bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4397: Regulation of tamoxifen sensitivity by a PAK1-EBP1 signaling pathway in breast cancer.
Authors: Awasthi* Smita , Ghosh* Arundhati , Peterson Jeffrey R. , Hamburger Anne W. 
Published: August 2014

Abstract
EBP1, an ErbB3 binding protein isolated in our laboratory, sensitizes breast cancer cells to tamoxifen in part by decreasing ErbB2 protein levels. The p21 regulated serine/threonine kinase PAK1, implicated in tamoxifen resistance, phosphorylates EBP1 in vitro and in vivo at T261. Phosphorylation of EBP1 at this site induces tamoxifen resistance. We thus postulated that inhibition of PAK1 activity, by restoring EBP1 function, could ameliorate the hormone refractory phenotype of ErbB2 overexpressing breast cancer cells. Transient transfection studies indicated that an EBP1 T261E mutant, which mimics EPB1 phosphorylated by PAK1, increased ErbB2 protein levels. An EBP1 T261A mutant, unable to be phosphorylated by PAK1, ameliorated PAK1-induced tamoxifen resistance, suggesting that phosphorylation of EBP1 by PAK1 contributes to tamoxifen resistance. We then tested if pharmacological inhibition of PAK1 activity might render hormone resistant cells, which endogenously overexpress PAK1 and ErbB2, tamoxifen sensitive. Transfection of EBP1 sensitized cells to tamoxifen. The T261A EBP1 mutant more potently sensitized cells to tamoxifen than wild type EBP1. IPA-3, a specific small MW PAK1 inhibitor, sensitized cells to tamoxifen only when EBP1 was ectopically expressed. However, IPA-3 did not further affect sensitivity of T261A overexperssing cells, suggesting that the phosphorylation of EBP1 by PAK1 played a role in the EBP1-induced hormone sensitivity. IPA had no effect on tamoxifen resistance in T47D cells in which EBP1 protein had been ablated by shRNA. The IPA-induced increase in tamoxifen sensitivity was accompanied by a decrease in ErbB2 levels in EBP1 overexpressing, but not vector control cells. These studies suggest that phosphorylation of EBP1 may be a novel additional mechanism of PAK1-induced hormone resistance. In addition, strategies that increase the pool of functional EBP1 and decrease PAK1 activity may affect hormone resistant cell growth. Our results also suggest that PAK1 directed therapies may be more effective in patients that express high levels of EBP1.
*contributed equally to this work
Citation Format: Smita Awasthi*, Arundhati Ghosh*, Jeffrey R. Peterson, Anne W. Hamburger. Regulation of tamoxifen sensitivity by a PAK1-EBP1 signaling pathway in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4397. doi:10.1158/1538-7445.AM2013-4397
Abstract 4406: CARD11 is critical for in vitro and in vivo growth of ABC-DLBCL cells.
Authors: Murtie Joshua C. , Zhu Julia , Wang Hongyun , Ospina Beatriz , Cindhuchao May , Hoffman Dietmar , Greco Rita , Dorsch Marion , Adrian Francisco 
Published: August 2014

Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma and can be divided into three distinct subtypes. The activated B cell-like (ABC) subtype is the most aggressive and is characterized by constitutive activation of the NF-κB pathway. CARD11 is a scaffolding protein and plays a critical role in the NF-κB pathway by coordinating IκB kinase activity and downstream pathway activation. Previous studies have revealed that ABC-DLBCL cell lines are dependent on the NF-κB pathway (Davis et al., 2001). Furthermore, activating mutations in CARD11 occur in approximately 10% of ABC-DLBCL patient tumors and result in constitutive activation of the NF-κB pathway (Lenz et al., 2008).
Using a combination of genetic and pharmacological tools we have further demonstrated that CARD11 is a critical node of the NF-κB pathway essential for B cell lymphoma growth in vitro and in vivo. Using a variety of pharmacological inhibitors, we demonstrate that anti-proliferative activity of each compound corresponds with its ability to inhibit the NF-κB pathway in an ABC-DLBCL cell line, TMD-8, engineered to express luciferase under the control of an NF-κB responsive promoter. Next, using doxycycline-inducible shRNAs targeting CARD11, we confirm the dependency of TMD-8 cells on CARD11 in vitro. The effects of CARD11 knockdown can be rescued by reactivation of the NF-κB pathway downstream of CARD11 by addition of TNF-α to a TMD-8 line engineered to express the TNF receptor. After validation of CARD11 dependency in vitro, we generated tumor xenografts using TMD-8 cells transduced with doxycycline-inducible shRNAs against CARD11. Upon treatment with doxycycline, TMD-8 tumor xenografts showed stasis or regression as a result of CARD11 knockdown. This inhibition of tumor growth also corresponded with significant down-regulation of the NF-kB responsive genes IL-6 and IL-10.
Together these data demonstrate that ABC-DLBCL cells and tumors require CARD11 for growth in an NF-kB dependent manner.
Citation Format: Joshua C. Murtie, Julia Zhu, Hongyun Wang, Beatriz Ospina, May Cindhuchao, Dietmar Hoffman, Rita Greco, Marion Dorsch, Francisco Adrian. CARD11 is critical for in vitro and in vivo growth of ABC-DLBCL cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4406. doi:10.1158/1538-7445.AM2013-4406
Abstract 4418: Overexpression of PGC-1α in rat cardiomyocytes protects against nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity.
Authors: Shim Eunwoo , Liu Daniel , Gibbons Alexander , Poirier Miriam C. , Liu Yongmin 
Published: August 2014

Abstract
The NRTIs Zidovudine (AZT) and Didanosine (ddI) are components of the antiretroviral combination therapies in widespread use for treatment of HIV-1 infection. However, AZT, a carcinogen in mice, is a DNA replication chain terminator that damages heart, skeletal muscle, brain and liver during long-term clinical use. In addition, both drugs are known to cause treatment-limiting mitochondrial compromise. In order to elucidate the mechanisms resulting in cardiac mitochondrial toxicity in patients using these drugs, we have evaluated rat cardiomyocyte H9c2 cells exposed for &gt;30 passages (P) to 50 μM AZT or 50 μM AZT/50 μM ddI, doses allowing for ≥80% survival. Mitochondrial integrity, evaluated as Oxygen Consumption Rate (OCR, by Seahorse Analyzer) was reduced by ≥50% (p&lt;0.05) in NRTI-exposed cells at most P compared to unexposed controls. Progressive abnormal mitochondrial morphology was observed, with time of exposure, by electron microscopy (EM). In addition, in AZT/ddI-exposed cells there were reductions (about 50%) in protein levels of PGC-1α, a master regulator of mitochondrial function and biogenesis, and its downstream effector NRF-1, compared to unexposed cells. Hypothesizing that up-regulation of PGC-1α might protect cells from AZT/ddI-induced mitochondrial damage, H9c2 cells were infected with lentivirus carrying PGC-1α, and shown by Western blot to overexpress PGC-1α. When both the H9c2 cells and the H9c2/ PGC-1α cells were exposed to 50 μM AZT/50 μM ddI, significantly-increased (20-50%) OCR levels were observed at P 2, 6, 8, 12 and 15 in the H9c2/ PGC-1α cells, compared to the H9c2 cells (p&lt;0.05 for all P). In addition, Western blot showed about 50% higher levels of NRF-1 in AZT/ddI-exposed H9c2/ PGC-1α cells, compared to AZT/ddI-exposed H9c2 cells. These studies support our hypothesis that PGC-1α overexpression protects cardiomyocytes from NRTI-induced mitochondrial compromise, and suggest that the AZT/ddI-induced reduction in protein levels of PGC-1α is a major mechanism contributing to AZT/ddI induced toxicity. We plan to search for natural products that offer similar protection and evaluate their effect on genotoxicity and mitochondrial toxicity of the antiretroviral NRTIs.
Citation Format: Eunwoo Shim, Daniel Liu, Alexander Gibbons, Miriam C. Poirier, Yongmin Liu. Overexpression of PGC-1α in rat cardiomyocytes protects against nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4418. doi:10.1158/1538-7445.AM2013-4418
Abstract 442: CD10 positive head and neck squamous cell carcinoma have chemoresistant and radioresistant properties.
Authors: Fukusumi Takahito 
Published: August 2014

