bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3812: FAK inhibition resensitizes platinum-resistant serous ovarian cancer
Authors: Bean Lisa M. , Sulzmaier Florian J. , Tancioni Isabelle , Uryu Sean , Jean Christine , Lawson Christine , Chen Xiao Lei , Kleinschmidt Elizabeth G. , Anderson Kristen M. , Cordasco Edward A. , Axelrod Joshua , Kolev Vihren N. , Pachter Jonathan A. , Stupack Dwayne G. , Schlaepfer David D. 
Published: July 2016

Abstract
Platinum and taxol administration is standard of care chemotherapy for serous ovarian cancer. Tumor recurrence occurs in a high percentage of patients, and this is directly related to poor overall survival. Ovarian cancer stem cell (CSC) resistance to chemotherapy treatment can give rise to tumor recurrence. Focal adhesion kinase (FAK), an intracellular tyrosine kinase, has been linked to mesothelioma and breast CSC survival. Here, we find that FAK activation is elevated in platinum (CP)-resistant ovarian cancer cells and that FAK tyrosine phosphorylation is increased after CP treatment of CP-sensitive ovarian cancer cells. Nanomolar levels of FAK inhibitor (VS-4718) selectively blocked CP-resistant ovarian carcinoma methylcellulose colony growth via cell cycle inhibition but not apoptosis. Oral VS-4718 administration to mice reduces CP-resistant orthotopic tumor burden with a concomitant decrease in tumor-associated aldehyde dehydrogenase (ALDH) activity, a marker of ovarian CSCs. Residual ovarian tumor cells from VS-4718-treated mice exhibit reduced ALDH activity and secondary tumor initiating capacity. CRISPR-mediated FAK knockout or VS-4718 treated ovarian carcinoma cells exhibit diminished Oct-4 transcription factor and ALDH-1A1 CSC-associated protein marker expression. Co-administration of VS-4718 with CP-taxol chemotherapy reduced CP-resistant tumor burden and exhibited additive inhibitory effects on ovarian carcinoma spheroid growth. As we find that CP activates FAK and that FAK activity sustains ovarian carcinoma CSC phenotypes, our results support the testing of FAK inhibitors in combination with CP to prevent recurrent and chemo-resistant ovarian cancer.
Citation Format: Lisa M. Bean, Florian J. Sulzmaier, Isabelle Tancioni, Sean Uryu, Christine Jean, Christine Lawson, Xiao Lei Chen, Elizabeth G. Kleinschmidt, Kristen M. Anderson, Edward A. Cordasco, Joshua Axelrod, Vihren N. Kolev, Jonathan A. Pachter, Dwayne G. Stupack, David D. Schlaepfer. FAK inhibition resensitizes platinum-resistant serous ovarian 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 3812.
Abstract 3848: Targeting hyaluronidase reduces stromal cell protection of chronic myeloid leukemia to imatinib therapy
Authors: Hostetler Bryan , Uchakina Olga , McKallip. Robert 
Published: July 2016

Abstract
An estimated 20-30% of CML patients will become resistant to tyrosine kinase inhibitors (TKIs) including imatinib. Recent reports suggest that CML resistance to TKI's is driven by interactions with protective microenvironment niches that influence their survival and self-renewal capacity. Hyaluronic acid (HA) has emerged as a key contributor in this phenomenon of CML resistance to TKI’s. HA influences cell viability through molecular weight dependent interactions with cell-surface receptors CD44 and RHAMM. Low molecular weight (LMW) HA, is typically found in association with many cancers including CML and promotes apoptotic resistance, proliferation, and migration of cancer cells. High molecular weight (HMW) HA is primarily produced by fibroblasts and its catabolism to LMW HA is mediated by hyaluronidase (HYAL) activity. HYAL activity may provide a potential therapeutic target in combination with current TKI treatments. Using a co-culture model, we investigated the role of HA produced by bone marrow stromal fibroblasts on CML viability when subject to imatinib (IM) treatment. Furthermore, we investigated the possibility of targeting hyaluronidase as an adjuvant in combination with IM for the treatment of CML. Co-culture with stromal fibroblasts protected CML cells from proliferation inhibition by IM. HA production and its catabolic products including LMW HA were elevated