bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 68: Exomic landscape of uterine leiomyosarcomas
Authors: Mäkinen Netta , Heikkinen Tuomas , Aavikko Mervi , Bützow Ralf , Vahteristo Pia 
Published: August 2015

Abstract
Uterine leiomyosarcomas are rare malignant tumors originating from the smooth muscle lining of the uterus, the myometrium. They account for 1-2% of all uterine malignancies with an estimated incidence of 0.3-0.4/100,000 women per year. The symptoms, signs, and histopathological features of uterine leiomyosarcomas widely overlap with those of uterine leiomyomas, their benign counterparts, which can cause diagnostic challenges in daily pathological practice. Because leiomyosarcomas are clinically aggressive tumors with poor 5-year survival and a high recurrence rate, early diagnosis is important for prolonged survival. Currently, the diagnosis of these tumors is often incidental and postoperative. Most leiomyosarcomas are aneuploid with complex numerical and structural chromosomal aberrations and show substantial cytogenetic heterogeneity. Although a few cancer genes have been implicated in uterine leiomyosarcomas, such as TP53, RB1, and CDKN2A, these genes represent, however, common cancer genes not specific for smooth muscle malignancies. The aim of this study is to examine somatic variation in the coding regions of uterine leiomyosarcomas by exome sequencing to identify potential new molecular biomarkers. Altogether 18 formalin-fixed paraffin-embedded tumor samples entered whole-exome sequencing. After the filtering of exome sequencing data, a list of genes which were mutated in at least two tumors was created. The list included over 50 genes TP53 being the most frequently mutated gene. The most prominent candidate variants are validated with Sanger sequencing and the validations are ongoing. Also a series of 35 additional tumors is available on tissue microarray for possible immunohistochemical validations. Identification of novel molecular genetic characteristics in uterine leiomyosarcomas is clinically relevant to further improve the diagnosis and prognosis of the patients. New knowledge on the mechanisms underlying the progression to malignancy is also essential for developing new treatments.
Citation Format: Netta Mäkinen, Tuomas Heikkinen, Mervi Aavikko, Ralf Bützow, Pia Vahteristo. Exomic landscape of uterine leiomyosarcomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 68. doi:10.1158/1538-7445.AM2015-68
Abstract 685: Mechanisms of intrinsic and acquired resistance to third generation inhibitors in EGFR mutant NSCLC
Authors: Niederst Matt J. 
Published: August 2015

Abstract
Acquired resistance is a fundamental problem limiting the efficacy of tyrosine kinase inhibitors (TKIs) in EGFR mutant NSCLC. In over half of the cases of acquired resistance to the first generation inhibitors gefitinib and erlotinib, a secondary mutation to EGFR, T790M, promotes resistance by preventing these drugs from fully suppressing the receptor. The recent development of next generation EGFR TKIs has proven to be a major breakthrough in the treatment of these patients. In clinical trials testing the third generation EGFR inhibitors CO-1686 and AZD9291, response rates of greater than 50% in T790M+ patients have been reported. While these drugs hold a great deal of promise, they too will be limited, initially by intrinsic resistance, and eventually by acquired resistance. To study intrinsic resistance in this setting, we have developed a panel of cell lines derived from biopsies of T790M+ erlotinib-resistant patients, tested their sensitivity to third generation inhibitors and identified biomarkers that predict a lack of response. To study acquired resistance, we have generated resistance in these cells lines in vitro and derived additional models directly from patient biopsies following progression on the clinical trial. Using a combination of functional, sequencing, and drug screening approaches we have begun to identify resistance mechanisms to third generation inhibitors.
Citation Format: Matt J. Niederst. Mechanisms of intrinsic and acquired resistance to third generation inhibitors in EGFR mutant NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 685. doi:10.1158/1538-7445.AM2015-685
Abstract 690: Characterization of serine/threonine phosphatase LAPP1 as a diagnostic and therapeutic target for lung cancer
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke 
Published: August 2015