Abstract
Background: Despite recent advances in the understanding of head and neck squamous cell carcinoma (HNSCC) and the development of novel therapeutic targets, five-year survival rates for HNSCC have not improved in more than three decades. Prognosis for recurrent or metastatic HNSCC remains poor. Thus, it is important for improvement of HNSCC therapy, to research therapeutic resistant mechanism. We found CD10 positive HNSCC cells have chemoresistant and radioresistant properties.
Materials and Methods: In order to investigate HNSCC chemoresistant and radioresistant properties, we used Lyoplate (company:BD).This reagent contains 242 purified monoclonal antibodies to cell surface markers and can be used for screening cells with flow cytometry. First, in three HNSCC cell lines, we compared cell surface antigen expression patterns to normal cultured cells, temporarily cisplatin exprosured cells and irradiated cells.
Result: We found four cell surface markers that upragulated in cisplatin exprosured cells and irradiated cells. These are CD10, CD15s, CD146, CD282. Next, we compered these expression pattern to normal cultured cells and cisplatinresistant cells. CD10 and CD282 was upregulated. Focused on CD10, we performed cisplatin MTT assay. CD10 positive cells had more resistant property than CD10 negative cells.
Conclusion: CD10 is a cell surface zinc-dependent metalloendopeptidase, which is expressed in a wide variety of normal cells. CD10 is also expressed by several solid tumors such as melanoma and several carcinomas originating from kidney, lung, skin, pancreas, prostate, liver, breast, stomach, cervix, and bladder. Several studies have shown that CD10 might be a good marker for differentiating between primary tumors and derived metastases, and therefore for evaluating tumor progression. In HNSCC, only one report demonstrated role of CD10 in the differentiation and growth of neoplastic cells and concluded that CD10 expression can have an important role in the tumor invasion, metastases. Our date is first report that CD10 positive HNSCC have chemoresisitant and radioresistant properties. This result may correlate with CD10 positive HNSCC has invasive and metastatic character.
Learning Objective: We identified CD10 positive HNSCC have chemoresisitant and radioresistant properties.
Citation Format: Takahito Fukusumi. CD10 positive head and neck squamous cell carcinoma have chemoresistant and radioresistant properties. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 442. doi:10.1158/1538-7445.AM2013-442
Abstract 4438: Gold nanoparticle imaging and radiotherapy of brain tumors in mice.
Authors: Hainfeld James F. , O'Connor Michael J. , Slatkin Daniel N. , Dilmanian F Avraham , Smilowitz Henry M. 
Published: August 2014

Abstract
Aims: To test intravenously injected gold nanoparticles for X-ray imaging and radiotherapy enhancement of large, imminently lethal intracerebral malignant gliomas. Materials & Methods: ∼11nm gold nanoparticles were injected intravenously and brains imaged by microCT. Fifteen hours after an iv dose of 4 g Au/kg, brains were irradiated with 30 Gy 100kVp X-rays. Results: Gold uptake gave a 19:1 tumor-to-normal brain ratio with 1.5% w/w gold in tumor, calculated to increase local radiation dose by ∼300%. Mice receiving gold and radiation (30 Gy) showed 50% long-term (&gt; 1 year) tumor-free survival, whereas all mice receiving radiation only died. In a second experiment using 35 Gy, long-term survival was 56% with AuNPs plus radiation versus 18% with radiation alone. Combining both experiments, the radiation plus AuNP treatments were statistically distinct from the radiation-only groups (p = 0.014). Conclusions: Intravenously injected gold nanoparticles cross the blood-tumor barrier but are largely blocked by the normal blood brain barrier, enabling high-resolution CT tumor imaging. Gold radiation enhancement significantly improved long-term survival compared to radiotherapy alone. This approach holds promise to improve therapy of human brain tumors and other cancers.
Citation Format: James F. Hainfeld, Michael J. O'Connor, Daniel N. Slatkin, F Avraham Dilmanian, Henry M. Smilowitz. Gold nanoparticle imaging and radiotherapy of brain tumors in mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4438. doi:10.1158/1538-7445.AM2013-4438
Abstract 4440: Identification and characterization of small molecule inhibitors that radiosensitize K-RAS mutant rectal cancers.
Authors: Kleiman Laura B. , Krebs Angela , Kim Stephen , Hong Theodore S. , Haigis Kevin M. 
Published: August 2014

