bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 911: Tyrosine kinase inhibitor Gefitinib selectivley induces apoptosis in Zap70+ chronic lymphocytic leukemia cells and inhibits B cell receptor signaling.
Authors: Dielschneider Rebecca , Xiao Wenyan , Yoon Ju Yoon , Noh Edward , Johnston James B. , Gibson Spencer B. 
Published: August 2014

Abstract
Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the western world, is characterized by an accumulation of B cells in the peripheral blood, lymph nodes, and bone marrow leading to immunosuppression. Patients can be stratified into two distinct groups based upon the expression of a T-cell receptor kinase, ZAP70. CLL patients with ≥20% cells staining for the ZAP70 have more aggressive disease and survive shorter times compared with patients with lower ZAP70 expression. Thus, tyrosine kinase inhibitors could be attractive therapeutic agents targeting ZAP70 over expressing CLL cells. In this study, we investigated tyrosine kinase inhibitor gefitinib that has been shown to inhibit tyrosine kinase Syk (a ZAP70 family member) and is not a myelo- or immuno-suppressive drug as other chemotherapeutic agents are in treating CLL. We found using MTT viability assay that the tyrosine kinase inhibitor gefitinib is effective in primary CLL cells with a significant preference for Zap70+ CLL; gefitinib had a median IC50 of 4.5 μM in Zap70+ patient cells and &gt;15.0 μM in Zap70- patient cells. Flow cytometry analysis showed a decrease of viable Zap70+ CLL cells 24 hours post gefitinib treatment. Although gefitinib decreased the viability of the Zap70+ Jurkat T leukemia cell line, it failed to affect T cells from CLL patients. Western blot analysis showed gefitinib inhibited tyrosine phosphorylation of ZAP70 and Syk in CLL cells. In addition, both basal and B cell receptor-stimulated tyrosine phosphorylation was reduced after gefinitib treatment. Compared with other known inhibitors dasatinib and ibrutinib, gefitinib has the same downstream inhibition of Erk and Akt phosphorylation in Zap70+ cells. The significance of Zap70 expression was further determined by treating the Raji B lymphoma cell line transduced with vector control or vector encoding Zap70; indeed Zap70 expression sensitized the B cell line Raji to gefitinib treatment whereas other tyrosine kinase inhibitors were less effective. Therefore, gefitinib inhibits the Zap70 signaling pathway in CLL cells and holds potential as a targeted therapy for aggressive CLL.
Citation Format: Rebecca Dielschneider, Wenyan Xiao, Ju Yoon Yoon, Edward Noh, James B. Johnston, Spencer B. Gibson. Tyrosine kinase inhibitor Gefitinib selectivley induces apoptosis in Zap70+ chronic lymphocytic leukemia cells and inhibits B cell receptor signaling. [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 911. doi:10.1158/1538-7445.AM2013-911
Abstract 939: Double mutation of KRAS and PIK3CA affects the efficacy of NVP-BEZ235, a dual PI3K/mTOR inhibitor, in regulating the PI3K/mTOR pathway in colorectal cancer.
Authors: Kim Areumnuri , Lee Seung-Sook , Kim Cherin , Kim Eun Mi , Shin Dong-Yeop , Lee Sun-Joo , Park Sunhoo 
Published: August 2014

