bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4957: Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with cancer
Authors: Schwaederle Maria , Daniels Gregory A. , Piccioni David E. , Fanta Paul T. , Schwab Richard B. , Shimabukuro Kelly A. , Parker Barbara A. , Kurzrock Razelle 
Published: August 2015

Abstract
Next generation sequencing is advancing at a breathtaking pace, and is transforming patient care by allowing physicians to customize and match treatment to their patients’ tumor alterations. Our goal was to study the association between key molecular alterations and outcome parameters. We retrospectively reviewed the clinicopathologic and clinical outcomes of 392 patients for whom molecular testing had been performed. Potential associations between clinical characteristics and outcome parameters (overall survival (OS), time to metastasis/recurrence, and best progression-free survival (PFS)) were examined. The Kaplan-Meier method and Cox regression models were used for our analysis, and results were subjected to internal validation using a resampling method (bootstrap analysis). In a multivariable analysis (Cox regression model), the parameters that were statistically associated with a poorer overall survival were the presence of metastases at diagnosis (P = 0.014), gastrointestinal histology (P&lt;0.0001), PTEN (P&lt;0.0001), and CDKN2A alterations (P = 0.0001). The variables associated with a shorter time to metastases/recurrence were gastrointestinal histology (P = 0.004), APC (P = 0.008), PTEN (P = 0.026) and TP53 (P = 0.044) alterations. TP53 (P = 0.003) and PTEN (P = 0.034) alterations were independent predictors of a shorter best PFS. A personalized treatment approach (matching the molecular aberration with a cognate targeted drug) also correlated with a longer best PFS (P = 0.046). Our study demonstrated that, across diverse cancers, anomalies in specific tumor suppressor genes (PTEN, CDKN2A, APC, and/or TP53) were independently associated with a worse outcome, as reflected by time to metastases/recurrence, best PFS on treatment, and/or overall survival. These observations suggest that molecular diagnostic tests may provide important prognostic information in patients with cancer.
Citation Format: Maria Schwaederle, Gregory A. Daniels, David E. Piccioni, Paul T. Fanta, Richard B. Schwab, Kelly A. Shimabukuro, Barbara A. Parker, Razelle Kurzrock. Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with 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 4957. doi:10.1158/1538-7445.AM2015-4957
Abstract 496: Checkpoint kinase 1 inhibition suppresses cell growth and enhances cisplatin sensitivity in medulloblastoma cells
Authors: Shah Monil , Prince Eric , Venkataraman Sujatha , Balakrishnan Ilango , Alimova Irina , Harris Peter , Remeke Marc , Taylor Michael D. , Handler Michael H. , Foreman Nicholas K. , Vibhakar Rajeev 
Published: August 2015

Abstract
Background: Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Checkpoint kinase 1 (CHK1) is highly expressed in many cancers and regulates critical steps in mitotic progression and DNA-damage response. Activation of CHK1 pathway promotes treatment resistance in tumor cells. Recent studies suggest that targeting CHK1 with a small molecule inhibitor, to sensitize tumors to a variety of DNA-damaging agents, is a promising approach to tumor therapy.
Methods: The expression of CHK1 mRNA in medulloblastoma patient samples and cell lines were examined using microarray analysis and qRT-PCR respectively. Western blot analysis was conducted on medulloblastoma cell lines to analyze expression level of CHK1 protein. The effect of AZD7762, a small molecule inhibitor of CHK1, on colony forming ability of medulloblastoma cell lines in combination with cisplatin was examined using colony formation assay and methylcellulose assay. The impact of AZD7762 in combination with cisplatin on tumor cell proliferation was further evaluated in real-time using xCELLigence. The effect of AZD7762 on cell viability was assessed using Guava ViaCount assay. Furthermore, the effects on key signaling pathways were analyzed using immunofluorescence, senescence assay, and apoptosis assay.
Results: Analysis of gene expression and western blot experiments revealed that CHK1 mRNA and protein levels are over expressed in all medulloblastoma patient samples and in cell lines when compared to normal pediatric cerebellum. High CHK1 expression correlates with adverse outcomes in a large cohort of medulloblastoma patients. Inhibition of CHK1 by a low nanomolar concentration of AZD7762 potently inhibited cell growth, suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, AZD7762 pretreatment sensitized medulloblastoma cells to cisplatin synergistically.
Conclusions: CHK1 expression is a prognostic marker in medulloblastoma and targeting CHK1 with a small molecule inhibitor, in combination with cisplatin, is an attractive strategy in treatment of medulloblastoma that warrants further investigation.
Citation Format: Monil Shah, Eric Prince, Sujatha Venkataraman, Ilango Balakrishnan, Irina Alimova, Peter Harris, Marc Remeke, Michael D. Taylor, Michael H. Handler, Nicholas K. Foreman, Rajeev Vibhakar. Checkpoint kinase 1 inhibition suppresses cell growth and enhances cisplatin sensitivity in medulloblastoma cells. [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 496. doi:10.1158/1538-7445.AM2015-496
Abstract 4979: SIRT1 regulates the function of the KRAB-associated protein 1 (KAP1) in DNA damage response signaling
Authors: Lin Yi-Hui , Lou Zhenkun 
Published: August 2015