Abstract
Around 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with resistance to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) (“radiosensitizers”) that could be incorporated into current treatment strategies for K-RAS mutant locally advanced rectal cancer (LARC) patients. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762 but not by BEZ235. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.
Citation Format: Laura B. Kleiman, Angela Krebs, Stephen Kim, Theodore S. Hong, Kevin M. Haigis. Identification and characterization of small molecule inhibitors that radiosensitize K-RAS mutant rectal cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4440. doi:10.1158/1538-7445.AM2013-4440
Abstract 4445: Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK translocated lung cancer.
Authors: Yamaguchi Norihiro , Nakayama Sohei , de Figueiredo-Pontes Lorena L. , Kobayashi Susumu , Costa Daniel B. 
Published: August 2014

Abstract
ABSTRACT
Introduction: The multitargeted tyrosine kinase inhibitor (TKI) crizotinib is active against ALK translocated non-small-cell lung cancer (NSCLC); however acquired resistance invariably develops over time. ALK mutations have previously been implicated in only a third of resistant tumors. We sought to evaluate alternative mechanisms of resistance and preclinical strategies to overcome these in a cell line driven by EML4-ALK.
Methods: We selected the NSCLC cell line NCI-H3122 (H3122: EML4-ALK E13;A20) and derived resistant variants that were able to grow in the presence of 1μM crizotinib. These were analyzed for ALK mutations, sensitivity to crizotinib in combination to other TKIs (imatinib, sorafenib, erlotinib and afatinib), and for activation of alternative tyrosine kinases.
Results: All H3122 crizotinib resistant (CR) clones lacked mutations in the kinase domain of ALK. To evaluate if possible alternative kinases functioned as “bypass” tracks for downstream signaling activation in these resistance cells, we used a functional approach of dual ALK TKI (with crizotinib) with combinatory TKI inhibition to screen for possible targets. Crizotinib + sorafenib (BRAF, RET, PDGFR, VEGFR TKI) and crizotinib + imatinib (ABL, PDGFR, KIT TKI) were ineffective. In contrast, crizotinib + erlotinib (reversible EGFR TKI) and crizotinib + afatinib (irreversible EGFR/ERBB2 TKI) were able to inhibit the growth of H3122 CR clones, indicating potential EGFR activation as a mechanism of resistance. Analyses of phosho-receptor tyrosine kinase arrays demonstrated that CR clones had 5-25 times higher phospho-EGFR signal than H3122 parental cells did after the exposure to 1μM crizotinib, indicating phospho-EGFR was the most predominant phosphorylated signal in crizotinib-resistant cells.
Conclusions: Using a functional approach of combining ALK and EGFR TKIs, we identified activation of EGFR as a mechanism of resistance to crizotinib in preclinical models of ALK translocated NSCLC. If EGFR activation is confirmed as a predominant mechanism of crizotinib resistance in patient-derived tumors, the use of crizotinib + EGFR TKIs should be tested in future clinical trials for this important cohort of NSCL
Citation Format: Norihiro Yamaguchi, Sohei Nakayama, Lorena L. de Figueiredo-Pontes, Susumu Kobayashi, Daniel B. Costa. Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK translocated lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4445. doi:10.1158/1538-7445.AM2013-4445
Abstract 4456: Biochemical and structural characteristics of crizotinib-resistant ALK mutants.
Authors: Timofeevski Sergei , Liu Wei , Deng Ya-Li , Brooun Alexei , Bergqvist Simon , Karlicek Shannon , Murray Brion , Bolaños Ben , McTigue Michele 
Published: August 2014

