bluuebunny/crossref_metadata_2025 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

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 >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

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

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

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

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

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

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

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 < 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

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
Abstract 977: Combination treatment of pantoprazole and TRAIL reduce cell viability by activating caspase cascade and down-regulation of phosphorylated ERK in AGS cell line.
Authors: Roh Sang Young , Byun Jae Ho , Shim Byoungyong , Hong Young Seon
Published: August 2014

Background Pantoparzole(PPZ) is a proton pump inhibitor which is known to have an apoptotic activity in gastric cancer cells. Meanshile, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in cancer cells. However, some types of cancer cells, including AGS human gastric adenocarcinoma cells show resistance for the TRAIL-mediated apoptosis. This study was aimed to investigate the sensitizing effectcs of PPZ on TRAIL-mediated apoptosis in AGS cell line.

Methods Sensitivity to TRAIL and activation of TRAIL-induced apoptotic pathways were analyzed in AGS cell lines. WST-1 method was used to evaluate cell viability; Western blots was used to evaluate TRAIL-induced apoptosis.

Results TRAIL alone had little effect on apoptosis in AGS cells. However, treatment with TRAIL in combination with subtoxic concentrations of PPZ sensitized TRAIL-mediated apoptosis in AGS cells. Combined treatment of PPZ and TRAIL induced caspase(caspase-8, -9, -3) and the pro-apoptotic molecules (Bax). In addition, the down regulation of phosphorylated ERK were also found in cells treated with the combination of PPZ and TRAIL.

Conclusion The combination of TRAIL and PPZ may be considered as an approach to overcome the resistance of TRAIL in cancer treatment.

Citation Format: Sang Young Roh, Jae Ho Byun, Byoungyong Shim, Young Seon Hong. Combination treatment of pantoprazole and TRAIL reduce cell viability by activating caspase cascade and down-regulation of phosphorylated ERK in AGS cell line. [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 977. doi:10.1158/1538-7445.AM2013-977
Abstract 98: The biological significance of T3-regulated endoglin in human hepatoma cells.
Authors: Lin Yang-Hsiang , Huang Ya-Hui , Chung I-Hsiao , Lin Kwang-Huei
Published: August 2014

Hypothyroidism has been associated with significantly elevated risk for hepatocellular carcinoma (HCC), although the precise underlying mechanisms remain unknown at present. Thyroid hormone (T3) and its receptor (TR) are involved in metabolism and growth. Endoglin is a T3/TR candidate target gene identified from our previous studies. Here, we demonstrated that T3 positively regulates endoglin mRNA and protein levels, both in vitro and in vivo. The thyroid hormone response elements (TRE) of endoglin were identified at positions -2114/-2004 and -2032/-1973 of the promoter region using the electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. Endoglin was downregulated in subgroups of HCC patients, and significantly associated with histology grade (negative association, p = 0.001), and this expression level was significantly associated with TRα1 in these HCC patients. Knockdown of endoglin expression in HCC cells promoted cell proliferation in the presence of T3. Moreover, endoglin stabilized p21 expression at the translational level. Based on the collective findings, we propose that endoglin is stimulated by T3 to stabilize p21, leading to the inhibition of cell proliferation. Endoglin and TRα1 levels are reduced in HCC, resulting in increased proliferative activity.

Citation Format: Yang-Hsiang Lin, Ya-Hui Huang, I-Hsiao Chung, Kwang-Huei Lin. The biological significance of T3-regulated endoglin in human hepatoma 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 98. doi:10.1158/1538-7445.AM2013-98
Abstract 981: The role of caffeine in sensitizing lung cancer cells to cisplatin-induced apoptosis.
Authors: Wang Gan
Published: August 2014

