bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2730: RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition
Authors: Howes Jennifer , Lu Bing-Feng , Powers Marissa , Mitsopoulos Costas , Al-Lazikani Bissan , Linardopoulos Spiros , Clarke Paul , Workman Paul 
Published: May 2015

Abstract
The molecular chaperone heat shock protein 90 (HSP90) maintains the conformation, stability and function of oncogenic client proteins, many of which are mutated or overexpressed. Therefore, HSP90 is an important cancer therapeutic target. To further increase the efficacy of HSP90 inhibitors, combinatorial therapeutic strategies may be beneficial. Here we report an unbiased global screening approach to identify genes that encode potentially druggable proteins that modulate cellular responses to HSP90 inhibition. From the 7,593 genes that were tested, three components of the anaphase-promoting complex (APC/C) were among the genes which when silenced caused significant HSP90 inhibitor sensitisation. siRNA knockdown of ANAPC1, -8 or -4 produced up to three-fold sensitisation to HSP90 inhibitors 17-AAG and AUY922 in human colon cancer cells. Intriguingly, we show that combinatorial siRNA-mediated ANAPC1 knockdown and HSP90 inhibition induced an accumulation of mitotic cells exhibiting a tri-polar spindle formation. A marked increase in cyclin B1 and aurora A protein levels was observed in response to combinatorial ANAPC1 knockdown and HSP90 inhibition. These effects may have been responsible for the observed formation of aberrations in the mitotic spindle architecture. Furthermore, after a period of prolonged mitotic arrest, cancer cells treated with combinational ANAPC1 knockdown and HSP90 inhibition were committed to apoptosis. Mimicking siRNA knockdown, treatment with the APC/C inhibitor proTAME synergistically sensitised human colon carcinoma cells to HSP90 inhibition. These exciting results provide a mechanistic explanation underlying the HSP90 inhibitor sensitisation phenotype, and suggest that the APC/C may represent an interesting therapeutic target to exploit in combination with HSP90 inhibitors. Furthermore, therapeutic approaches may be developed which exploit the vulnerability of mitotic cancer cells in the context of HSP90 inhibition.
Citation Format: Jennifer Howes, Bing-Feng Lu, Marissa Powers, Costas Mitsopoulos, Bissan Al-Lazikani, Spiros Linardopoulos, Paul Clarke, Paul Workman. RNAi knockdown or chemical inhibition of anaphase-promoting complex components is synthetic lethal with HSP90 inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2014-2730
Abstract 2736: Thymidine catabolic and salvage pathways are responsible for the heterogeneity of anticancer agent dT-QX in liver cancer cells
Authors: Zhou Qibing , Wei Qiong , Zhang Dejun 
Published: May 2015

Abstract
Thymidine analog 3′-deoxythymidine phenylquinoxaline conjugate (dT-QX) can selectively kill cancer cell lines while is low cytotoxic towards normal liver cells. However, the cytotoxicity of dT-QX varied among cell lines of the same type cancer. Thus, the mechanism of the heterogeneity towards dT-QX was investigated. Considering that dT-QX is a thymidine analog, pathways of cellular thymidine metabolism were studied including catabolic and salvage pathways. The expression levels of enzymes of these two pathways among different cell lines of liver cancer were determined and compared. In addition, the impact on the activity of dT-QX by overexpressing and silencing the enzymes of these two pathways was assessed. Furthermore, a series of dT-QX analogs were synthesized and tested to reveal the potential structure-activity relationship to address the heterogeneity. Our initial results indicated that there was dramatic difference on the enzyme levels of thymidine catabolic and salvage pathways among the different cell lines of liver cancer. Modulation of the level of these enzymes resulted in significant impact on the activity of dT-QX. Variation on the cytotoxic activity was even observed with different structural analogs tested on these liver cancer cell lines. Our data suggested that thymidine catabolic and salvage pathways counteracted toward each other and thus were responsible for the heterogeneity of dT-QX in liver cancer cells.
Citation Format: Qibing Zhou, Qiong Wei, Dejun Zhang. Thymidine catabolic and salvage pathways are responsible for the heterogeneity of anticancer agent dT-QX in liver cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2736. doi:10.1158/1538-7445.AM2014-2736
Abstract 2738: Expression of p73 isoforms regulates proliferation and chemotherapeutic response in diffuse large B-cell lymphoma
Authors: Hassan Hesham M. , Varney Michelle L. , Singh rakesh K. , Dave Bhavana J. 
Published: May 2015