in the supernatant of co-cultures exposed to IM. The expression of genes encoding for HA metabolic proteins including hyaluronic acid synthases and HYALs, were significantly increased in co-cultures subject to IM stress. Additionally, HA treatment of CML mono-culture protected against chemotherapy-induced apoptosis. Treatment of CML co-culture with HYAL inhibitor, glycrrhizic acid (GA), inhibited HYAL activity, greatly reduced proliferation and increased apoptosis of CML cells alone and in combination with IM. This investigation provides additional evidence of the importance of stromal cell support in CML pathology and that resistance to TKI therapy may be mediated in part through upregulation of total HA production and its catabolism. Furthermore, we establish the potent therapeutic effects of GA on CML cells alone and in combination with current IM treatment strategies as a prospective method of circumventing TKI-resistant CML. For the first time we demonstrate GA's effectiveness as a HYAL inhibitor in culture. HYALs are an attractive target not only in CML resistance but in many cancers due to the reported role of its product, LMW HA, in inflammation, proliferation, and apoptotic resistance.
Citation Format: Bryan Hostetler, Olga Uchakina, Robert McKallip. Targeting hyaluronidase reduces stromal cell protection of chronic myeloid leukemia to imatinib therapy. [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 3848.
Abstract 3851: Synergy between statins and BCL-2 inhibitors in blood cancers
Authors: Lee Jong-Hoon S. , Vo Thanh-Trang T. , Fruman David A. 
Published: July 2016

Abstract
BCL-2 is a key pro-survival protein that is highly expressed in many leukemias and lymphomas. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2 that has demonstrated promising clinical potential in chronic lymphocytic leukemia (CLL). However, other hematologic malignancies are less responsive to ABT-199 as a single agent, suggesting that combinations of targeted therapies may be required to elicit more promising responses. We have investigated the potential of combining ABT-199 with HMG-CoA reductase (HMGCR) inhibitors (statins), which have known anti-cancer potential in hematologic malignancies. Using multiple chemically distinct statin compounds, we observed profound synergistic induction of apoptosis when combined with ABT-199 in both human diffuse large B cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML) cell lines. This synergy was also seen in primary murine B lymphoma cells over-expressing MYC and BCL-2. Importantly, addition of exogenous mevalonate completely rescued cells from the combination, confirming on-target efficacy of HMGCR inhibition. Using BH3 profiling, we found that simvastatin significantly primed lymphoma cells for undergoing apoptosis (termed mitochondrial priming). Notably, the degree of priming correlated with its ability to synergize with ABT-199, suggesting that this method may be used to predict patient responses. Strikingly, the combination did not synergize to kill normal human peripheral blood mononuclear cells from healthy donors, suggesting that statins may selectively prime cancer cells for apoptosis. Mechanistic studies support the hypothesis that statins synergize with ABT-199 by suppressing protein prenylation, particularly protein geranylgeranylation. In support, the addition of exogenous geranylgeranyl pyrophosphate (GGPP) completely rescued cells from the effects of simvastatin. Furthermore, selective inhibition of protein geranylgeranyl transferase (GGT) was sufficient to recapitulate the effects of simvastatin in combination with ABT-199. Lastly, we have identified Rap1A de-prenylation as a marker of pharmacodynamic response to statins in vivo. Thus, this project highlights a novel combination for use in aggressive lymphomas, establishes its efficacy and tolerability using preclinical models, and provides proof-of-concept to warrant investigation of its clinical potential.
Citation Format: Jong-Hoon S. Lee, Thanh-Trang T. Vo, David A. Fruman. Synergy between statins and BCL-2 inhibitors in blood 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 3851.