Cisplatin is an important anticancer drug that has been used widely for treatment of many types of cancer, including lung cancer. The effectiveness of the drug, however, often diminishes quickly due to the development of tumor cell drug resistance in patients. Therefore, it is important to explore different strategies that either can sensitize tumor cells to cisplatin or can reverse the tumor cell drug resistance. We have studies the effect of caffeine in cisplatin-induced apoptosis of lung cancer cells. Using both CRL5985 lung adenocarcinoma cells and HTB182 lung squamous carcinoma cells, the results of our caspase-3 activation studies demonstrated that the caffeine prior treatment significantly increased the cisplatin-induced caspase-3 activation in these lung cancer cells. Our quantitative PCR (real time PCR) results revealed that the prior caffeine treatment caused a great increase in transcription of PUMA, a pro-apoptotic protein, in the cisplatin-treated HTB182 and CRL5985 lung cancer cells. Our western blot results further indicated that the protein level of the PUMA was significantly more increased when the lung cancer cells was treated with caffeine prior to the cisplatin treatment. In addition, our western blot results also revealed that the phosphorylation level of Chk1 at serine 317 was decreased but the phosphorylation level of ATM at serine 1981 was increased for the lung cancer cells treated with caffeine prior to the cisplatin treatment compared to that of the cells treated with only cisplatin. These results suggest that caffeine can sensitize lung cancer cells to cisplatin via inhibiting ATR but increasing ATM activation, resulting in an increase in PUMA expression and apoptosis of the treated lung cancer cells. Therefore, caffeine can sensitize lung cancer cells to cisplatin-induced apoptosis.

Citation Format: Gan Wang. The role of caffeine in sensitizing lung cancer cells to cisplatin-induced apoptosis. [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 981. doi:10.1158/1538-7445.AM2013-981
Abstract 987: XCE853: A novel anticancer candidate preferentially killing drug-resistant human tumor cells.
Authors: Gutmann Matthieu , Briand Jean-François , Prevost Gregoire Pierre , Carniato Denis , Pitty Marc-Henry
Published: August 2014

Cancer drug pan-resistance is associated with patients having a disease progression despite receiving new treatments. Often resistance arises in two steps, initially, the tumor responds to the drug, but not all tumor cells are killed leading to a selection of tumor cells that do not respond to any current drug. The nature of the residual disease is linked to different conditions such the efflux pumps, the quiescent cells, the stem cells, the DNA repair deficiency or the EMT. Here, we have identified a family of synthetic compounds displaying a preferential antiproliferative activity on drug resistant human cancer cells. The lead compound XCE853 is 5 to 94 more potent on drug resistant cancer cell lines compared to their parental tumor cell lines (HL60/HL60-Doxorubicin; MCF7/MCF7-Doxorubicin; A2780/A2780-Cisplatin and A549/AA549-Taxotere). XCE853 induced a strong and irreversible cytolysis of MCF7-Adriamycin cells after a short exposure in vitro (250nM, 6 hours). The mechanism of action of XCE853 is independent of efflux pumps and involves an early high ROS production leading to cell death by autophagy. The antitumor activity of XCE853 is also observed using in vivo xenograft models of human NSCLC. Altogether, these data support further efforts on this drug candidate to better understand its molecular mechanism of action and the description of the most sensitive tumor types.

Citation Format: Matthieu Gutmann, Jean-François Briand, Gregoire Pierre Prevost, Denis Carniato, Marc-Henry Pitty. XCE853: A novel anticancer candidate preferentially killing drug-resistant human tumor 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 987. doi:10.1158/1538-7445.AM2013-987
Abstract ADV01: National Cervical Cancer Coalition.
Authors: Appel-Prigo Michele
Published: August 2014

The National Cervical Cancer Coalition (NCCC) was founded in 1996 as a grass-roots non-profit dedicated to serving women with, or at risk for, cervical cancer and HPV disease. In 2011 the NCCC merged with the American Social Health Association (ASHA). Since the early 1900s, ASHA has been educating and raising awareness on sexual health issues.

The NCCC coordinates outreach efforts with healthcare providers, bio tech firms, cancer researchers, and hospitals. These efforts include low and no-cost screening programs, vaccination information, psychological support to women, family members, friends, and caregivers to those currently seeking treatment, survivors, and those who have lost loved ones.

