bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3700: Association of the G/G-SNP309 variant in the mdm2 gene with earlier tumor onset in female renal cell carcinoma patients
Authors: Stoehr Christine G. , Stoehr Robert , Wenners Antonia , Hartmann Arndt , Bertz Simone , Spath Verena , Walter Bernhard , Junker Kerstin , Moch Holger , Hintze Raoul , Denzinger Stefan , Bond Elisabeth E. , Bond Gareth L. , Bluemke Karen , Weigelt Katrin , Lieb Verena , Nolte Elke , Fornara Paolo , Wullich Bernd , Wach Sven , Taubert Helge W. 
Published: July 2016

Abstract
Mdm2 (Human mouse double minute 2) is an important opponent of the tumor suppressor p53. The G/G variant of SNP309 in the MDM2 promoter can increase Mdm2 mRNA/protein expression and is associated with an increased risk and earlier onset of different cancers especially in Asian populations. But the frequency and impact of the G/G variant has not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years)
were diagnosed 13.5 years earlier than the T/T females (median age 73 years). Next, when separating all females into two groups at their median age (68 years), 7 patients and 1 patient with the G/G variant and 9 patients and 13 patients with the T/T variant were noted in these age groups (P = 0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was analyzed, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P = 0.039 and P = 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs. 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP 309 G/G variant showed a significantly earlier tumor onset than patients with the wildtype T/T genotype.
Citation Format: Christine G. Stoehr, Robert Stoehr, Antonia Wenners, Arndt Hartmann, Simone Bertz, Verena Spath, Bernhard Walter, Kerstin Junker, Holger Moch, Raoul Hintze, Stefan Denzinger, Elisabeth E. Bond, Gareth L. Bond, Karen Bluemke, Katrin Weigelt, Verena Lieb, Elke Nolte, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert. Association of the G/G-SNP309 variant in the mdm2 gene with earlier tumor onset in female renal cell carcinoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3700.
Abstract 3716: Potent radiation enhancement with VX-984, a selective DNA-PKcs inhibitor for the treatment of NSCLC
Authors: Boucher Diane , Hoover Russell , Wang Yuxin , Gu Yong , Newsome David , Ford Pamella , Moody Cameron , Damagnez Veronique , Arimoto Reiko , Hillier Shawn , Wood Mark , Markland William , Eustace Brenda , Cottrell Kevin , Penney Marina , Furey Brinley , Tanner Kirk , Maxwell John , Charifson Paul 
Published: July 2016

Abstract
Ionizing radiation (IR), which is widely used for the treatment of cancer, causes double-strand breaks (DSBs) in DNA. If left unrepaired, these DSBs are lethal to the cell. DNA-dependent protein kinase (DNA-PK) is a key enzyme in the non-homologous end joining (NHEJ) pathway that repairs DSBs caused by IR, or chemotherapeutic agents that cause DSBs such as doxorubicin. The goal of these studies was to characterize the radiation enhancing effects of VX-984, a selective and potent ATP-competitive inhibitor of the catalytic subunit of DNA-PK (DNA-PKcs), with a focus on non-small cell lung cancer (NSCLC) cells and tumor xenografts. VX-984 enhances the cytotoxicity of IR in a panel of cancer cell lines including NSCLC cell lines in vitro with dose enhancement factors (DEF) greater than 3. Notably, VX-984 combined with IR in normal human lung fibroblasts minimally enhanced the cytotoxicity compared to IR alone. Additionally, VX-984 decreased DNA-PKcs autophosphorylation on S2056 both in vitro and in vivo in NSCLC cells and attenuated the decay of the DNA damage markers γH2AX and pKAP1 in response to IR. In NSCLC PDX models VX-984, in combination with IR (2 Gy x 3), caused durable complete responses while IR alone only led to a delay in tumor growth, consistent with delayed DNA damage repair. In these models, the combination of VX-984 and IR was well tolerated. These data demonstrate that VX-984 is a potent radiation-enhancing agent and provide a strong rationale for the use of VX-984 in combination with IR for the treatment of NSCLC.
Citation Format: Diane Boucher, Russell Hoover, Yuxin Wang, Yong Gu, David Newsome, Pamella Ford, Cameron Moody, Veronique Damagnez, Reiko Arimoto, Shawn Hillier, Mark Wood, William Markland, Brenda Eustace, Kevin Cottrell, Marina Penney, Brinley Furey, Kirk Tanner, John Maxwell, Paul Charifson. Potent radiation enhancement with VX-984, a selective DNA-PKcs inhibitor for the treatment of NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3716.
Abstract 3724: Combination of TRAIL and Chal-24 synergistically kills lung cancer cells through autophagy-mediated degradation of IAPs and c-FLIPL
Authors: Xu Jennings , Xu Xiuling , Shi Shaoqing , Wang Qiong , Saxton Bryanna , Xing Chengguo , Lin Yong 
Published: July 2016