Abstract 3852: U3-1784, a human anti-FGFR4 antibody for the treatment of cancer
Authors: Bartz Rene , Fukuchi Keisuke , Lange Tanja , Gruner Katrin , Ohtsuka Toshiaki , Watanabe Ichiro , Hayashi Shinko , Redondo-Müller Mauricio , Takahashi Mizuki , Agatsuma Toshinori , Bange Johannes , Abraham Reimar 
Published: July 2016

Abstract
Fibroblast Growth Factor Receptor 4 (FGFR4) is the fourth member of the Fibroblast Growth Factor Receptor (FGFR) family of receptor tyrosine kinases. All of the FGFR's have been implicated in cancer development due to increased activation of their enzymatic activity either by gene mutation, over-expression or inadvertent ligand-mediated stimulation. One important alteration that may lead to FGFR4 activation in cancer is the overexpression of its ligand FGF19 in 20-40% of primary liver cancer.
Here, we report the development of U3-1784, a phage display-derived fully human antibody that specifically binds to FGFR4 but not to isoforms of FGFR1-3. The antibody binds to an epitope in the putative ligand binding domain of the receptor and consequently inhibits ligand binding and downstream signaling. In a panel of 10 tumor models derived from hepatocellular carcinoma, U3-1784 significantly inhibits the growth of FGF19-expressing models up to 90% whereas models without FGF19 expression are insensitive. These results strongly suggest that the FGFR4/FGF19 axis is an oncogenic driver in hepatocellular carcinoma. U3-1784 is currently in phase I clinical trials.
Citation Format: Rene Bartz, Keisuke Fukuchi, Tanja Lange, Katrin Gruner, Toshiaki Ohtsuka, Ichiro Watanabe, Shinko Hayashi, Mauricio Redondo-Müller, Mizuki Takahashi, Toshinori Agatsuma, Johannes Bange, Reimar Abraham. U3-1784, a human anti-FGFR4 antibody for the treatment of 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 3852.
Abstract 3883: Variant peptide identification system for bottom-up proteomics: Finding hidden sequence alterations in MS data
Authors: Hajduch Marian , Hruska Miroslav , Varanasi Lakshman , Voller Jiri , Dzubak Petr 
Published: July 2016

Abstract
In database search, acquired spectra are matched with theoretical spectra of database peptides. Peptides from large databases are likely to match to more than one spectrum, but only a small proportion of peptide interpretations are correct. Incorrect interpretations are likely to arise for two reasons: random matches and non-random matches to homologous peptides. The former is often eliminated by selection of an appropriate similarity threshold or by utilization of the statistical significance of a spectral match. The match to homologous peptide poses a challenge as there is often large similarity in their fragmentation spectra as well. Non-random, but incorrect matches occur surprisingly often in the identification of peptide sequence variants. For this reason, a high identification score does not imply correctness of interpretation. Increasing spectral score threshold enhances specificity in general, but results in significant loss of sensitivity. Therefore, a single spectral criterion is inadequate for distinguishing between homologous peptides.
In this study, we reconceive the system for elimination of incorrect interpretations. We propose a system that uses multidimensional LC/MS information in combination with a priori knowledge of sample content to filter out unlikely interpretations. The system calculates retention time of candidate peptides, performs isotopic analysis of precursors and constructs preliminary protein assembly to increase separation between correct and incorrect matches. The approach is used for reevaluation of database search results and is generally applicable to the analysis of standard bottom-up proteomic data.
The system was used for identification of alterations in MS2 proteomics data and validated against RNA-Seq data from the same sample. The results demonstrate that non-spectral data can be used to efficiently eliminate peptide interpretations that have no correspondence in the RNA and as such are likely false positives. The approach is sensitive and yields a large proportion of altered peptides that have RNA-Seq support. The method can potentially help overcome the problem of the large database search present, e.g., in proteogenomic studies, particularly important in cancer research and diagnostics. In summary, general prior knowledge of sample content and the use of LC and MS1 data improve on the MS2-based identification of peptides.
Citation Format: Marian Hajduch, Miroslav Hruska, Lakshman Varanasi, Jiri Voller, Petr Dzubak. Variant peptide identification system for bottom-up proteomics: Finding hidden sequence alterations in MS data. [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 3883.