Citation Format: Michele Appel-Prigo. National Cervical Cancer Coalition. [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 ADV01. doi:10.1158/1538-7445.AM2013-ADV01
Abstract ADV03: My breast cancer yellow brick road.
Authors: Axler Susan
Published: August 2014

From DCIS, stage 0 breast cancer, to invasive recurrence four years later, to Stage IV spread eight years after that, and now living with advanced breast cancer since 2000, I have traveled the winding path of researching, support groups, consultations, treatment and therapies. My road is not one solid concrete walkway. One organization cannot do it all: research innovative technologies and signaling cellular pathology; provide funding for research grants; support patients and families; meet financial needs as they arise. I started on this winding road when I questioned my route and I tiptoed gingerly at first, then raced along, often stumbling, to physicians and organizations that could make a difference and help me with my decisions.

ACS's Reach to Recovery mission "…dedicated to eliminating cancer…by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy and service" and "to assist people with breast cancer throughout the continuum of their disease experience." Linda Creed Foundation, working hand and hand with the National Breast Cancer Coalition whose mission has become curing breast cancer by 2020, lobbies full force making yellow bricks stronger, funding major innovative and costly research, for consumer-advocate input on review panels for grants from Department of Defense.

Metastic Breast Cancer Network's mission "to raise awareness of metastatic breast cancer by putting a public face on the metastatic experience (and) give those living with Stage IV disease a greater voice and visibility in the breast cancer and research communities as well as the public at large," provides education and information on treatments and coping. My road includes other organizations that lovingly mold beautiful yellow bricks. The Cancer Support Community (formerly Gilda's Club and the Wellness Community) provides educational and emotional resources. The S.J. Cancer Fund's patient assistance mission addresses financial needs such as paying utility bills, transportation and medical co-pay bills, and Living Beyond Breast Cancer does anything and everything they can to help the breast cancer patient, from phone support for first timers or recurrent "survivors," to conferences, to special events providing companionship and letting women know they are not alone.

Citation Format: Susan Axler. My breast cancer yellow brick road. [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 ADV03. doi:10.1158/1538-7445.AM2013-ADV03
Abstract ADV05: From the golf course to education, outreach, and support for prostate cancer.
Authors: Brown Egbert
Published: August 2014

Central Ohio Men Against Prostate Cancer (COMAPC) is a community-based, all volunteer, non-profit organization. Our mission is to increase prostate cancer awareness and routine screening through education, support, and advocacy across cultural and economic barriers. Our primary focus is to reduce disparities that exist in prostate cancer among minorities and the medically underserved.

Prostate cancer is the second leading cause of cancer death in African American men. An estimated 35,110 cases of prostate cancer were expected to occur among African American men in 2011, accounting for 40% of all cancers diagnosed in African American men. It was estimated that 5,300 deaths from prostate cancer would occur in African American men in 2011. In addition, African American men have the highest mortality rate for prostate cancer of any racial or ethnic group in the United States with the death rate being 1 in 22 cases compared to 1 in 38 cases for white men.

Our goal is to help Central Ohio men and their families become more informed about prostate cancer, better informed about treatment options for the disease and encourage men to seek early screening. COMAPC provides prostate cancer education, outreach and support for men, the friends and families of at-risk men and those diagnosed with prostate cancer. Our efforts help people connect with those resources so they become more aware of prostate cancer, better informed about treatment options, and support men to seek early screening for prostate cancer.

Individual COMAPC board members actively participate in national service and advocacy initiatives such as the U. S. Army Research and Materials Command Prostate Cancer Research Program. American Association of Cancer Research Survivor<->Advocate Program, US Too National Prostate Cancer Education and Support Team, National Association of African American Prostate Cancer Advocates, National Alliance of State Prostate Cancer Coalitions, American Cancer Society Cancer Action Network, We Work for Health-Ohio, and State and National Congressional Lobby Days.