Abstract
KRAB-Associated Protein 1 (KAP1) is a master regulator for genome stability, heterochromatin formation, and target gene silencing. Many studies have suggested that post-translational modification is required for KAP1 to execute pleiotropic effects. Here, we have identified the physical interaction between KAP1 and SIRT1, which is a widely recognized NAD+-dependent deacetylase in DNA damage response. Therefore, the objective of this study was to characterize the functional significance of KAP1 deacetylation in DNA damage repair signaling.
In this study, SIRT1 was identified as a major interacting partner of KAP1 via biochemical approaches. Inhibition of SIRT1 activity by shRNA or selective inhibitor was able to upregulate the total acetylation level on KAP1, suggesting that KAP1 is a novel target of SIRT1. The major SIRT1-regulated KAP1 deacetylation sites (Lys266, Lys377, Lys469, and Lys770) were detected by quantitative mass spectrometric analysis. Next, to explore the functional significance of KAP1 deacetylation in NHEJ-mediated repair, KAP1 depleted cells reconstituted with wild-type KAP1 or 4KR acetylation mutant were used in the in vivo end-joining reporter system. Compare to wild-type KAP1, the 4KR mutant presented higher activity in promoting NHEJ efficiency. Furthermore, 4KR mutant showed stronger binding affinity to 53BP1, a crucial NHEJ promoting factor, and stabilized the 53BP1 foci formation in response to DNA damage.
In summary, this study unambiguously established KAP1 as a target of SIRT1 and that the deacetylation of KAP1 on Lys266, Lys377, Lys469, and Lys770 stabilizes the formation of 53BP1 foci on sites of double-strand breaks, thereby promotes NHEJ-mediated repair pathway.
Citation Format: Yi-Hui Lin, Zhenkun Lou. SIRT1 regulates the function of the KRAB-associated protein 1 (KAP1) in DNA damage response signaling. [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 4979. doi:10.1158/1538-7445.AM2015-4979
Abstract 4980: Rational design of combination therapies and block of acquired targeted drug resistance
Authors: Reuveni Hadas , Kuperschmidt Lana , Carmi Shani , Moskovitz Neta , Stemmer Salomon , Haviv Izhak 
Published: August 2015

Abstract
Recent successes of targeted drugs on end stage cancer patients highlight the value of mutation-based biomarkers with high positive predictive value for drug response predictions. However, the impact of these drugs is often temporary, and the patients progress to acquired resistance. A common mechanism of drug evasion involves feedback mechanisms that increase expression or phosphorylation-driven activation of an alternative oncogenic pathway. The objective of this work was to set up a streamlined methodology for pre-clinical assessment of the novel drug for refractory cancer targeting, with specific focus of personalized medicine, mediated by sequencing, and seek combination therapies that would block the spontaneous drug evasion. We explored the efficacy of the combination approach on a panel of cancer patient derived xenografts in mice, using tumor size, or metabolic imaging as an end point. Each cancer case was subject to target somatic mutation screening, which resulted in a targeted drug recommendation, and then, mouse groups were treated either with sequeincing-based therapy, or with combination of these therapies with blockers of the suspected evasion mechanisms. As a blocker of the evasion mechanism and epithelial to mesenchymal transition, we characterized the utility of a molecule that leads to the destruction of IRS1/2 of the IGF1R pathway. IRS1/2 are altered during EMT and drug resistance, thus blocking them could block drug resistance, and found multiple scenarios, where the combination of this blockage with currently used targeted drugs, such as Erlotinib, Zelboraf, and Gleevec, all increase the attenuation of the cancer growth and progression. Addition of the IRS1/2 destruction to Erlotinib and Zelboraf resistant H&N and melanoma cancers, respectively, lead to regression of the recurrent tumor mass. This combination therapy was further characterized by shRNA-negative screens, and kinome activity profiling, to assess further drug treatments that could be added, and in search for biomarkers that would identify patients likely to respond to the therapeutic combinations, We believe blocking the IGF1R in combination with drugs that inhibit the MAPK and tyrosine kinase receptor pathways may increase the progression free survival and expand the responding population within an array of cancer types, many of which are currently refractory to chemotherapy.
Citation Format: Hadas Reuveni, Lana Kuperschmidt, Shani Carmi, Neta Moskovitz, Salomon Stemmer, Izhak Haviv. Rational design of combination therapies and block of acquired targeted drug resistance. [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 4980. doi:10.1158/1538-7445.AM2015-4980
Abstract 4993: β-arrestin-2 regulates CXCR7-mediated EGFR transactivation and tumor cell proliferation in prostate cancer cells
Authors: Kallifatidis Georgios , Munoz Daniel , Singh Rajendra K. , Lokeshwar Bal L. 
Published: August 2015

