bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3071: Proteasome subunit composition contributes to unusually poor sensitivity of H727 cells to carfilzomib
Authors: Lee Min Jae , Kim Kyung Bo 
Published: July 2016

Abstract
Background: While proteasome inhibitors (PIs) have significantly improved the survival of multiple myeloma (MM) patients, significant subsets of MM patients do not respond to the PI- based therapy. Currently, mechanisms of de novo PI resistance in these patients remain completely unknown. In this study, we aim to identify previously unexplored mechanisms of de novo carfilzomib (Cfz) resistance using H727 cancer cells with poor sensitivity to carfilzomib.
Results: Our carfilzomib sensitivity investigation in a panel of 16 cancer cell lines revealed that H727 lung cancer cells are markedly resistant to Cfz compared to other cell lines. H727 cells displayed no detectable P-glycoprotein (P-gp) expression and subsequently were not sensitized by reversin 121 (a P-gp inhibitor) to Cfz, ruling out the involvement of P-gp in the resistance of H727 cells to Cfz. Interestingly, we found that H727 cells are killed by PYR-41 (ubiquitin activating enzyme E1 inhibitor) and WP-1130 (deubiquitinase inhibitor) as effectively as Cfz- sensitive H23 cells, suggesting that ubiquitin-proteasome pathway is essential in H727 cells as in H23 cells. In addition, knock-down of proteasome α7 subunit, a component required for the assembly of a proteasome α-ring and thereby a 20S proteasome complex, resulted in an almost complete cell death, indicating that the proteasome is indispensable for the survival of H727 cells. Intriguingly, despite their poor sensitivity to Cfz, H727 cells were highly sensitive to other structurally distinguished PIs such as bortezomib, epoxomicin, and UK-101. Finally, exposure of H727 cells to interferon-γ (IFN-γ), which has been widely used as a biochemical tool to switch cellular proteasome catalytic subunit composition to the one containing immunoproteasome subunits, sensitized H727 cells to Cfz (Changing IC50 values from 1,355 nM to 185 nM). On the contrary, IFN-γ pretreatment did not affect the sensitivity of H23 cells to Cfz.
Conclusion: We report that H727 cells have a poor sensitivity to carfilzomib (or de novo resistance to Cfz), and that previously reported resistance mechanism involving P-gp upregulation does not play a role. Given our data presented here, we conclude that de novo Cfz resistance of H727 cells may be attributed to distinguished proteasome subunit composition. We believe that our investigation using cancer cell line models may provide important insights into understanding the mechanisms of de novo PI resistance in clinic.
Citation Format: Min Jae Lee, Kyung Bo Kim. Proteasome subunit composition contributes to unusually poor sensitivity of H727 cells to carfilzomib. [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 3071.
Abstract 3077: Potent inhibition of bromodomain-containing BET family with ABBV-075 induces robust antitumor efficacy in preclinical models of breast cancer and exhibits in vitro synergy with doxorubicin
Authors: Faivre Emily J. , Lin Xiaoyu , Wilcox Denise M. , Huang Xiaoli , Sarthy Aparna , Magoc Terry , Albert Daniel H. , Fang Guowei , Rosenberg Saul H. , McDaniel Keith F. , Kati Warren M. , Shen Yu 
Published: July 2016