Abstract
Colorectal cancer (CRC) with mutational activation of KRAS is observed frequently. In addition, PIK3CA mutations commonly coexist with KRAS mutations and lead to additive activation of the PI3K/mTOR signaling pathway. Here, we investigated how CRC cells that harbor KRAS and PIK3CA mutations affect sensitivity to inhibition of PI3K/mTOR with NVP-BEZ235 (BEZ235). We selected CRC patient samples and assessed their mutational status.
CRC patients with KRAS or PIK3CA mutations show activation of Akt and mTOR, particularly when KRAS and PIK3CA mutations coexist. Suppression of PI3K/mTOR by BEZ235 results in a growth inhibitory effect and enhanced apoptosis via Bim activation in KRAS mutant cells. Mutational activation of KRAS when accompanied by a PIK3CA mutation converges at PI3K/mTOR pathway activation, resulting in resistance to BEZ235. Bim knockdown blocked the apoptotic response to BEZ235 in KRAS mutant cells, suggesting that PI3K inhibition leads to Bim accumulation. Moreover, BEZ235 treatment resulted in induction of FOXO3a activity and its induced transcription of Bim activation, which sensitized cells to cytotoxic agents leading to apoptosis in double mutant cells in vitro and in vivo. Taken together, our data suggest that targeting PI3K/mTOR sensitizes cells to apoptosis, implying that activation of PI3K/mTOR signaling via KRAS or PIK3CA mutation is an important pathway in CRC cell growth. Based on these results, coexistent KRAS and PIK3CA mutations confer resistance to BEZ235 via suppression of Bim-induced apoptosis, suggesting that combined treatment with conventional chemoagents is a potential strategy in the clinic.
Citation Format: Areumnuri Kim, Seung-Sook Lee, Cherin Kim, Eun Mi Kim, Dong-Yeop Shin, Sun-Joo Lee, Sunhoo Park. Double mutation of KRAS and PIK3CA affects the efficacy of NVP-BEZ235, a dual PI3K/mTOR inhibitor, in regulating the PI3K/mTOR pathway in colorectal 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 939. doi:10.1158/1538-7445.AM2013-939
Abstract 940: Differential sensitivity of BRAF mutant glioma cell lines to the new oncogenic BRAF kinase inhibitor UI-152.
Authors: Lee Michael , Ahn Jun-Ho , Ahn Soon Kil , Lee Yong W. 
Published: August 2014

Abstract
Glioblastomas are a highly aggressive and detrimental brain tumor, comprising 50% of all human gliomas. Glioblastomas have a median survival of less than two years after diagnosis because it has a high capacity for proliferation and is extremely chemoresistant. A common molecular event that characterizes glioblastoma is constitutive activation of the RAS-RAF-MAPK signaling pathway. Activating mutation of BRAF (BRAF-V600E) has been reported in a subset of these tumors. We recently developed UI-152 as the new oncogenic BRAF targeting drug. In biochemical assays, UI-152 inhibited BRAF-V600E at very low nanomolar concentrations and showed a 10-fold higher potency against BRAF-V600E than another well-known oncogenic BRAF inhibitor, PLX4032/4720. In the present study, we evaluated the individual IC50 values of UI-152 from the cell growth inhibitory effects of the six malignant glioma cell lines with different BRAF mutational status. KG-1-C, NMC-G1, and DBTRG-05MG cell lines are heterozygous for BRAF-V600E; A-172, T98G, and U-87MG cell lines are homozygous for wild-type (WT) BRAF. The IC50 values of UI-152 were determined using crystal violet assays. UI-152 displayed the greatest level of selectivity for BRAF-mutant cells, inhibiting their proliferation more potently than that of cells expressing BRAF-WT. The IC50 of UI-152 in B-Raf mutant cells was less than 0.2 μM, whereas the IC50 of cells expressing BRAF-WT were not reached even at 20 μM UI-152. Corresponding immunoblot results showed that UI-152 completely abolished MEK-ERK phosphorylation in DBTRG-05MG cells harboring BRAF-V600E. However, in U-87MG cells expressing BRAF-WT, UI-152 caused the paradoxical activation of the MAPK pathway. UI-152 induced the phosphorylation of MEK/ERK at 5 μM but caused a return to control levels at 10 μM in U-87MG cells. These results indicate that the genetic profile test of glioma is necessary prior to BRAF-targeted therapy to patients. Taken together, our data suggest that UI-152 may be an effective BRAF inhibitor and contribute to a potential therapeutic strategy for brain tumor patients with BRAF mutations.
Citation Format: Michael Lee, Jun-Ho Ahn, Soon Kil Ahn, Yong W. Lee. Differential sensitivity of BRAF mutant glioma cell lines to the new oncogenic BRAF kinase inhibitor UI-152. [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 940. doi:10.1158/1538-7445.AM2013-940
Abstract 945: Inhibition of T-type calcium channels sensitizes ovarian cancer cell growth and metastasis to platinum-based chemotherapy.
Authors: Casarez Eli V. , Gray Lloyd , Jazaeri Amir A. , Slack-Davis Jill K. 
Published: August 2014