Abstract
We have previously shown that the chemokine receptor CXCR7 trans-activates the epidermal growth factor receptor (EGFR) and is implicated in prostate tumor growth. However, the molecular mechanisms of CXCR7 mediated EGFR-trans-activation are not known. In the present work we show that CXCR7 induced EGFR transactivation is independent of EGF-like ligands such as amphiregulin and heparin-bound EGF. Importantly, treatment with pertussis toxin, a known G-protein inhibitor, had no effect on EGFR phosphorylation, indicating that G-protein signaling was not involved in CXCR7 mediated EGFR transactivation. Since CXCR7 is known to signal through β-arrestin-2 in its ligand dependent manner, we evaluated the role of β-arrestin-2 in CXCR7 induced EGFR trans-activation in prostate cancer cells. We used shRNA to stably down regulate β-arrestin-2 in LNCaP cells to evaluate the role of β-arrestin-2 in CXCR7 mediated induction of EGFR and downstream mitogenic signaling such as ERK1/2 and the phosphoinositide 3-kinase/Akt pathway. Interestingly, down regulation of β-arrestin-2 significantly induced phosphorylation of EGFR at Y1110 and Y1068 along with the phosphorylation/activation of ERK and AKT and an induction of proliferation/colony formation in prostate tumor cells. Moreover, shRNA mediated down regulation of β-arrestin-2 resulted in a decrease of p21 which is in accordance with the observed increased proliferation rate. The results of our study suggest that β-arrestin-2 is crucial negative regulator of CXCR7/EGFR signaling and underscore the importance of β-arrestin-2 in regulation of CXCR7/EGFR mediated tumor cell proliferation.
Citation Format: Georgios Kallifatidis, Daniel Munoz, Rajendra K. Singh, Bal L. Lokeshwar. β-arrestin-2 regulates CXCR7-mediated EGFR transactivation and tumor cell proliferation in prostate cancer cells. [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 4993. doi:10.1158/1538-7445.AM2015-4993
Abstract 4994: RET isoforms differentially contribute to focal adhesion formation
Authors: Yoganathan Piriya , Lian Eric , Mulligan Lois M. 
Published: August 2015

Abstract
RET is a receptor tyrosine kinase crucial for the development of the kidney, and some neuroendocrine tissues. RET activation by its ligand, glial cell-line derived neurotrophic factor (GDNF), results in autophosphorylation of several key tyrosine kinase residues in the intracellular region, which allow binding of adaptor and signalling proteins, and consequently activation of various cellular processes, including survival, proliferation and migration. RET has two major protein isoforms, called RET9 and RET51 after the number of unique amino acids at the C-terminus, generated by alternative splicing. Although the RET isoforms are highly conserved across species, and both isoforms are normally co-expressed, they have major molecular and functional differences, including different transforming abilities, and trafficking properties. RET is implicated in several human diseases. Gain-of-function RET mutations result in the cancer syndrome multiple endocrine neoplasia type 2, that affects neuroendocrine tissues, somatic RET rearrangements are found in papillary thyroid carcinoma, and lung adenocarcinoma, and aberrant wild-type RET activation occurs in many cancers, including breast and pancreatic cancer. Focal adhesion protein complexes are involved in interactions of cells with the extracellular matrix, and are crucial for controlling cancer-related processes, including cell migration and invasion. The contributions of RET isoforms to the processes of focal adhesion formation and dynamics have not yet been investigated. To explore the roles of RET isoforms in focal adhesion formation, we used total internal resonance fluorescence (TIRF) microscopy to assess localization of various focal adhesion proteins, including paxillin, vinculin and zyxin in response to GDNF in a cell-based model system. Our results suggest that RET51 promotes more early (ie. paxillin) and late (ie. zyxin) stage focal adhesion formation than does RET9. Additionally, we demonstrate that the kinase dead form of RET51 results in a decrease of the number of focal adhesions compared to RET51 wild-type, suggesting that the increase in focal adhesion formation in the presence of RET51 is phosphorylation-dependent. Inhibition of SRC and FAK led to a reduction in focal adhesion formation, indicating that these pathways play roles in this process. Ongoing studies are investigating the focal adhesion dynamics of the RET isoforms and further characterizing the molecular differences underlying the ability of RET51 to induce greater focal adhesion formation than RET9.
Citation Format: Piriya Yoganathan, Eric Lian, Lois M. Mulligan. RET isoforms differentially contribute to focal adhesion formation. [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 4994. doi:10.1158/1538-7445.AM2015-4994
Abstract 4997: Phosphorylation of SLAP by the KIT-D816V oncogenic mutant suppresses SLAP-mediated negative regulation of KIT signaling
Authors: Kazi Julhash U. , Sun Jianmin , Rönnstrand Lars 
Published: August 2015