Abstract
Breast cancer diagnosisis highly prevalent in the US, with an estimated 231,840 new cases occurring in 2015. Targeted therapies, such as tamoxifen or Trastuzumab (herceptin) are available to woman whose tumors are estrogen receptor (ER) positive or HER2 positive, respectively. However, women with triple negative breast cancer or relapsed metastatic disease have limited treatment options. ABBV-075 is a novel BET family bromodomain inhibitor currently under phase I clinical investigation for a wide spectrum of cancer indications. Here we show that ABBV-075 exhibits broad anti-proliferative activity across cell lines representing ER positive, HER2+, and triple negative breast cancer. Notably, ABBV-075 induced G1 arrest and growth inhibition of breast cancer cell lines regardless of ER or RB status. This result suggests that ABBV-075 may provide therapeutic benefit to a broader patient population relative to the recently approved cdk4/6 inhibitor, palbociclib. The G1 arrest mechanism of ABBV-075 was efficacious in breast cancer xenograft studies, where significant tumor growth inhibition was observed. Additionally, ABBV-075 exhibited synergy in ER positive cell lines with doxorubicin, a TOPO2 inhibitor and DNA intercalating agent prescribed to ER positive patients refractory to hormone therapies. Intriguingly, the mechanism by which ABBV-075 and doxorubicin interact was independent of the TOP2-trapping activity of doxorubicin and instead required DNA intercalation. Together, these results demonstrate the potential of ABBV-075 as a treatment option across the different subtypes of breast cancer and in combination with doxorubicin in patients with ER positive disease
Citation Format: Emily J. Faivre, Xiaoyu Lin, Denise M. Wilcox, Xiaoli Huang, Aparna Sarthy, Terry Magoc, Daniel H. Albert, Guowei Fang, Saul H. Rosenberg, Keith F. McDaniel, Warren M. Kati, Yu Shen. Potent inhibition of bromodomain-containing BET family with ABBV-075 induces robust antitumor efficacy in preclinical models of breast cancer and exhibits in vitro synergy with doxorubicin. [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 3077.
Abstract 3078: GSK-3 inhibitor 9ING41 potentiates the antitumor effects of CPT-11 in human breast cancer
Authors: Ugolkov Andrey , Gaisina Irina , White Kevin , Kozikowski Alan , O’Halloran Thomas , Mazar Andrew 
Published: July 2016

Abstract
Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been demonstrated to be potential therapeutic target in human breast cancer. Our objective was to evaluate novel GSK-3 inhibitors alone and in combination with chemotherapeutic drugs for the targeted therapy of breast cancer. Using a short-term treatment, we found that the GSK-3 inhibitor 9ING41 significantly potentiates the antitumor effects of CPT-11, cisplatin and 5-FU to inhibit breast cancer cell growth. We established hormone-refractory BC-1 and BC-2 patient-derived xenograft (PDX) tumor models from metastatic pleural effusions that were obtained from breast cancer patients. We considered BC-1 and BC-2 PDX tumors as chemoresistant, because metastatic disease progressed in both cases in despite of the fact that patients received many cycles of chemotherapy. Although we found that BC-1 and BC-2 PDX tumors express estrogen receptor (ER), both PDX tumors carried activating mutations in ESR1. These mutations confer ligand-independent activity of the ER in tamoxifen-resistant breast tumors. We found that BC-1 and BC-2 PDX tumors grew without estradiol supplementation in immunodeficient mice, which suggests a hormone-refractory nature of these tumors. We found that GSK-3 inhibitor 9ING41 potentiates the effects of chemotherapeutic drug CPT-11, and leads to the regression of BC-1 and BC-2 breast PDX tumors. Our results demonstrate inhibition of GSK-3 as a promising therapeutic approach to overcome breast cancer chemoresistance, and identify GSK-3 inhibitor 9ING41 as a drug candidate for the targeted therapy of human breast cancer.
Citation Format: Andrey Ugolkov, Irina Gaisina, Kevin White, Alan Kozikowski, Thomas O’Halloran, Andrew Mazar. GSK-3 inhibitor 9ING41 potentiates the antitumor effects of CPT-11 in human breast 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 3078.
Abstract 3094: Identification of mimotopes of the epithelial mucin-1 (MUC1) in non-small cell lung cancer
Authors: Qiu Yu , Jianfei Wang , Ruoqiong Cao , Yi Zhang , Yangyang Sun , Zhong Li 
Published: July 2016