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Since the number of patients responding well to current standard therapies is still small, further development of new anti-cancer drugs with minimum risk of adverse event is urgently awaited. To screen oncoantigens which could be used for the development of new diagnostic biomarkers and molecular targeted drugs, we have established a screening system as follows; i) To identify overexpressed genes in 120 lung cancers by genome-wide screening using the microarray representing 27,648 genes and pure populations of tumor cells taken from cancer tissues by laser microdissection, ii) To verify the candidate genes for their very low or absent expression in normal tissues by northern-blotting, iii) To validate the clinicopathological significance of their expression with tissue microarray covering hundreds of archived lung cancers, iv) To verify whether the target genes are essential for the growth or survival of cancer cells by RNAi and cell growth assays. During this process, we selected dozens of druggable oncoproteins with various enzymatic activities, and identified overexpression of Serine/Threonine phosphatase LAPP1 (lung cancer-associated protein phosphatase 1) in the majority of lung cancers and its scarce expression in normal tissues except testis. Strong LAPP1 expression was an independent prognostic factor for lung cancer patients who underwent curative surgery (P&lt;0.0001). We identified EF-1δ (a cadmium-responsive proto-oncogene) as a LAPP1-interacting protein that was also over-expressed in cancer cells. Knock-down of LAPP1 or EF-1δ expression by siRNAs inhibited cell growth, whereas exogenous expression of LAPP1 in EF-1δ(+) cells enhanced the dephosphorylation of EF-1δ(+), and subsequent increase in the levels of active phospho-AKT. Inhibition of interaction between LAPP1 and EF-1δ by a cell-permeable peptide corresponding to a leucine zipper motif in EF-1δ, resulted in the destabilization of EF-1δ and inhibited cancer cell growth and invasion. LAPP1 is likely to be a prognostic biomarker and a potential therapeutic target for lung cancer.
Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Characterization of serine/threonine phosphatase LAPP1 as a diagnostic and therapeutic target for lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 690. doi:10.1158/1538-7445.AM2015-690
Abstract 693: A yeast synthetic lethal screen identifies a conserved interaction between PLK1 and CKS1b affecting cancer cell viability
Authors: Reid Robert J. , Du Xing , Sunjevaric Ivana , Rayannavar Vinayak , Dittmar John , Maurer Matthew , Rothstein Rodney 
Published: August 2015

Abstract
The CKS1b gene is located on chromosome 1q21 and is frequently amplified in breast, lung and liver cancers. CKS1b codes for a conserved regulatory subunit of cyclin-CDK complexes that functions at multiple stages of cell cycle progression. We used a high throughput screening protocol to mimic cancer-related over-expression in Saccharomyces cerevisiae mutants to identify genes whose functions become essential only when CKS1 is over- expressed, a genetic interaction termed synthetic dosage lethality (SDL). Mutations in genes affecting the mitotic entry checkpoint and genes affecting mitotic exit are evident among the SDL interactions identified. The mitotic entry checkpoint controls the stability of the mitotic inhibitor Swe1 (Human WEE1), resulting in delayed mitosis when cell polarity is disrupted. Swe1 is a tyrosine kinase that inhibits the cyclin-dependent kinase (CDK) complex by phosphorylation of a conserved tyrosine-19 on Cdc28 (Human CDK1). We find that the SDL interaction between Cks1 and the mitotic entry checkpoint requires both Swe1 and the Cdc28 tyrosine-19 residue. The mitotic exit network is a signaling cascade that controls post-anaphase inhibition of CDK activity necessary for progression into G1. Since the polo-like kinase Cdc5 (Human PLK1) functions in both the mitotic entry and mitotic exit pathways, we investigated the effect of targeting PLK1 in breast cancers with varying expression of CKS1b. We analyzed published datasets and found that growth inhibition resulting from PLK1 knockdown was strongly correlated with increased CKS1b expression levels in breast cancer cell lines [Marcotte, R., Brown, K., Suarez, F., & Sayad, A. (2012). Cancer Discovery, 2:172]. We independently confirmed sensitivity to PLK1 knockdown in 8 breast cancer cell lines in which 3 of 4 sensitive lines had high CKS1b expression and 3 of 4 insensitive lines had low CKS1b expression. We modified CKS1b expression in hMEC cells and showed that increased expression enhanced apoptosis upon PLK1 knockdown while decreased CKS1b expression abrogated sensitivity. Thus identification of a yeast synthetic dosage lethal (SDL) interactions identifies a conserved interactions that may be targeted to kill cancer cells.
Citation Format: Robert J. Reid, Xing Du, Ivana Sunjevaric, Vinayak Rayannavar, John Dittmar, Matthew Maurer, Rodney Rothstein. A yeast synthetic lethal screen identifies a conserved interaction between PLK1 and CKS1b affecting cancer cell viability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 693. doi:10.1158/1538-7445.AM2015-693
Abstract 708A: Suppression of glycolysis by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib via AMPK activation
Authors: Shiota Goshi , Shimizu Hiroki , Kanki Keita 
Published: August 2015