Abstract
Combination chemotherapy is an effective strategy for increasing anticancer efficacy, reducing side effects and alleviating drug resistance. Here we report that combination of the recently identified novel chalcone derivative, chalcone-24 (Chal-24), and TNF-related apoptosis-inducing ligand (TRAIL) significantly increases cytotoxicity in lung cancer cells. Chal-24 treatment significantly enhanced TRAIL-induced activation of caspase-8 and caspase-3, and the cytotoxicity induced by combination of these agents was effectively suppressed by the pan-caspase inhibitor z-VAD-fmk. Chal-24 and TRAIL combination suppressed expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (c-FLIPL) and cellular inhibitor of apoptosis proteins (c-IAPs), and ectopic expression of c-FLIPL and c-IAPs inhibited the potentiated cytotoxicity. In addition, TRAIL and Chal-24 cooperatively activated autophagy. Suppression of autophagy effectively attenuated cytotoxicity induced by the Chal-24 and TRAIL combination, which was associated with attenuation of c-FLIPL and c-IAPs degradation. Altogether, these results suggest that Chal-24 potentiates the anticancer activity of TRAIL through autophagy-mediated degradation of c-FLIPL and c-IAPs, and that combination of Chal-24 and TRAIL could be an effective approach in improving chemotherapy efficacy.
Citation Format: Jennings Xu, Xiuling Xu, Shaoqing Shi, Qiong Wang, Bryanna Saxton, Chengguo Xing, Yong Lin. Combination of TRAIL and Chal-24 synergistically kills lung cancer cells through autophagy-mediated degradation of IAPs and c-FLIPL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3724.
Abstract 3761: The MDM2 inhibitor AMG 232 causes tumor regression and potentiates the anti-tumor activity of MEK inhibition and DNA-damaging cytotoxic agents in preclinical models of acute myeloid leukemia
Authors: Canon Jude R. , Osgood Tao , Saiki Anne Y. , Oliner Jonathan D. 
Published: July 2016