Abstract
Background
Mimotope analysis has been widely used in mapping epitopes for drug target, and also used in the development of new diagnostics, therapeutics and vaccines. The epithelial mucin-1 (MUC1) is a glycoprotein in human endometrium and has been found highly expressed in tumor tissues of NSCLC patients. Mimotopes of MUC1 has great potentials to be immunotherapy targets for NSCLC. In this study, we use phage display technology to screen a T7 NSCLC phage library to identify mimotope peptides of MUC1 proteins.
Method
A T7 NSCLC phage library was screened by 3-round of biopanning with anti-MUC1 monoclonal antibody acting as a molecular target. Forty positive clones were picked for ELISA confirmation using anti-MUC1 antibody. In addition, these clones were then amplified and coated with ELISA plates. Forty NSCLC patient and 40 control serum samples were used to test the ELISA plates. Statistical analysis was preformed, and the most significant clones were picked and PCR amplified for sequencing.
Result
Two peptide sequences, AAPDFRP and SAPDDRP, were identified and the competitive inhibitory rates of MUC1 were more than 50%. The intensity between MUC1 monoclonal antibody and the positive clones of these two sequences had positive correlation. In addition, in serum binding specificity detection, these two amino acid sequences showed higher tumor binding specificity with lung cancer patients serum than that of healthy human serum(P&lt;0.05).
Conclusion
Peptides of AAPDFRP and SAPDDRP showed a high homology in the mimic epitopes of the epithelial mucin-1 (MUC1) glycoprotein in NSCLC. These may be potential immunotherapy targets which could also act as candidates of tumor vaccines
Citation Format: Yu Qiu, Wang Jianfei, Cao Ruoqiong, Zhang Yi, Sun Yangyang, Li Zhong. Identification of mimotopes of the epithelial mucin-1 (MUC1) 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 3094.
Abstract 3096: Mapping lysine acetyltransferase-metabolite interactions in complex proteomes: a window into the metabolic regulation of epigenetic signaling
Authors: Meier Jordan L. 
Published: July 2016

Abstract
Substantial evidence indicates that chromatin modifiers are sensitive to changes in the cellular concentration of metabolites and cofactors. These findings potentially connect metabolism and gene expression, and have major implications for the regulation of cell signaling in cancer. However, missing from many of these studies has been the direct identification of the specific chromatin modifiers that sense change in metabolic state. Their identification is critical to our basic understanding of how metabolism regulates epigenetically-driven phenotypes, and may inform novel strategies to combat pathologies characterized by aberrant metabolism, including cancer. Towards this goal, here we report a chemical proteomic strategy to globally map chromatin modifier-metabolite interactions in complex proteomes. Our initial efforts have focused on lysine acetyltransferases (KATs), a central class of chromatin modifiers responsible for histone acetylation. First, we validate an optimized chemical proteomic method and demonstrate its ability to globally profile members of the KAT enzyme superfamily at endogenous expression levels. Then we apply this approach to rapidly profile KAT-ligand interactions, and identify novel candidate metabolic regulators of protein acetylation, including acyl-CoAs cofactors and metabolites, as well as new metabolically-sensitive KAT enzymes. By defining the molecular interactions linking metabolism and gene expression, these studies have the potential to illuminate our understanding of biology and inspire new therapeutic strategies targeting acetylation in disease.
Citation Format: Jordan L. Meier. Mapping lysine acetyltransferase-metabolite interactions in complex proteomes: a window into the metabolic regulation of epigenetic signaling. [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 3096.
Abstract 31: Metabolic reprogramming in ovarian cancer
Authors: HA JI HEE , Radhakrishnan Rangasudhagar , Ward Jeremy D. , Jayaraman Muralidharan , Dhanasekaran Danny N. 
Published: July 2016

Abstract
Ovarian cancer is currently the most lethal gynecologic malignancy, with no new significant changes in treatment options for these patients in the last 30 years. Importantly, ovarian cancer patients have increased levels of lysophosphatidic acid (LPA), a bioactive phospholipid in ascites and serum that has been linked to driving oncogenesis and progression of ovarian cancer. Accumulating evidence has implicated Hypoxia-inducible factor-1α (HIF-1α) as a critical mediator of the glycolytic shift observed in cancer cells. However, the precise biological role of LPA in regulating HIF-1α-mediated glycolytic shift is largely unknown. Therefore, we were interested in examining the potential role of LPA in promoting metabolic reprogramming in ovarian cancer via HIF-1α signaling. In this study, we identified a novel mechanism by which LPA upregulates HIF-1α expression via Gαi2 (the gip2 oncogene) in human ovarian cancer cells. This study demonstrates that LPA induces a glycolytic shift via LPA-mediated activation of Gαi2, which causes a subsequent upregulation of HIF-1α in ovarian cancer cells. Additionally, we show that LPA-signaling via Gαi2 induces an increase in the expression of Hexokinase-2 (HK2) and Glucose transporter 1 (GLUT1), which are known targets of HIF-1α. We also demonstrate that LPA induces an increase in extracellular acidification rate (ECAR) in a dose dependent manner in both ovarian cancer cell lines and in patient-derived cells taken from the ascites fluid of ovarian cancer patients using an XFe96 analyzer. Furthermore, we found that inhibition of Rac signaling caused a reduction in LPA-induced ECAR, identifying Rac as a critical downstream component of Gαi2-medidated increase of ECAR. Moreover, using NAC, an inhibitor of redox signaling, we found that this caused a decrease in LPA-induced ECAR in SKOV3-ip cells, indicating that inhibition of redox signaling abolishes LPA-induced ECAR in ovarian cancer cells. Similarly, the use of EUK-134, a scavenger of superoxide and H2O2, also decreased LPA-induced increase in ECAR. Altogether, these results indicate that LPA regulates glycolysis through redox signaling via a Gαi2-Rac-HIF1α-dependent signaling pathway. Most importantly, the Gαi2-Rac-dependent pathway identified in this study more than likely serves as a potential driver of HIF-1α-mediated metabolic changes in ovarian cancer cells and represents a potential target for therapy in these patients.
Citation Format: JI HEE HA, Rangasudhagar Radhakrishnan, Jeremy D. Ward, Muralidharan Jayaraman, Danny N. Dhanasekaran. Metabolic reprogramming in 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 31.
Abstract 3104: Stapled peptide inhibitors of the estrogen receptor/steroid receptor coactivator interaction
Authors: Moore Terry W. , Speltz Thomas E. , Fanning Sean W. , Mayne Christopher G. , Frasor Jonna , Greene Geoffrey L. , Tajkhorshid Emad 
Published: July 2016