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). TP73 gene is a member of the p53 tumor suppressor gene family, which is critical in the regulation of cell cycle and apoptosis. TP73 is located in distal 1p36 chromosomal region that is commonly disrupted in DLBCL. TP73 gene function is controlled by a balance between two isoforms with opposing functions, the full length TAp73 protein (pro-apoptotic) and the NH2-terminally truncated ΔNp73 protein (anti-apoptotic by antagonizing both TAp73 and p53). Up-regulated expression of -Np73 isoforms has been reported in activated and germinal center B- cells as compared to very low levels in memory B- cells and follicular mantle cells, suggesting temporal expression of -Np73 isoforms during specific B- cell developmental stages. In the present study we have investigated the biological relevance of p73 isoforms in DLBCL. The DLBCL cell line DHL-16 was transfected with TAp73 encoded mammalian expression vector. The ‘control cells’ comprised of DHL-16 cells transfected with control vector. To evaluate growth differences under basal conditions as well as with serum deprivation, phenotypic comparison was performed between the two cell lines. Further, to evaluate the response to chemotherapy and to determine the differences in transcriptional targets, the p73 transfected and control cells were studied for the expression of p73 transcriptional targets PUMA, BIM, and GRAMD4. TAp73-transfected cells were more sensitive to serum deprivation and chemotherapy and showed an increased expression of the pro-apoptotic p73 transcriptional targets compared to control cells. We transfected DHL-16 cells with a truncated p73 isoform functionally similar to ΔNp73. These ΔNp73-transfected cells were resistant to serum deprivation and chemotherapy and showed a reduction in the expression of the pro-apoptotic p73 transcriptional targets PUMA, BIM, and GRAMD4 compared to control-vector transfected cells. Together, our data demonstrate that modulation of p73 isoform expression can alter the behavior of DLBCL and highlights p73 as a potential new therapeutic target in DLBCL.
Note: This abstract was not presented at the meeting.
Citation Format: Hesham M. Hassan, Michelle L. Varney, rakesh K. Singh, Bhavana J. Dave. Expression of p73 isoforms regulates proliferation and chemotherapeutic response in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2738. doi:10.1158/1538-7445.AM2014-2738
Abstract 2742: The PARP inhibitor niraparib demonstrates robust activity in a subset of patient-derived triple-negative breast cancer xenograft models
Authors: Wang Yan , Cairo Stefano , Nicolle Delphine , Cristescu Razvan , Loboda Andrey , Nebozhyn Michael , Zhang Theresa , Judde Jean-Gabriel , Wilcoxen Keith 
Published: May 2015