Abstract
Aims: Hepatocellular carcinoma (HCC) is the fifth cause of cancer death all over the world and its prognosis is very poor. To improve the prognosis of HCC patients, a novel therapy including chemotherapy against HCC should be developed. The strategies to enhance the efficacy of anticancer drugs are required. Sorafenib is the only drug to prolong overall survival of the patients with HCC, however, the outcome is not still satisfactory. In this study, we investigated the effects of combination treatment of anticancer drugs and retinoids,which has been known to show antitumor activity, in HCC cells. Methods: Cytotoxicity of combination treatment of retinoids (all-trans retinoic acid (ATRA), NIK-333 and Am80) and anticancer drugs (sorafenib, adriamycin, cisplatin, mitomycin C and 5-FU) was examined by cell viability assay. The effect on energy metabolic pathway, such as AMPK activation, intracellular ATP level, and the expression of glycolytic and TCA cycle genes were examined in HepG2 cells treated with sorafenib alone or in combination with retinoids. Induction of apoptosis was evaluated in the cells treated with the combination treatment of sorafenib and ATRA. Results: ATRA enhanced the cytotoxic effects of all 5 anticancer drugs tested, being much more effective than NIK-333 andAm80.AMPK activation, reduction of ATP content, and downregulation of glycolytic genes GLUT-1 and LDHA were observed in the cells treated with ATRA alone or in combination with sorafenib. In the combination treatment, increased apoptosis which was followed by activation of p38MAPK and JNK, upregulation and translocation of Bax to mitochondria, and activation of caspase-3 was observed. Conclusion: ATRA is useful for enhancing the cytotoxicity of antitumor drugs for HCC by regulating energy metabolism in HCC cells.
Citation Format: Goshi Shiota, Hiroki Shimizu, Keita Kanki. Suppression of glycolysis by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib via AMPK activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 708A. doi:10.1158/1538-7445.AM2015-708A
Abstract 749: Both amplification and protein expression are required to predict FGFR tyrosine kinase inhibitor sensitivity in lung cancer
Authors: Ebi Hiromichi , Kotani Hiroshi , Yano Seiji 
Published: August 2015