Citation Format: Egbert Brown. From the golf course to education, outreach, and support for prostate 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 ADV05. doi:10.1158/1538-7445.AM2013-ADV05
Abstract ADV11: Cancer communication to minority populations/MOCHA Prostate Cancer Symposium.
Authors: Jeames Sanford E.
Published: August 2014

The development of programs targeted toward underrepresented populations and evaluation of communications strategies to assess the effectiveness of such programs to improve health outcomes is essential to diminish disparities. The purpose of this research is to evaluate the effectiveness of a community symposium and education program to highlight prostate cancer disparities among high risk populations.

MOCHA was contacted in March 2012, by Mass Department of Public Health, to present a community program to highlight prostate cancer. The prostate cancer symposium was intended to utilize an innovative community based partnership and research concept to disseminate health information in specific settings for special populations. Over 150 persons attended the MOCHA Prostate Cancer symposium, held at a regional convention and events center in Springfield, Massachusetts. 118 completed distributed surveys to assess opinions about PSA screening and impact of program format.

A utilization of community based programs that focus on minority populations can represent an effective strategy and approach to communicate with special populations- particularly men of color. Men of color still support use of PSA blood test as a screening tool for prostate cancer, and minority groups will attend symposiums if encouraged by representatives that resemble their population. Men of color will support programs with research focuses and find information beneficial to their overall health.

Citation Format: Sanford E. Jeames. Cancer communication to minority populations/MOCHA Prostate Cancer Symposium. [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 ADV11. doi:10.1158/1538-7445.AM2013-ADV11
Abstract ADV17: A journey from diagnosis to survivor to advocate.
Authors: Parks Meredith
Published: August 2014

In September 2011, at age 43, Meredith Parks was diagnosed with triple negative breast cancer. She had no medical history and was a mother of four young, school-age children. With the tireless support of her husband, Michael, and other family members, Meredith beat the disease.

In the 16 months since her diagnosis, Meredith has had six rounds of chemotherapy, five surgeries, including a bilateral mastectomy and participated in a clinical trial for 12 months. While undergoing chemotherapy, Meredith captained and organized a team of 82 Relay for Life “Team Meredith” members, who walked 18 hours in June and contributed over $12,000 to Cancer Research. In addition to participating in the AACR Scientist<->Survivor Program, Meredith is a Komen Advocate in Science. Meredith is also an active volunteer in the Johns Hopkins Breast Center in Baltimore, MD, where she provides one-on-one support in their imaging center.

Meredith has found the answer to the question, “Why am I here?” She is determined to assist those furthering the hope, drive and necessity of a cure.

Citation Format: Meredith Parks. A journey from diagnosis to survivor to advocate. [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 ADV17. doi:10.1158/1538-7445.AM2013-ADV17
Abstract ADV19: A mayo clinic cancer center spore-wide approach to advocacy.
Authors: Rieder Mark
Published: August 2014

The Mayo Clinica Inter-SPORE Advocates Group is to help all of the patient advocates at mayo become more educated and qualified.

Our mission statement is: Support and improve each disease-specific SPORE advocace group through sharing ideas, information and experiences.

The goals of the Mayo Clinic Inter-SPORE Advocates Group are:

- promote a collaborative relationship among the disease specific SPORE advocate groups in support of SPORE research, education and activities

- explore opportunities for collaboration on activities

- support a collaborative relationship across the SPOREs to further the translational research goals of each SPORE

- promote communications, education, and awareness among researchers, advcoates and patients

- participate in development of research proposals and informed consent for SPORE projects and clinical studies

The Mayo Clinic Inter-SPORE Advocates Group meets quarterly to share ideas information and experiences in its pursuit of a collaboratie relationship among the disease-specific SPORE advocate groups. Conference call-in is provided for those who cannot attend in person. The Group will continually assiss its efforts and look for opportunities to add value to the SPORE advocate groups.