Abstract
Despite undeniable successes, one of the major unsolved problems in estrogen receptor-positive breast cancer therapy is resistance to endocrine therapy. One-third of breast cancer patients who are given tamoxifen will develop recurrent cancer within 15 years. Importantly, the estrogen receptor is still present and active in 80-85% of these recurrent cases, but it is no longer sensitive to current therapies, so new ways of targeting the estrogen receptor are needed. Because selective estrogen receptor modulators indirectly block estrogen receptor/coactivator interactions, our hypothesis is that directly blocking the estrogen receptor/coactivator interaction will provide a more robust blockade that will antagonize forms of estrogen receptor that are active in both wild-type and some endocrine-resistant breast cancers.
As our starting point for inhibiting estrogen receptor/coactivator interactions, we have chosen to use a class of compounds that mimic α-helices: “stapled peptides.” These non-natural, synthetic peptides have a key alkene bond that resembles a staple. Typically, peptides make poor drugs because they are rapidly hydrolyzed by proteases and are poorly cell-permeable. Because of their non-natural linkage, stapled peptides are poor substrates for proteases, so they are metabolically stable. Some stapled peptides are also cell-penetrant. This effect is highly sequence-specific, but it seems to be aided when peptides have a relatively high formal positive charge. Stapled peptides have been used to inhibit a variety of important protein-protein interactions in cell culture and animal models. In this work, we have created a library of stapled peptides that inhibit the interaction of the estrogen receptor with the steroid receptor coactivator in vitro. The best peptides show nanomolar IC50 values in a time-resolved fluorescence resonance energy transfer assay. They show high helical content according to circular dichroism studies. We have solved x-ray crystal structures of these molecules bound to the estrogen receptor mutant Y537S, which demonstrate their binding mode, and these studies are in agreement with molecular dynamics simulations of these molecules bound to the estrogen receptor ligand binding domain.
Citation Format: Terry W. Moore, Thomas E. Speltz, Sean W. Fanning, Christopher G. Mayne, Jonna Frasor, Geoffrey L. Greene, Emad Tajkhorshid. Stapled peptide inhibitors of the estrogen receptor/steroid receptor coactivator interaction. [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 3104.
Abstract 3110: MASH1 expression in high grade astrocytoma may demonstrate a potential model for prognosis that may lead to a molecular target for future therapy
Authors: Tacha David E. , Tyrrell Jillian , Lobo Margaret 
Published: July 2016