Abstract
The inability to successfully treat women with ovarian cancer is due in large part to the advanced stage of disease at diagnosis and the development of platinum resistance. T-type calcium channels have recently garnered interest as potential targets for the treatment of many cancers. We investigated the hypothesis that inhibiting T-type calcium channels would sensitize ovarian cancer cells to platinum based chemotherapy using cell culture and mouse models. Sequential treatment of cultured ovarian cancer cell lines or primary cells obtained from patients with mibefradil followed by carboplatin showed a dose-dependent decrease in cell number that was greater than observed with either drug alone. Importantly, treatment of platinum-resistant tumor cells with mibefradil followed by carboplatin also decreased cell number. Moreover, either simultaneous administration of both drugs or treatment with carboplatin followed by mibefradil did not alter cellular response to carboplatin. Based on these findings, we tested the effect of mibefradil and carboplatin in a mouse model of peritoneal ovarian cancer metastasis with platinum-resistant ovarian cancer cells. Tumor-bearing mice were subjected to 3 cycles of Interlaced TherapyTM, which consists of 5 days of mibefradil treatment followed by one dose of carboplatin and 2 days off. We found that while neither drug alone significantly affected tumor growth compared to control, the mice that received the dual treatment had a dramatic reduction in tumor burden. Together, the data provide pre-clinical evidence supporting the use of T-type calcium channel blockers with platinum-based chemotherapy to treat ovarian cancer.
Citation Format: Eli V. Casarez, Lloyd Gray, Amir A. Jazaeri, Jill K. Slack-Davis. Inhibition of T-type calcium channels sensitizes ovarian cancer cell growth and metastasis to platinum-based chemotherapy. [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 945. doi:10.1158/1538-7445.AM2013-945
Abstract 953: Knockdown of kinases that regulate microtubule stability and centrosome function enhance paclitaxel sensitivity in multiple ovarian cancer cell lines.
Authors: Yang Hailing , Wang Xiaoyan , Ahmed Ahmed A. , Lu Zhen , Bast Robert C. 
Published: August 2014

Abstract
Virtually all patients with newly diagnosed ovarian cancer are treated with a combination of paclitaxel and carboplatin. While 70% of ovarian cancers respond to carboplatin, more than half do not respond to the paclitaxel. Inhibition of kinases that modulate primary resistance to paclitaxel, could enhance response to therapy. To identify kinases that regulate sensitivity to paclitaxel, high throughput screening with a kinome wide siRNA library was performed in SKOv3 ovarian cancer cells. Among 45 hits, 14 target proteins (AATK, ACRBP, BMP2K, CHUK, EDN2, IKBKB, ILK, RAPGEF3, RAPGEF4, RFP, SIK2, STK24, STK39 and TBK1) regulated sensitivity to paclitaxel and were expressed or overexpressed in a fraction of ovarian cancers. siRNAs against each of these kinases were tested for the ability to enhance sensitivity to paclitaxel in each of 12 ovarian cancer cell lines that reflected the heterogeneity observed in ovarian cancers including mutations of TP53, BRCA1/2, KRAS, BRAF, PI3K and PTEN. Knockdown of 7 individual genes reduced the IC50 of paclitaxel in more than half of the cell lines by 25 to 80 percent. Knockdown of STK39 and NFKB pathway kinases IKBKB and TBK1 enhanced microtubule stability judged by microtubule fractionation assay. Other kinases are known to affect centrosome function (SIK2, ACRBP). Our studies have identified several proteins that regulate primary sensitivity to paclitaxel in ovarian cancer cells and that could serve as targets to enhance response to primary therapy.
Citation Format: Hailing Yang, Xiaoyan Wang, Ahmed A. Ahmed, Zhen Lu, Robert C. Bast. Knockdown of kinases that regulate microtubule stability and centrosome function enhance paclitaxel sensitivity in multiple ovarian cancer cell lines. [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 953. doi:10.1158/1538-7445.AM2013-953
Abstract 955: CT45A6, cancer/testis antigen 45 family member, confer drug resistance to lung cancer cell lines.
Authors: Kim Shin-Tae , Kim Seong-Jin 
Published: August 2014