Abstract
AMG 232 is a potent inhibitor of the MDM2-p53 interaction and is a promising clinical candidate for treating tumors, in particular those harboring wild-type p53. AML represents a compelling indication for AMG 232 given the low rate of p53 mutation, frequent MDM2 overexpression, and unmet medical need. We evaluated the effect of AMG 232 treatment on AML tumors in vitro and in vivo, elucidated the mechanism of anti-tumor efficacy, and tested the effect of combining AMG 232 with targeted agents and chemotherapeutics. Combinations were identified based on evidence of in vitro synergy from cell based screens, or based on biological rationale and clinical opportunity with standard of care agents. Combinations evaluated included MEK inhibitors, and p53-inducing, DNA-damaging cytotoxics cytarabine, doxorubicin, and decitabine. In vitro assays demonstrated that AMG 232 as a single agent was effective at inducing cell death across a panel of p53 wild-type AML cell lines. The anti-tumor efficacy involved activation of the p53 pathway, robust inhibition of the cell cycle and induction of apoptosis. AMG 232 treatment caused AML tumor regression in vivo which was related to dose- and time-dependent induction of the p53 targets p21 and PUMA. The combination of AMG 232 and MEK inhibition resulted in synergistic tumor cell killing in vitro, and enhanced in vivo anti-tumor activity which was significantly better than either single agent. Combinations of AMG 232 with chemotherapies which induce DNA damage resulted in synergistic in vitro cell killing, and superior anti-tumor efficacy in vivo with increased induction of p53 signaling in tumors. These data support a clinical strategy for evaluating AMG 232 as a monotherapy and in combination with targeted and cytotoxic agents to treat AML patients.
Citation Format: Jude R. Canon, Tao Osgood, Anne Y. Saiki, Jonathan D. Oliner. The MDM2 inhibitor AMG 232 causes tumor regression and potentiates the anti-tumor activity of MEK inhibition and DNA-damaging cytotoxic agents in preclinical models of acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3761.
Abstract 3795: Novel and selective MELK kinase inhibitors active in breast cancer cell lines
Authors: Carpinelli Patrizia , Montemartini Marisa , Amboldi Nadia , Ballinari Dario , Cribioli Sabrina , Ciomei Marina , Colombo Riccardo , Re Depaolini Stefania , Avanzi Nilla , Canevari Giulia , Ceccarelli Walter , Posteri Helena , Brasca Maria Gabriella , Donati Daniele , Felder Eduard Rudolf , Isacchi Antonella , Galvani Arturo , Montagnoli Alessia 
Published: July 2016

Abstract
Maternal Embryonic Leucine zipper Kinase (MELK) is a serine-threonine kinase implicated in stem cell renewal, override of cell cycle checkpoints, pre-mRNA splicing and resistance to apoptosis, while MELK gene expression levels correlate inversely with poor prognosis in breast cancer, prostate cancer and glioblastoma patients. Moreover, recent findings underlie the oncogenic role of this kinase in triple negative breast cancer (TNBC), a category of high-grade, invasive tumors which lack expression of estrogen receptor (ER) and progesterone receptor (PR) and HER2 amplification and which is resistant to current cytotoxic and targeted therapies. Furthermore, they are highly heterogeneous with respect to genomic alterations, and common therapeutic targets are lacking, although substantial evidence implicates dysregulated kinase signaling.
Here, we describe the preclinical characterization of novel, potent and selective ATP-competitive MELK kinase inhibitors identified by means of high-throughput screening of the NMS proprietary compound collection. Leading compounds possess biochemical activity against MELK in the nanomolar range with high selectivity against a panel of 60 further kinases representative of the human kinome. Amongst human tumor cell lines tested in 2-dimensional colony outgrowth assays, marked sensitivity was observed in breast cancer cell lines, with sub-micromolar anti-proliferative activity. This effect was accompanied by dose-dependent induction of apoptosis and by modulation of cellular biomarkers, consistent with a MELK-dependent mechanism of action.
Overall, these data provide further evidence that MELK is a promising biological target for the development of novel anticancer therapies.
Citation Format: Patrizia Carpinelli, Marisa Montemartini, Nadia Amboldi, Dario Ballinari, Sabrina Cribioli, Marina Ciomei, Riccardo Colombo, Stefania Re Depaolini, Nilla Avanzi, Giulia Canevari, Walter Ceccarelli, Helena Posteri, Maria Gabriella Brasca, Daniele Donati, Eduard Rudolf Felder, Antonella Isacchi, Arturo Galvani, Alessia Montagnoli. Novel and selective MELK kinase inhibitors active in breast cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3795.
Abstract 3799: The PAK4 allosteric modulator (KPT-9274) attenuates the growth of renal cell carcinoma
Authors: Weiss Robert H. , Abu Aboud Omran , Baloglu Erkan , Senapedis William , Shacham Sharon 
Published: July 2016