Abstract
Triple negative breast cancer (TNBC), which comprises 15% of all breast cancers, has a poor prognosis and currently lacks effective treatment. TNBCs are highly proliferative, genomically unstable and share molecular characteristics with BRCA1-/- breast cancer. Poly(ADP-ribose) polymerase-1 (PARP) is a key DNA repair enzyme that mediates single strand break (SSB) repair through the base excision repair (BER) pathway. PARP inhibitors have been demonstrated to selectively kill tumor cells that harbor BRCA1 and BRCA2 mutations. In addition, pre-clinical and preliminary clinical data suggest that PARP inhibitors are selectively cytotoxic for tumors with homologous recombination repair deficiency caused by mutations in genes other than BRCA1 or BRCA2. Niraparib is a potent, orally active PARP inhibitor that is being evaluated in Phase 3 clinical studies for ovarian cancer and BRCA related breast cancer. In exploring additional tumor indications that may be sensitive to niraparib, we investigated niraparib monotherapy activity in a panel of 17 basal breast cancer (BBC) patient-derived xenograft (PDX) models. Thirteen of the seventeen BBC models are TNBC models. Niraparib was administered po at a dose of 50 mg/kg once per day for 28 consecutive days, and tumor volume and body weight were measured twice weekly. Niraparib was well tolerated in nude mice bearing human TNBC PDXs growing subcutaneously, as there was no indication of body weight loss or decreased body weight gain relative to the vehicle control. Niraparib exhibited robust efficacy in five of the seventeen models tested. All five responsive models were TNBC. To understand the selectivity observed, a comprehensive analysis of the tumors was conducted which included analysis of gene mutation, gene copy number, gene expression and miRNA expression. A number of individual biomarkers and gene expression signatures were identified consistent with niraparib sensitivity across the 17 PDX models and will be discussed. In conclusion, in vivo activity of niraparib in TNBC was demonstrated in a panel of breast cancer PDX models, and several potential markers of niraparib sensitivity have been identified. Collectively this data supports the clinical investigation of niraparib in a subset of TNBC patients.
Citation Format: Yan Wang, Stefano Cairo, Delphine Nicolle, Razvan Cristescu, Andrey Loboda, Michael Nebozhyn, Theresa Zhang, Jean-Gabriel Judde, Keith Wilcoxen. The PARP inhibitor niraparib demonstrates robust activity in a subset of patient-derived triple-negative breast cancer xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2742. doi:10.1158/1538-7445.AM2014-2742
Abstract 2745: Pharmacological characterisation of cell active inhibitors of Poly(ADP-ribose) glycohydrolase (PARG)
Authors: James Dominic , Jordan Allan , Hamilton Nicola , McGonagle Alison , Smith Kate , Stowell Alexandra , Waddell Ian , Waszkowycz Bohdan , Ogilvie Donald 
Published: May 2015

Abstract
Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, thereby reversing the effects of poly(ADP-ribose) polymerases. Total PARG deficiency leads to cell death whilst PARG depletion, using RNAi, leads to pleiotropic effects such as PAR chain persistence, progression of single- to double-strand DNA lesions and NAD+ depletion.
Whilst efforts to develop small molecule inhibitors of PARG activity have generally been hampered by poor physiochemical properties, off-target pharmacology and a lack of cell permeability, we have now developed a series of PARG inhibitors which have proved to be useful biological tool compounds.
Displaying selective activity in both biochemical and, more importantly, cellular assays of PARG function, these derivatives have allowed an exploration of the phenotypes resulting from reversible, pharmacological PARG inhibition.
Citation Format: Dominic James, Allan Jordan, Nicola Hamilton, Alison McGonagle, Kate Smith, Alexandra Stowell, Ian Waddell, Bohdan Waszkowycz, Donald Ogilvie. Pharmacological characterisation of cell active inhibitors of Poly(ADP-ribose) glycohydrolase (PARG). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2745. doi:10.1158/1538-7445.AM2014-2745
Abstract 2746: An evaluation of poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer
Authors: Heitmann Jana , Geeleher Paul , Keck Michaela , Zuo Zhixiang , Khattri Arun , Tepper Susanne , Beckett Michael , Weichselbaum Ralph R. , Fetscher Sebastian , Vokes Everett E. , Seiwert Tanguy 
Published: May 2015

Abstract
Background: Synthetic lethality induced by poly (ADP-ribose) polymerase (PARP) inhibitors can occur in tumors without BRCA mutations. This “BRCAness” phenomenon has been observed in ovarian and triple negative breast cancers, but its role in other malignancies is not known. This study aims to evaluate the potency of PARP inhibitors in head and neck cancer, where BRCA mutations are rare.
Methods: First, we compared three PARP inhibitors (veliparib, olaparib and rucaparib). We subsequently established dose response curves for rucaparib for ten head and neck cancer cell lines and compared with two BRCA deficient breast cancer cell lines. Furthermore, we used immunofluorescent staining for γH2AX and RAD51 to study the capability for the DNA repair mechanism homologous recombination.
Results: We identified rucaparib as the most potent of the three PARP inhibitors tested and found a subset of tumors that show high rucaparib sensitivity (IC50 values: 7.0µM, 10.3µM and 11.7µM) comparable to a BRCA deficient breast cancer cell line (IC50 value: 8.9µM). Foci formation of the homologous recombination marker RAD51 did not serve as a reliable post-treatment biomarker.
Conclusion: In conclusion, we demonstrate that PARP inhibitors are effective in a subset of head and neck cancer cell lines, suggesting that these compounds could play a role in the treatment of a subset of head and neck tumors that exhibit the “BRCAness” phenotype. Further studies regarding the underlying mechanism of this phenotype are warranted.
Citation Format: Jana Heitmann, Paul Geeleher, Michaela Keck, Zhixiang Zuo, Arun Khattri, Susanne Tepper, Michael Beckett, Ralph R. Weichselbaum, Sebastian Fetscher, Everett E. Vokes, Tanguy Seiwert. An evaluation of poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2746. doi:10.1158/1538-7445.AM2014-2746
Abstract 2749: SRPK1 inhibition and modulation of VEGF alternative splicing as a potential therapeutic strategy in prostate cancer
Authors: Mavrou Athina , Bates Dave , Oltean Sebastian 
Published: May 2015