Abstract
Lung cancer is the leading cause of cancer related death in the world. Although recent advances in development of new chemotherapeutics offer a great promise to clinical outcome, drug resistance is still major concern of clinician. Cisplatin is platinum based drug that variously, combined with many other chemotherapeutics, have been widely used in the treatment of cancer. However, tumors usually become resistant to cisplatin during treatment. We performed RNA sequencing with 7 lung cancer cell lines and selected candidate genes to identify novel drug-resistance genes. RNA sequence analysis showed that one of these genes contained CT45A6. CT45A6 is a member of CT45 family. CT45 is a cancer/testis antigen family 45 that is located in Xq26.3 and expressed normally in testis and various cancers including lung cancer. However, little is known about its biological function, especially about drug resistance. Here, we show that CT45A6 confers cisplatin resistance into lung cancer cell lines. CT45A6 gene is significantly over-expressed in A549PR (cisplatin-resistant A549 lung cancer cell line) compared with wild type A549 lung cancer cell line. Interestingly, overexpression of CT45A6 in CT45A6-low NCI-H2009 and NCI-H358 lung cancer cell lines showed increased resistance to cisplatin and G2 phase population. Inversely, knockdown of CT45A6 in A549PR cells significantly decreased cisplatin-resistance. Thus, our findings indicate that CT45A6 may be a potential target to overcome drug resistance.
Citation Format: Shin-Tae Kim, Seong-Jin Kim. CT45A6, cancer/testis antigen 45 family member, confer drug resistance to lung cancer cell lines. [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 955. doi:10.1158/1538-7445.AM2013-955
Abstract 96: Estrogen modulates cellular and molecular markers of hypoxic tumor microenvironment in thyroid cancer.
Authors: Rajoria Shilpi , Hanly Elyse , George Andrea , Suriano Robert , Geliebter Jan , Saman Masoud , Schantz Stimson , Tiwari Raj K. 
Published: August 2014

Abstract
Thyroid proliferative diseases are three to four times more prevalent in women than in men. Our laboratory has systemically elucidated the role of estrogen in thyroid cancer as a promoter of increased aggressiveness, however the role of estrogen within the hypoxic environment of thyroid cancer is not known. Based on our observation that estrogen promotes neo-vascularization of thyroid tumors by modulating angiogenic factors, vascular endothelial growth factors (VEGF) and matrix metalloproteinases (MMPs), we hypothesize that tumor hypoxia synergizes with estrogen to produce an inflammatory microenvironment that helps the progression of thyroid cancer. We observed that thyroid cancer cells are responsive to hypoxic conditions and estrogen induces hypoxia inducible factor-1α (HIF-1α) nuclear translocation in these cells. Furthermore, estrogen and hypoxia modulate the HIF-1 signaling in thyroid cancer cells which is abrogated by the anti-estrogen fulvestrant and the HIF-1 inhibitor YC-1 (3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole). Conditioned medium from estrogen treated thyroid cancer cells lead to enhanced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs), due to secretion of hypoxia and estrogen responsive proteins by thyroid cancer cells leading to increased angiogenesis of endothelial cells. This phenomenon was abrogated by HIF-1 inhibitor. These results demonstrate for the first time that estrogen signaling pathways mimic the signaling pathways in the hypoxic environment in thyroid cancer cells, thus suggesting that estrogen potentially mimics oxygen deprivation at the molecular level to produce an inflammatory tumor microenvironment thus fostering the progression of thyroid cancer. We conclude that apart from the direct activity of estrogen on thyroid cancer phenotype, estrogen also modulates the tumor microenvironment specifically maintaining hypoxic conditions which may be essential for thyroid cancer progression and/or metastases.
Citation Format: Shilpi Rajoria, Elyse Hanly, Andrea George, Robert Suriano, Jan Geliebter, Masoud Saman, Stimson Schantz, Raj K. Tiwari. Estrogen modulates cellular and molecular markers of hypoxic tumor microenvironment in thyroid 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 96. doi:10.1158/1538-7445.AM2013-96
Abstract 970: Acquired sorafenib resistance is associated with enhanced invasive capability in A549 cells.
Authors: Zhou Qingyu S. , Allen-Gipson Diane 
Published: August 2014