Abstract
Renal cell carcinoma (RCC) is an increasingly prevalent cancer type that is frequently asymptomatic on presentation and is associated with poor responses and resistance even to the current targeted therapies. Thus, novel therapeutic approaches to treat this disease are urgently needed. P21-activated kinase 4 (PAK4) is a mediator of filopodia formation and stabilizes β-catenin transcriptional activity, both of which are integral to nephrogenesis and cancer. We hypothesized that inhibitors of the PAK4 signaling pathway would result in salutary effects on RCC. To test this, we evaluated the in vitro response of several human RCC cells and normal kidney proximal epithelial cells (NHKs) to the specific PAK4 Allosteric Modulators (PAMs; KPT-8752 and KPT-9274). 786-O (VHL-mutant RCC) and caki-1 (VHL-wt RCC) cells showed decreases in cell viability (MTT), induction of apoptosis and arrest in G2/M phase when incubated with these inhibitors. These responses were diminished in NHK cells which served as a “normal” control cell line. Target and specific pathway proteins (phospho-PAK4, Phospho-β-catenin, c-Myc and cyclin D1) were reduced after RCC, but not NHK, were incubated with KPT-8752 and KPT-9274. To confirm specificity of the inhibitor to PAK4, all these responses were reproduced in RCC cells using specific PAK4 siRNA. Since ∼85% of RCC cases are associated with mutation in vhl we used 786-0 xenograft mouse model to evaluate the clinical candidate KPT-9274. KPT-9274 was orally administered at 100 and 200 mg/kg BIDX5 for 4 weeks, resulting in clear attenuation of tumor growth at both doses. There was no obvious change in the health or weight of any of the animals when compared to vehicle group suggesting manageable tolerability. We are currently evaluating combination therapy and plan to test this inhibitor on a metastatic RCC model. In summary, PAK4 inhibitors show considerable promise as novel treatments of RCC as a single agent and warrants further investigation.
Citation Format: Robert H. Weiss, Omran Abu Aboud, Erkan Baloglu, William Senapedis, Sharon Shacham. The PAK4 allosteric modulator (KPT-9274) attenuates the growth of renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3799.
Abstract 3809: Protein arginine methyltransferase 1 (PRMT1) is a candidate therapeutic target for breast cancers
Authors: Silvestre David , Brisson Amélie , Marty-Prouvost Bérengère , Ye Mengliang , Bonsang Hélène , Maire Virginie , Loew Damarys , Gentien David , Meseure Didier , Reyal Fabien , Tucker Gordon C. , Roman-Roman Sergio , Dubois Thierry 
Published: July 2016

Abstract
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In the present study, we found that Protein Arginine Methyltransferase 1 (PRMT1) is overexpressed in TNBC at the mRNA level. At the protein level, PRMT1 is overexpressed in all breast cancer subtypes compared to normal breast tissues. The depletion of PRMT1 using siRNA in breast cancer cell lines triggered apoptosis, reduced cell viability and the ability to form colonies in an anchorage-independent manner. Treatment with a PRMT1 inhibitor blocked proliferation specifically in breast cancer cells, with no effect in normal breast cells. Importantly, the expression of PRMT1 is an indicator of prognosis and response to treatment specifically in TNBC patients. To address the cellular pathways regulated by PRMT1, we identified its protein partners by mass spectrometry and the transcriptomic changes following its depletion in TNBC cell lines. Interestingly, we found that PRMT1 directly activates key oncogenic pathways. Furthermore, we found a synergistic interaction between PRMT1 inhibitors and inhibitors for some of those pathways. We show that PRMT1 activity is necessary for breast cancer cell survival and oncogenic pathway activation. Altogether, our results point out PRMT1 as an emerging target for the treatment of breast cancers.
Citation Format: David Silvestre, Amélie Brisson, Bérengère Marty-Prouvost, Mengliang Ye, Hélène Bonsang, Virginie Maire, Damarys Loew, David Gentien, Didier Meseure, Fabien Reyal, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. Protein arginine methyltransferase 1 (PRMT1) is a candidate therapeutic target for breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3809.
Abstract 3814: Synthetic lethal approaches targeting E-cadherin-deficient cancers
Authors: Chen Augustine , Telford Bryony J. , Single Andrew , Beetham Henry , Simpson Kaylene J. , Guilford Parry 
Published: July 2016