Abstract
Angiogenesis is required for tumor growth and is induced principally by VEGF-A. VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer. In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by SRPK1. Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intra-epithelial neoplasia lesions as well as malignant adenocarcinoma compared to benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in prostate cancer may be under control of SRPK1 activity. SRPK1 levels were up-regulated in several prostate cancer cell lines in comparison with normal prostate epithelial cells. A switch in the expression of VEGF165 towards the anti-angiogenic isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knock-down (KD). PC-3 -SRPK1 KD cells resulted in tumors that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1 KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Moreover, VEGF over-expression from a splicing-insensitive construct in PC-3/SRPK1 KD cells rescued tumor growth. Small molecule inhibitors of SRPK1 are able to switch splicing towards the anti-angiogenic isoform, VEGF165b in PC3 cells in vitro and decrease tumor growth when administered intraperitoneally in vivo in a mouse model of orthotopic prostate cancer. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumor angiogenesis by regulation of VEGF splicing can alter prostate tumor growth and supports further studies into the use of SRPK1 inhibition as a potential anti-angiogenic therapy in prostate cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Athina Mavrou, Dave Bates, Sebastian Oltean. SRPK1 inhibition and modulation of VEGF alternative splicing as a potential therapeutic strategy in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2749. doi:10.1158/1538-7445.AM2014-2749
Abstract 2756: Ceramide analog targets xIAP and cIAP1 to sensitize metastatic colon carcinoma cells to apoptosis induction to suppress tumor progression
Authors: Paschall Amy , Zimmerman Mary , Torres Christina , Yang Dafeng , Chen May , Li Xia , Bieberich Erhard , Bai Aiping , Bielawski Jacek , Bielawska Alicja , Liu Kebin 
Published: May 2015

Abstract
Sphingolipids are bioeffectors that mediate various cellular processes. We aimed to identify molecular targets of ceramide in the apoptosis pathway and to determine the efficacy of a ceramide analog in overcoming cancer cell resistance to apoptosis induction. We observed that exposure of human colon carcinoma cells to ceramide analog LCL85 results in apoptosis in a dose-dependent manner. Interestingly, a sublethal dose of LCL85 increased C16 ceramide content and overcame tumor cell resistance to FasL-induced apoptosis. Subsequently, treatment of tumor cells with exogenous C16 ceramide resulted in increased tumor cell sensitivity to FasL-induced apoptosis. LCL85 resembles Smac mimetic in sensitization of colon carcinoma cells to FasL-induced apoptosis by inducing proteasomal degradation of cIAP1 and xIAP proteins. Consistent with its apoptosis sensitization activity, LCL85 suppressed colon carcinoma cell metastatic potential in an experimental colon carcinoma lung metastasis mouse model. Taken together, we determined that a sublethal dose of LCL85 is effective as a sensitizer in overcoming apoptosis resistance of metastatic human colon carcinoma cells, and LCL85 is effective in suppressing tumor metastasis in vivo.
Citation Format: Amy Paschall, Mary Zimmerman, Christina Torres, Dafeng Yang, May Chen, Xia Li, Erhard Bieberich, Aiping Bai, Jacek Bielawski, Alicja Bielawska, Kebin Liu. Ceramide analog targets xIAP and cIAP1 to sensitize metastatic colon carcinoma cells to apoptosis induction to suppress tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2756. doi:10.1158/1538-7445.AM2014-2756
Abstract 2758: Development of small molecule Bax agonists for lung cancer treatment
Authors: Xin Meiguo , Li Rui , Park Dongkyoo , Owonikoko Taofeek K. , Sica Gabriel L. , Corsino Patrick E. , Zhou Jia , Ding Chunyong , Magis Andrew T. , Ramalingam Suresh S. , Curran Walter J. , Khuri Fadlo R. , Deng Xingming 
Published: May 2015