Abstract
FGFR1 amplification has been suggested to be a driver oncogene in squamous and small cell lung carcinoma. However, early clinical trials show that response rate of FGFR tyrosine kinase inhibitors (FGFR-TKIs) is 20-30% in patients with FGFR1 amplified lung cancer. To elucidate the reason for de novo resistance to FGFR-TKI, six FGFR1 amplified lung cancer cell lines (NCI-H1581, DMS-114, NCI-H520, NCI-H1703, HCC95, and Calu-3) were analyzed. These cells were confirmed to have FGFR1 amplification by FISH analysis. Cell viability assay showed only 2 of six cell lines, NCI-H1581 and DMS-114, are sensitive to a FGFR-TKI, BGJ-398. Among BGJ-398 insensitive cells, NCI-H1703, HCC95, and Calu-3 cells express low mRNA and protein level of FGFR1 even in the presence of FGFR1 amplification. In addition, while BGJ-398 downregulates ERK phosphorylation in FGFR1 protein expressing cells, the drug had no effect on ERK signaling in BGJ-398 resistant cells with low FGFR1 protein expression. Importantly, other driver oncogenes were found in these BGJ-398 insensitive cell lines. PDGFRa amplification in H1703 cells and HER2 amplification in Calu-3 cells were reported previously. In this study, we have also found ERBB3 ligand NRG1 was overexpressed in HCC95 cells. Knockdown of NRG1 suppressed cell growth and combination of lapatinib with BGJ-398 led to cell death. To further determine whether FGFR1 protein expression is enough for the sensitivity to FGFR-TKIs, lung cancer cell lines were screened to FGFR-TKIs, BGJ-398 and PD-173034. This screen identified that all FGFR-TKI sensitive cell lines harbor FGFR1 amplification with high protein expression. These results suggest FGFR-TKIs should be used to patients harboring both FGFR1 amplification and protein expression. In case tumors with FGFR1 amplification, but expressing low FGFR1 protein, another driver oncogene may coexist and targeting both FGFR1 and these coexisting driver oncogenes are required to treat these tumors.
Citation Format: Hiromichi Ebi, Hiroshi Kotani, Seiji Yano. Both amplification and protein expression are required to predict FGFR tyrosine kinase inhibitor sensitivity in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 749. doi:10.1158/1538-7445.AM2015-749
Abstract 750: Overcoming resistance to anti-EGFR therapy in non-small cell lung cancer with a T-type Ca2+ channels inhibitor
Authors: Dziegielewska Barbara , Gray Lloyd S. , Dziegielewski Jaroslaw 
Published: August 2015

Abstract
This study's aim was to define a novel molecular target and to develop an effective agent capable of overcoming intrinsic and acquired resistance to anti-EGFR therapy. Despite introduction of new therapies, lung cancer is a major cause of cancer death. One of its characteristics is the expression and activation of epidermal growth factor receptor (EGFR). Activating mutations in EGFR are present in approximately 20% of patients with non-small cell lung cancer (NSCLC), mostly in never-smokers. While most patients initially respond to treatment with anti-EGFR therapy, essentially all patients develop acquired drug resistance. T-type calcium channels, are present in lung cancer and support cell proliferation. Importantly, their expression often coincides with abnormal expression or mutations in EGFR. In this study, we investigated the effects of T-type channel inhibition on NSCLC survival and resistance to targeted therapy in vitro. We used a panel of cell lines differing in EGFR mutation status and sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Our results show that T-type channel inhibitors alone arrest cells in the G1/G0 phase of the cell cycle and induce cell death. The treatment reduces activity of both PI3K/AKT/mTOR and JAK2/STAT5 pathways, often upregulated as a mechanism of acquired resistance to TKIs. Importantly, combined treatment with TKI, gefitinib, and T-type channels inhibitor, mibefradil, resulted in synergistic growth inhibition. Our results demonstrate a connection between T-type Ca2+ channels and aberrant EGFR activity in NSCLC, and provide the rationale for future use of two targeted therapies together. Since T-type calcium channel inhibitors are already undergoing clinical trials, our discoveries could be quickly translated into clinical practice.
Citation Format: Barbara Dziegielewska, Lloyd S. Gray, Jaroslaw Dziegielewski. Overcoming resistance to anti-EGFR therapy in non-small cell lung cancer with a T-type Ca2+ channels inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 750. doi:10.1158/1538-7445.AM2015-750
Abstract 782: Modulation of receptor tyrosine kinase signaling by cMET inhibitor, INC280, in cMETmut/amp gastric carcinoma cell line Hs746.T
Authors: Pinzon-Ortiz Maria C. , Rong Xianhui , Liang Jinsheng , Wang Hui Qin , Huang Alan , Schlegel Robert , Cao Z. Alexander 
Published: August 2015