Abstract
Introduction:
A large U.S. study showed that 25% of patients diagnosed with grade 3 astrocytoma survived for 5 years or more after diagnosis. Unfortunately, the outlook is even worse for patients diagnosed with GBM, as most patients live for less than a year. Achaete-scute complex homolog 1 (ASCL1, MASH1) is a proneural transcription factor that has an essential role in the formation of multiple neuronal lineages. Recent studies have shown that the upregulation of MASH1 and inhibition of the Notch signaling pathway characterize progressive astrocytoma. Proneural proteins have been shown to regulate stem-cell proliferation and differentiation. The convergence with oncogenic pathways combined with the overexpression in glioblastoma has been shown to correlate with poor clinical outcome and has identified these transcription factors as promising therapeutic targets. Recently, a MASH1 mouse monoclonal antibody has been developed. Most studies have shown MASH1 to be a specific marker of neuroendocrine carcinomas; however, only one immunohistochemical study on astrocytoma using a polyclonal antibody has been reported. This study examined MASH1 expression in grade 1-4 astrocytoma cases.
Materials and Methods:
Formalin-fixed paraffin-embedded tissue microarrays consisting of samples of normal brain and astrocytomas [grade 1 (n = 22), grade 2 (n = 34), grade 3 (n = 16) and glioblastoma (n = 35)] were evaluated by immunohistochemical analysis using a monoclonal MASH1 antibody. A value of &gt;1% staining was scored as positive.
Results:
MASH1 stained 61.7% (66/107) of astrocytomas (grades 1-4). In grade 1 astrocytoma, MASH1 was expressed in 31.8% versus 85.3% in grade 2, 68.7% in grade 3 and 54.3% in grade 4 (p ∼ 0.0028).
Conclusion:
MASH1 is highly expressed in astrocytoma. There was a variable and progressive increase of MASH1 expression in grade 1 versus grade 2-4 astrocytoma; and thus, may demonstrate a potential model for prognosis that may lead to future target therapeutic strategies.
Citation Format: David E. Tacha, Jillian Tyrrell, Margaret Lobo. MASH1 expression in high grade astrocytoma may demonstrate a potential model for prognosis that may lead to a molecular target for future 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 3110.
Abstract 3117: Pleiotrophin is a marker of poor prognosis in Middle Eastern papillary thyroid carcinoma
Authors: Beg Shaham , Ahmed Maqbool , Hussein Azhar , Bu Rong , Qadri Zeeshan , AlSobhi Saif , Dayel Fouad Al , Siraj Abdul K. , Al-Kuraya Khawla S. 
Published: July 2016

Abstract
Pleiotrophin (PTN) is a heparin binding growth factor known to have role in neuronal development. It is highly expressed in embryo but has a very limited expression in adult tissues. PTN is considered a proto-oncogene and has been hypothesized to play role in oncogenesis as its expression is found to be increased in many different cancer subtypes. Its role in cell transformation, cell growth, survival, migration and angiogenesis has also been shown in various different types of cancers. The function of PTN is hypothesized to be carried out by its interaction with cell surface proteoglycans or binding to its selective cell surface receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1). The significance of role of PTN in pathogenesis of thyroid cancer has not been explored especially with the fact that papillary thyroid carcinoma (PTC) originating in this ethnic population is the second most common female malignancy, after breast. So in search for novel druggable molecular target we sought for PTN expression in a large cohort of Saudi PTC. We analysed PTN alteration in more than 1000 primary papillary thyroid carcinoma in a tissue microarray format with clinical follow up data. We found that PTN was overexpressed in 65.5% (658/1006) of PTC and was significantly associated with aggressive clinical parameters such as tall cell variant histological subtype (p = 0.0333), extrathyroidal extension (p = 0.0292), lymphovascular invasion (p = 0.0182) and large tumour size (p = 0.0160). Important significant molecular association was seen with PTPRZ-1 (p = 0.0316), Midkine (p = 0.0008) and pSTAT-3 (p&lt;0.0001). Finally patients showing PTN overexpression have worse disease free survival compared to patients showing low or absent PTN expression (p = 0.0218). On multivariate analysis PTN is found to be an independent marker of poor prognosis taking into consideration parameters such as Age, Stage, Lymph node status and Extrathyroidal extension (p = 0.0430). This study highlights the importance of PTN as druggable molecular target which can be therapeutically exploited by its inhibitors in treatment of PTC.
Keywords: Papillary Thyroid Cancer; Pleiotrophin; Pleiotrophin Receptor
Citation Format: Shaham Beg, Maqbool Ahmed, Azhar Hussein, Rong Bu, Zeeshan Qadri, Saif AlSobhi, Fouad Al Dayel, Abdul K. Siraj, Khawla S. Al-Kuraya. Pleiotrophin is a marker of poor prognosis in Middle Eastern papillary thyroid 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 3117.