Abstract 3888: Systematic characterization of aberrant signaling induced by oncogenic fusions in non-small cell lung cancer
Authors: Wagner Sebastian A. , Beli Petra , Serve Hubert 
Published: July 2016

Abstract
Recent studies have greatly expanded the knowledge about genetic alterations in non-small cell lung cancer (NSCLC). Gene fusions involving the tyrosine kinases ALK, ROS and RET are found in 5 - 10% of NSCLC patients and are considered as oncogenic drivers. However, the cellular signaling activated downstream of oncogenic fusions has not been systematically investigated and it remains unclear if different fusions induce specific targetable signaling patterns.
In this study we have employed quantitative mass spectrometry (MS)-based phosphoproteomics to systematically characterize the signaling induced by oncogenic fusions frequently found in NSCLC. To this end, cDNA sequences of oncogenic fusions containing the tyrosine kinases ALK, ROS and RET and different fusion partners were constructed and ectopically expressed in HEK 293 and lung cancer cell lines. Subsequently, tyrosine phosphorylated peptides were enriched and identified by LC-MS. Stable isotope labeling with amino acids in cell culture was employed to precisely quantify the abundance of phosphorylation sites in cells expressing different oncogenic fusions.
Our data demonstrate that all investigated oncogenic fusions induce massive tyrosine phosphorylation of proteins and lead to increased phosphorylation of the majority of all quantified phospho-tyrosine sites. For instance, we quantified ∼1300 unique phosphotyrosine sites from HEK 293 cells expressing EML4-ALK. Of those, 952 increased more than 4-fold in abundance. Comparative analyses of the signaling patterns allowed defining kinase-specific phosphorylation signatures. In addition, comparison of signaling patterns induced by different fusions permitted us to investigate the contribution of the non-kinase fusion partner to the downstream signaling. We were able to identify several phosphorylation events that were associated with specific non-kinase fusion partners. For example, kinase fusions containing the kinesin-1 heavy chain (KIF5B) specifically led to phosphorylation of cytoskeletal proteins, including cytoskeleton-associated protein 5 (CKAP5). We are currently investigating the functional role of these phosphorylation events for the oncogenic transformation.
In summary, we demonstrate that MS-based phosphoproteomics is a powerful tool to investigate aberrant signaling induced by oncogenic fusions in non-small cell lung cancer. Importantly, we find that the kinases involved in the oncogenic fusions largely define the downstream signaling and that the investigated fusion partners only exhibited a minor effect on the downstream signaling.
Citation Format: Sebastian A. Wagner, Petra Beli, Hubert Serve. Systematic characterization of aberrant signaling induced by oncogenic fusions in non-small cell lung 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 3888.
Abstract 3920: Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations
Authors: Eum Sung Yong , Lee Eunkyung , Wright Jean L. , Takita Christiane , Martin Eden R , Slifer Susan , Hu Jennifer J. 