Abstract
E-cadherin is a cellular adhesion protein that is frequently mutated in lobular breast cancer and diffuse gastric cancer. The E-cadherin protein which is encoded by the CDH1 gene has key roles in establishing and maintaining cell polarity and differentiation, the organization of cell migration and architecture and the mediation of signaling through various proliferation and survival pathways. E-cadherin also has a tumor suppressor role and its loss in cancer cells would preclude drug targeting by conventional therapy. To circumvent this, we have taken a synthetic lethal approach to exploit any vulnerability created by the loss of E-cadherin. In the therapeutic setting, synthetic lethality refers to a combination of a mutated gene and a drug targeted at a second gene or protein causing cell death (specifically in cancer cells). To identify the vulnerabilities created by E-cadherin loss, we performed a genome-wide siRNA knockdown screen in isogenic MCF10A cell lines with and without E-cadherin expression. From the functional screen, we identified broad classes of G-protein-coupled receptor (GPCR) signaling proteins and families of cytoskeletal proteins which were highly enriched among the synthetic lethal candidates. Indeed, we identified drug classes with linkages to several of the GPCR and cytoskeletal targets that showed evidence of E-cadherin synthetic lethality when we performed a 4,057 known drug screen. These included certain PI3K inhibitors (PI-103), anti-glucocorticoid (mifepristone), tyrosine kinase inhibitor (saracatinib) and multiple histone deacetylase inhibitors (vorinostat and entinostat). Interestingly, the combination of saracatinib and mifepristone gave a synergistic effect (combination index &lt; 1.0) in targeting E-cadherin-deficient MCF10A cells. These results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both of sporadic and familial lobular breast cancer and diffuse gastric cancer.
Citation Format: Augustine Chen, Bryony J. Telford, Andrew Single, Henry Beetham, Kaylene J. Simpson, Parry Guilford. Synthetic lethal approaches targeting E-cadherin-deficient cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3814.
Abstract 3824: Targeting MUC1-C oncoprotein inhibits AKT-S6K1-elF4A pathway regulated TIGAR translation in colorectal cancer
Authors: Ahmad Rehan , Alam Maroof , Al-Obaid Omar , Hasegawa Masanori , Kufe Donald 
Published: July 2016

Abstract
Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 multi-domain oncoprotein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. However, it is not known if MUC1 is of functional significance to colorectal tumors. Here, we investigate the effects of the MUC1-C inhibitor (GO-203), which disrupts MUC1-C homo-oligomerization, on AKT-mTORC-S6K translation pathway in human colorectal cancer cells. The present study demonstrates that GO-203 treatment was associated with inhibition of AKT-S6K1 signaling in colorectal cancer cells. Targeting MUC1-C with GO-203 downregulates TP53-inducible glycolysis and apoptosis regulator (TIGAR) protein. We show that GO-203-induced suppression of TIGAR is mediated by inhibition of AKT and the downstream mTOR pathway. The results also demonstrate that targeting MUC1-C blocks eIF4A cap-dependent translation of TIGAR. TIGAR promotes the shunting of glycolytic intermediates into the pentose phosphate pathway and thus is of importance for maintaining redox balance. In concert with these results, GO-203-induced suppression of TIGAR was associated with decreases glutathione levels. GO-203 treatment also resulted increases in reactive oxygen species (ROS) and loss of mitochondrial transmembrane potential. Consistent with these results, GO-203 inhibited the growth of colon cancer cells in vitro and xenografts in nude mice. These findings thus indicate that MUC1-C is a potential target for the treatment of colorectal cancer.
Citation Format: Rehan Ahmad, Maroof Alam, Omar Al-Obaid, Masanori Hasegawa, Donald Kufe. Targeting MUC1-C oncoprotein inhibits AKT-S6K1-elF4A pathway regulated TIGAR translation in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3824.