Abstract
Anaplastic lymphoma kinase (ALK), when aberrantly regulated through gene translocations or mutations, has been implicated as an oncogenic driver in a variety of cancers. XALKORI (crizotinib) is an FDA-approved therapy for locally advanced or metastatic (ALK)-positive non-small cell lung cancer (NSCLC). Mutations of certain residues within the ALK kinase domain have been associated with crizotinib resistance. To understand the molecular basis of mutational resistance, we have kinetically and structurally characterized several clinical mutations of ALK kinase domain. In the basal-state (nonphosphorylated) proteins, mutations C1156Y, F1174L, L1152R and L1196M resulted in 14 to 52-fold increase in catalytic efficiency of phosphorylation of an activation loop peptide. Accordingly, these mutants were more rapidly autophosphorylated, compared to wild-type enzyme. In addition, F1174L, C1156Y and L1156Y had 2 to 6-fold higher catalytic efficiencies when fully activated by autophosphorylation. Conversely, catalytic efficiencies of nonphosphorylated and phosphorylated G1269A variant decreased by 1.2 and 1.6-fold, respectively. Inhibition of L1152R, L1196M and G1269A by crizotinib was reduced by 3-28-fold, compared to wild-type enzyme, from Ki determinations. From direct binding studies of the L1196M “gatekeeper” mutation, the loss of crizotinib binding occurred 6 and 13-fold for phosphorylated and nonphosphorylated proteins, respectively. By crystallographic studies apoenzyme and crizotinib complexes of ALK kinase domain displayed an inactive kinase conformation that is stabilized by an extended hydrophobic network of residues. F1174 and L1196 are part of this hydrophobic core, and mutations of these residues are predicted to destabilize the inactive ALK conformation. Taken together, these results suggest that most of the resistant mutations (e.g. L1196M, F1174L, C1156Y, L1152R) result in a more dynamic protein that increases substrate turnover. In addition, the reduction of crizotinib binding for the mutations in the vicinity of the inhibitor binding site (L1196M, G1269A) is likely a contributing factor for the resistance. This structural and kinetic analysis of mutational resistance may be useful for design of new inhibitors targeting multiple clinical mutations of ALK.
Citation Format: Sergei Timofeevski, Wei Liu, Ya-Li Deng, Alexei Brooun, Simon Bergqvist, Shannon Karlicek, Brion Murray, Ben Bolaños, Michele McTigue. Biochemical and structural characteristics of crizotinib-resistant ALK mutants. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4456. doi:10.1158/1538-7445.AM2013-4456
Abstract 4468: Cripto-1 elicits innate resistance to EGFR inhibitors in non-small cell lung cancer harboring EGFR-sensitizing mutations.
Authors: Park Kang-Seo , Giuseppe Giaccone , Wang Yisong , Pham Trung , Moon Yongwha , Luo Ji , Lee Liam Changwoo , Mitsudomi Tetsuya , Okamoto Isamu , Yatabe Yasushi , Mok Tony , Raffeld Mark , Xi Liqiang , Salomon David S. , Bianco Caterina 
Published: August 2014

Abstract
Non-small cell lung cancer (NSCLC) carrying sensitizing epidermal growth factor receptor (EGFR) mutations can initially benefit from erlotinib (EGFR inhibitor) treatment. However, patients invariably develop resistance through secondary EGFR mutations, c-MET amplification, epithelial-mesenchymal transition (EMT), small cell lung cancer transformation, PIK3CA mutation and other unknown mechanisms. Here we examined whether Cripto1, which has been shown to induce EMT, could cause erlotinib resistance. We show that innate erlotinib-resistant lung adenocarcinomas carrying sensitizing EGFR mutations exhibit higher level of Cripto1 expression than their erlotinib sensitive counterparts. Ectopic expression of Cripto1 rendered erlotinib-sensitive lung adenocarcinoma cells resistant to erlotinib both in vitro and in a xenograft model. Moreover, Cripto1 activated Zeb1/EMT signaling pathway in EGFR-TKI resistant cells. High Cripto1 expression correlated with poor prognosis of NSCLC patients. Our study provides a novel Cripto1-dependent mechanism of EGFR-TKI resistance that may pave the way for the development of therapies to overcome EGFR-TKI resistance in lung cancer patients.
Citation Format: Kang-Seo Park, Giaccone Giuseppe, Yisong Wang, Trung Pham, Yongwha Moon, Ji Luo, Liam Changwoo Lee, Tetsuya Mitsudomi, Isamu Okamoto, Yasushi Yatabe, Tony Mok, Mark Raffeld, Liqiang Xi, David S. Salomon, Caterina Bianco. Cripto-1 elicits innate resistance to EGFR inhibitors in non-small cell lung cancer harboring EGFR-sensitizing mutations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4468. doi:10.1158/1538-7445.AM2013-4468