Published: July 2016

Abstract
Radiotherapy-induced skin toxicity is one of the critical quality of life issues in breast cancer patients receiving adjuvant radiation therapy (RT). Finding a biomarker which can predict the development of acute RT-induced toxicity prior to RT is critical to improve precision medicine in radiation oncology. This study evaluated the association of single nucleotide polymorphisms (SNPs) in DNA-repair genes in 268 breast cancer undergoing adjuvant RT. We analyzed 3,747 polymorphisms in 119 DNA repair-related genes; 15 genes in base excision repair (BER), 11 in mismatch repair (MMR), 26 in nucleotide excision repair (NER), 15 in homologous recombination, 5 in non-homologous end-joining (NHEJ), 15 in DNA polymerases, and 47 in other DNA repair-related pathways. Skin toxicity was assessed at post-RT using the modified NCI's Common Toxicity Criteria for Adverse Events (CTCAE) and multiple logistic regression analyses were conducted to assess the associations between SNPs and grade ≥ 4 skin toxicity n = 115). After controlling for covariates, 221 SNPs were significant at p &lt;0.05 and 34 at p &lt; 0.01. Significant associations (p&lt;0.01) were found in 7 SNPs in PAPD5 gene, 1 in POLD1, POLE, and POLI in DNA polymerase; 5 in RAD51L1 and 1 in RAD54L in HR; 4 in MMS19 in NER; 2 in MSH4 and 1 in PMS1 in MMR; 2 in RPA3 in BER; 2 in RAD18, and 1 in UBE2V2 in Rad6 pathway; 2 in CHEK2 in DNA damage response pathway; 1 in MGMT in direct reversal of DNA damage; and 1 in BLM in diseases associated with sensitivity to DNA damaging agents pathways. Among these, most significant association was found in BLM variant (s16944918) which showed that carrying at least one minor T allele was associated with increased risk of RT-induced skin toxicity (odds ratio [OR] = 3.36; 95% confidence interval (CI) = 1.62-6.97, p = 0.001). For RPA3 (rs11978293), carriers with at least one minor G allele were more likely to develop RT-induced skin toxicity (OR = 2.17, 95% CI = 1.34-3.52, p = 0.002). The current study suggests that genetic variations in multiple DNA-repair genes/pathways may contribute to inter-individual variation in RT-induced normal tissue toxicity in breast cancer patients and suggests the possibility of potential predictive values of genetic polymorphisms in RT sensitivity. Further validation studies with larger sample size are warranted.
Citation Format: Sung Yong Eum, Eunkyung Lee, Jean L. Wright, Christiane Takita, Eden R, Martin, Susan Slifer, Jennifer J. Hu. Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations. [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 3920.
Abstract 3927: The presence of COX-2 and tumor-associated macrophages as a prognostic marker for invasive breast carcinoma patients
Authors: Esbona Karla , Saha Sandeep , Yi Yanyao , Yu Menggang , Wisinski Kari , Wilke Lee G. , Keely Patricia J. 
Published: July 2016

Abstract
Inflammation is an important mediator of tumor progression. The objective of this study was to assess whether the tissue localization of COX-2 and tumor-associated macrophages were associated with clinicopathological features of invasive carcinoma, including collagen deposition and patient survival outcome. A tumor microarray (TMA) of 371 biopsy specimens from patients with invasive breast carcinoma was analyzed for expression of high levels of COX-2, and the macrophage markers CD68 and CD163 in either the tumor nest (TN) or the tumor-associated stroma (TS). The study population for this TMA was female patients, 18 to 80 years of age with a median follow up of 8.4 years. Survival tables were calculated according to the Kaplan-Meier method. We found that elevated collagen deposition was associated with high stromal expression of COX-2 (P &lt; 0.0001); however, the amount of collagen deposition was not a predictor for survival outcome. In order to better analyze patient data, samples were divided into quartiles based on their levels of COX-2 expression and/or macrophage infiltration. Tumor nests with high COX-2 expression had worse patient outcome (P = 0.011). One possible mechanism for this is COX-2 dependent recruitment of macrophages to the tumor microenvironment, supported by our finding of high infiltration of CD68+ macrophages in the TS, and CD163+ macrophages in both TN and TS. This recruitment of macrophages was associated with worse overall survival (OS). Furthermore, patient survival was worsened even more if macrophages expressed COX-2, suggesting positive amplification of COX-2 signaling via macrophage recruitment. This notion is further established by the finding of high presence of CD163+ macrophages in the TN as an independent prognostic factor as revealed by multivariate analysis (P &lt; 0.0001, HR = 4.67). These results suggest that in invasive carcinoma the localization of inflammatory markers within the tumor are biomarkers for patient survival outcome. Therefore, we propose that these patients may benefit from therapy with a selective COX-2 inhibitor such as celecoxib.
Citation Format: Karla Esbona, Sandeep Saha, Yanyao Yi, Menggang Yu, Kari Wisinski, Lee G. Wilke, Patricia J. Keely. The presence of COX-2 and tumor-associated macrophages as a prognostic marker for invasive breast 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 3927.