Abstract
Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently discovered that the serine(S) 184 site on Bax is a critical functional switch for controlling the proapoptotic activity of Bax. The structural pocket around the S184 residue holds great promise as an ideal target for small molecule docking. We therefore employed the S184 residue as a docking site for screening small molecule therapeutic agents using the UCSF DOCK program suite and the NCI library of small molecules. Three compounds named small molecule Bax agonists (i.e. SMBA1, SMBA2 and SMBA3) were found to induce a conformational change of Bax by blocking phosphorylation of its S184 site, facilitating Bax insertion into mitochondrial membranes and formation of Bax oligomers leading to cytochrome c release and apoptosis in human lung cancer cells. Intriguingly, SMBA1 potently suppresses lung tumor growth via apoptosis in vivo without significant normal tissue toxicity. Survival outcomes remain very poor for lung cancer patients due to resistance to standard therapeutic interventions with radiation and systemic chemotherapy. Development of novel Bax agonists as an entirely new class of anti-cancer drugs has translational value to foster novel strategies for the treatment of lung cancer and other Bax expressing malignancies.
Citation Format: Meiguo Xin, Rui Li, Dongkyoo Park, Taofeek K. Owonikoko, Gabriel L. Sica, Patrick E. Corsino, Jia Zhou, Chunyong Ding, Andrew T. Magis, Suresh S. Ramalingam, Walter J. Curran, Fadlo R. Khuri, Xingming Deng. Development of small molecule Bax agonists for lung cancer treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2758. doi:10.1158/1538-7445.AM2014-2758
Abstract 2763: EGFR endocytosis is a rational target in lung cancer with wild-type EGFR
Authors: Jo Ukhyun , Park Kyong Hwa , Whang Young M. , Sung Jae Sook , Won Nam Hee , Park Jong Kuk , Kim Yeul Hong 
Published: May 2015

Abstract
Oncogenic alterations of epidermal growth factor receptor (EGFR) signaling are frequently observed in lung cancer patients with worse differentiation and poor prognosis. However, the therapeutic efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is currently limited in selected patients with EGFR mutations. Therefore, in this study, we investigated the potential molecular mechanism that contributes to cell viability and the response of gefitinib, one of the EGFR-TKIs, in lung cancer models with wide-type EGFR (wtEGFR). Interestingly, we found that EGF-induced EGFR endocytosis is existed differently between gefitinib-sensitive and -insensitive lung cancer cell lines. Suppressing EGFR endocytos decreased cell viability and increased apoptotic cell death in gefitinib-insensitive lung cancer with wtEGFR in vitro and in vivo. In addition, we found that Rab25 was differentially expressed in between gefitinib-sensitive and -insensitive lung cancer cells. Rab25 knockdown caused the changed EGFR endocytosis and reverted the gefitinib response in gefitinib-sensitive lung cancer with wtEGFR in vitro and in vivo. Taken together, our findings suggest a novel insight that EGFR endocytosis is a rational therapeutic target in lung cancer with wtEGFR, in which the combined efficacy with gefitinib is expected. Furthermore, we demonstrated that Rab25 plays an important role in EGFR endocytosis and gefitinib therapy.
Citation Format: Ukhyun Jo, Kyong Hwa Park, Young Mi Whang, Jae Sook Sung, Nam Hee Won, Jong Kuk Park, Yeul Hong Kim. EGFR endocytosis is a rational target in lung cancer with wild-type EGFR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2763. doi:10.1158/1538-7445.AM2014-2763