Abstract
The SRC-like-adaptor protein (SLAP) is a negative regulator of mitogenic signaling. SLAP shares considerable structural homology with SRC, apart from lacking a kinase domain. SLAP is known to be expressed in a variety of cells and regulates cell surface receptor signaling by direct association. Here we show that SLAP interacts with the type III receptor tyrosine kinase KIT and also with its oncogenic mutant KIT-D816V. This mutant has been described as a driving mutant in several cancers including mastocytosis and certain types of acute myeloid leukemia. The association is mediated through phosphotyrosine residues in KIT and the SLAP-SH2 domain. Despite high structural similarity between SLAP and SRC, these tyrosine residues are different from the ones mediating SRC binding to KIT. This association results in increased ubiquitination and degradation of KIT. siRNA-mediated depletion of SLAP selectively potentiates wild-type KIT downstream signaling but not KIT-D816V signaling. Although SLAP displays similar localization pattern with both ligand-stimulated KIT and KIT-D816V, only KIT-D816V can phosphorylate SLAP on three tyrosine residues (Y120, Y258 and Y273). This phosphorylation takes place when SLAP interacts with KIT-D816V. Mutations on these tyrosine residues in SLAP restores normal SLAP regulation on oncogenic KIT-D816V. Taken together, our data suggest that the oncogenic mutant of KIT can bypass normal cellular regulation of signaling by phosphorylating regulatory proteins such as SLAP.
Citation Format: Julhash U. Kazi, Jianmin Sun, Lars Rönnstrand. Phosphorylation of SLAP by the KIT-D816V oncogenic mutant suppresses SLAP-mediated negative regulation of KIT signaling. [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 4997. doi:10.1158/1538-7445.AM2015-4997
Abstract 5016: Short-term blockade of EGF signaling improves immune-mediated cytotoxicity of NSCLC cells
Authors: Dominguez Charli 
Published: August 2015

Abstract
One of the manifestations of tumor plasticity is the acquisition of mesenchymal-like features by epithelial tumor cells via the phenomenon of epithelial-mesenchymal transition (EMT). This phenotypic conversion of tumor cells is known to be associated with tumor resistance to multiple cancer therapies, including chemotherapy, radiation and some small molecule-targeted therapies. Recent work from our group demonstrated that tumor cells undergoing the EMT may also become resistant to immune-mediated cytotoxicity involving antigen-specific and innate effector cells. As signaling through the epidermal growth factor receptor (EGFR) is a major inducer of EMT in epithelial cells, in the present study we sought to investigate the effect of short-term EGFR inhibition with erlotinib on tumor phenotype, and provide rationale for combination with immune-mediated therapies. Our data shows that pretreatment with the EGFR TKI erlotinib for less than 72 hours modulates tumor plasticity and immune-mediated cytotoxicity in NSCLCs harboring a sensitizing EGFR mutation. A significant modulation in expression of multiple EMT markers can be observed, including significant changes in the levels of expression of the transcription factor brachyury, a driver of human tumor EMT and a target for immunotherapeutic interventions. In addition, significant modulation of immune-relevant molecules on the surface of tumor cells can be observed, including changes in the levels of TRAIL-receptors, co-stimulatory and checkpoint molecules. The observed phenotypic changes in response to short-term erlotinib treatment correlate with an enhancement of immune-mediated tumor cell lysis, without any observed adverse affect on effector cell populations. Taking into account that brachyury-based cancer vaccines are currently being evaluated in clinical trials, modulation of brachyury levels and the observed enhancement of immune-mediated lysis in erlotinib-treated tumors may provide the rationale for future combinations of erlotinib and brachyury-based vaccines for the treatment of lung carcinomas.
Citation Format: Charli Dominguez. Short-term blockade of EGF signaling improves immune-mediated cytotoxicity of NSCLC cells. [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 5016. doi:10.1158/1538-7445.AM2015-5016