Abstract
Acquired tumor resistance to molecular targeted anti-cancer therapeutics poses a significant challenge in cancer therapy. Extensive studies have revealed diverse mechanisms that give rise to resistant phenotypes. The present study aims to identify phenotypic characteristics associated with acquired tumor resistance to sorafenib, a multi-targeted tyrosine kinase inhibitor, using both in vitro and in vivo sorafenib-resistant human lung cancer models. We established our in vitro sorafenib-resistant model using A549 human lung adenocarcinoma cells, which were continuously exposed to increasing concentrations of sorafenib (from 4 μM to 9 μM) over 10 months. Sorafenib-resistant A549 (A549R) cells gained the spindle-shaped morphology and exhibited an approximately 2-fold increase in the IC50 as compared with parental A549 cells [mean IC50 of 9.0 μM vs. 4.4 μM, p &lt; 0.01 (N=6)]. Both Western blotting and immunocytochemical analysis revealed the loss of E-cadherin expression in A549R cells. Measurements of transendothelial electrical resistance (TEER; ohms) were conducted using Electric Cell Impendence Sensing (ECIS) in human umbilical vascular endothelial cell (HUVEC) monolayer co-cultured with A549 parental or A549R cells. A549R cells reduced HUVEC resistance and exhibited greater ability to invade HUVEC monolayer as compared with A549 parental cells. Our in vivo sorafenib-resistant tumor model was established by exposing A549 xenografts to once daily treatment with 40 mg/kg of sorafenib for 3 months. Complete tumor regression was observed in 5 out of 8 sorafenib-treated mice bearing A549 xenografts, while invasive tumor growth was seen in the other 3 animals. The resultant in vivo sorafenib-resistant A549 xenografts further provide evidence that the development of sorafenib resistance in A549 cells are associated with enhanced invasive and disseminative capabilities. The ongoing effort is focused on the characterization of in vivo sorafenib-resistant A549 xenografts in order to identify the important drivers of invasion and motility of human lung cancer cells with acquired resistance to sorafenib.
Citation Format: Qingyu S. Zhou, Diane Allen-Gipson. Acquired sorafenib resistance is associated with enhanced invasive capability in A549 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 970. doi:10.1158/1538-7445.AM2013-970
Abstract 976: CUDC-101, a hybrid molecular targeted agent, reverses multiple mechanisms of drug resistance.
Authors: To Kenneth K.W. , Poon Daniel C. , Chen XG , Lin Ge , Fu Li-wu 
Published: August 2014

Abstract
CUDC-101, a hybrid molecular targeted agent, reverses multiple mechanisms of drug resistance
CUDC-101 is a potent molecular targeted anticancer agent, rationally designed to simultaneously inhibit HDAC, EGFR and HER2. It exhibits potent antiproliferative and proapoptotic activities in both in vitro and in vivo assays and it is currently in Phase 1b clinical trial.
Multidrug resistance (MDR) is a major unresolved obstacle to successful cancer chemotherapy. It is often associated with increased ABC transporters-mediated efflux of substrate anticancer drugs out of the cell. Platinum (Pt)-based anticancer drugs, exemplified by cisplatin and oxaliplatin, are the mainstay of treatment for most solid cancers. However, resistance to Pt anticancer drugs develops rapidly upon their administration, which can be caused by overexpression of MDR transporters and activated DNA repair mechanisms.
We investigated the potentiation effect of CUDC-101 on the anticancer activity of conventional cytotoxic drugs in MDR cells with overexpression of various ABC transporters and in Pt-resistant cancer cells. CUDC-101 was found to increase the cytotoxicity and accumulation of substrate anticancer drugs in MPR-1 (doxorubicin) and MRP-2 (methotrexate) overexpressing cells, while no effect was observed in the parental sensitive cells. Mechanistically, CUDC-101 was found to inhibit MRP-1 and MRP-2 efflux function, probably by acting as an uncompetitive inhibitor and interfering with their ATPase activity. In Pt-resistant cancer cells, CUDC-101 appears to circumvent the resistance through inhibition of both MRP-2 and other DNA repair-mediated mechanisms. The combinations of CUDC-101 with cisplatin or oxaliplatin were found to display synergistic cytotoxic effect in cisplatin- or oxaliplatin-resistant cancer cell lines, respectively. Upon the concomitant administration of CUDC-101, cellular accumulation of Pt drugs and formation of DNA-Pt adducts were found to be increased whereas expression levels of DNA repair genes (e.g. ERCC1) was inhibited in Pt-resistant cells. The data advocates further development of CUDC-101 as a novel MDR reversal agent for use in combination cancer chemotherapeutic regimens.
Citation Format: Kenneth K.W. To, Daniel C. Poon, XG Chen, Ge Lin, Li-wu Fu. CUDC-101, a hybrid molecular targeted agent, reverses multiple mechanisms of drug resistance. [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 976. doi:10.1158/1538-7445.AM2013-976