.tgen.org/software/EDDY/CTRP
Citation Format: Seungchan Kim, Gil Speyer, Harshil Dhruv, Jeff Kiefer, Michael Berens. Synergistic drug combination prediction through drug differential dependency network analysis [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 1083. doi:10.1158/1538-7445.AM2017-1083