Abstract
Aberrant Receptor Tyrosine Kinase (RTK) activity is one of the hallmarks of cancer. The genetic alternations of ABL and EGFR are classical examples of RTK-dependent oncogenesis. Recent data suggest that non mutated RTK signaling can form feedback pathways to serve as resistant mechanism against targeted therapies. Here, we examined the regulation of RTK signaling by a potent cMET inhibitor, INC280 (enzymatic EC50 against c-MET = 0.13 nM), in a cMET-dependent human gastric tumor model Hs746.T.
Hs746.T is a heavily cMET dependent cell line with both cMET amplication (12.9 copies) and mutation (G-T mutation at slice donor site to cause juxtamembrane domain deletion). This model is exquisitely sensitive to cMET inhibitor, INC280 in vitro (GI50 = 9 nM) and in vivo. The treatment of INC280 lead to significant inhibition of pcMET. Furthermore, the treatment of INC280 resulted in the suppression of pEGFR, though INC280 does not actively inhibit EGFR (enzymatic EC50 against EGFR &gt; 10 microM). This result supports prior reports that cMET and EGFR can form physical complex, with cMET modulating EGFR activation. Consequently, INC280 inhibited downstream signaling nodes of pAKT, pS6RP, pMEK and pERK in Hs746.T.
To examine the RTK signaling underlying possible treatment relapse, we treated Hs746.T cells chronically in vitro under increasing concentrations of INC280. After 8 weeks of treatment, Hs746.T-R cells were generated that grew at 600 nM of INC280. RTK signaling was examined in Hs746.T-R cells under treatment of INC280. As expected, cMET signaling was significantly curtailed in Hs746.T-R cells, as was pEGFR. Interestingly, pPDGFRb was elevated in Hs746.T-R, compared to the parental cell line. We hypothesize that the increased signaling through PDGFRb may serve as resistance mechanism to INC280 in Hs746.T-R cells.
In summary, we have examined RTK signaling in the cMET-dependent Hs746.T cell line. Our finding supported the notion of RTK cross-talk between cMET and EGFR in this setting. Additionally, our data reveal that additional RTK signaling (PDGFRb) can be induced under chronic treatment of INC280 to possibly mediate resistance to cMET inhibition.
Citation Format: Maria C. Pinzon-Ortiz, Xianhui Rong, Jinsheng Liang, Hui Qin Wang, Alan Huang, Robert Schlegel, Z. Alexander Cao. Modulation of receptor tyrosine kinase signaling by cMET inhibitor, INC280, in cMETmut/amp gastric carcinoma cell line Hs746.T. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 782. doi:10.1158/1538-7445.AM2015-782
Abstract 802: The inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis
Authors: Xu Qin , Xie Furong 
Published: August 2015

Abstract
Hemangioma is the most frequent vascular tumor of early childhood. However, the mechanism leading to their development, progression and maintenance has remained unclear. In this study, we generated an endothelial-specific PyMT-expressing transgenic (Tg) mouse (Tie2-PyMT) that spontaneously develop hemangioma. Using Tie2-PyMT transgenic mice and bEnd.3 cells, an PyMT induced mouse brain endothelial cell line idicates that the direct expression of PyMT gene in vascular endothelial cells leads to rapid cell proliferation and hemangioma development. An interaction between the core AC dimer of protein phosphatase 2A (PP2A) and PyMT, but not B regulatory subunit was verified both in hemangioma endothelial cells of Tie2-PyMT Tg mice and bEnd.3 cells by immunoprecipitation. Whereas in endothelial cells of Tg negative mice and PyMT silenced bEnd.3 cells, the B regulatory subunit binds to the core AC dimer of PP2A. PyMT binding to PP2A led to the inactivation of PP2A phosphatases and subsequently activates its downstream ERK1/2 and AKT pathway, which may be responsible for the proliferative effect of PyMT on vascular endothelial cells. Moreover, the effect of PyMT on PP2A phosphatases activity could be rescued by Okadaic acid (OA), a specific inhibitor of PP2A. Treamtment of Tie2-PyMT transgenic mice with the PP2A activator, FTY720, significantly delayed hemangiomagenesis in this model. Furthermore, PP2A complex composition and its phosphatases activity were also examined in patient hemangioma specimens. Consisten with the animal model, a decreased PP2A phosphatases activity and the dissociation of B subunit from the PP2A core dimer were observed. These findings suggest that the inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis.
Citation Format: Qin Xu, Furong Xie. The inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 802. doi:10.1158/1538-7445.AM2015-802