Citation Format: Mark Rieder. A mayo clinic cancer center spore-wide approach to advocacy. [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 ADV19. doi:10.1158/1538-7445.AM2013-ADV19
Abstract ADV24: Clinical Trials may be the safer treatment option with Personalized Medicine.
Authors: Whelan Jack
Published: August 2014

The next generation of scientists and investigators that embrace the latest generation of Health IT, will play a pivotal role in developing solutions that deliver on the promise of Personalized Medicine. The poster presented shows Jack Whelan's six year journey and five clinical trials/treatment options for his rare, incurable blood cancer, his e-Patient observations about Clinical Trials and Personalized Medicine and recommended sources of patient advocate educational materials for these subject matters.

Citation Format: Jack Whelan. Clinical Trials may be the safer treatment option with Personalized Medicine. [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 ADV24. doi:10.1158/1538-7445.AM2013-ADV24
Abstract ADV25: Relentless in the fight against blood cancer: The Leukemia & Lymphoma Society.
Authors: Wilkerson Lauren
Published: August 2014

Founded in 1949, The Leukemia & Lymphoma Society (LLS) is the world's largest voluntary health organization desiccated to funding blood cancer research and providing education and patient services.

Our Mission: cure leukemia, lymphoma, Hodgkin's disease and myeloma and improve the quality of life for patients and their families.

What we do: Invest in blood cancer research. Provide critical information and support for patients and their families. LLS's innovative programs and services are reviewed by nationally recognized thought leaders in hematology and oncology, helping us provide the best services to our patients. Advocate for issues impacting blood cancers.

Why: An estimated 1.1 million people in the United States are living with, or are in remission from leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma or myeloma.

Who we serve: In additional to our national headquarters in White Plains, NY, we have a network of 61 chapters throughout the United States and Canada. Our constituents live in urban, suburban and rural communities, seek treatments and large comprehensive cancer centers and community clinics and represent cultures from around the world. We work in partnership with community organizations, treatments centers and government agencies to deliver quality cancer support services to patients in our region. We work in partnership with other oncology and health organizations to meet the needs of underserved people within our community.

Citation Format: Lauren Wilkerson. Relentless in the fight against blood cancer: The Leukemia & Lymphoma Society. [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 ADV25. doi:10.1158/1538-7445.AM2013-ADV25
Abstract LB-126: Replication-associated DNA double-strand breaks and checkpoint abrogation promote gene amplification.
Authors: Kondratova Anna , Marotta Michael , Watanabe Takaaki , Tanaka Hisashi
Published: August 2014

Gene amplification, a copy number increase of genomic segments through DNA rearrangements, drives cancer progression and acquired resistance to anti-cancer drugs. Understanding the cellular processes involved in gene amplification is important to rationally develop management strategies for cancer patients with such aggressive tumors. DNA double-strand breaks (DSBs) are the most dangerous lesions of DNA and often initiate gene amplification. A main cellular process giving rise to DSBs in cancer cells is DNA replication, as cancer cells are under strong replication stress. We hypothesized that failure to repair replication-associated DSBs would result in DNA rearrangements and gene amplification. To test this hypothesis, we suppressed the expression of DNA repair protein MRE11 in mammalian cells. MRE11 is a component of the MRN (Mre11-Rad50-NBS1) complex that repairs DSBs of different origin including those arising during DNA replication. Indeed, knocking down MRE11 resulted in the 10-fold increase in the frequency of gene amplification. DSBs were markedly increased in the MRE11 knockdown cells in the S phase of the cell cycle, suggesting a DNA replication-associated origin of DSBs. Importantly, DSBs continued to be abundant in the M phase, indicating that MRE11 knockdown cells lack both intra-S and G2/M checkpoints. The possibility that checkpoint abrogation could also promote gene amplification was further tested in the I-SceI endonuclease-induced gene amplification system, where checkpoint abrogation by caffeine resulted in the 4-fold increase in amplification frequency. These results provide a proof-of-concept that pharmacological modulation of cell cycle checkpoints can alternate the gene amplification frequency, and may be used to prevent proliferation of cells with gene amplification.

Citation Format: Anna Kondratova, Michael Marotta, Takaaki Watanabe, Hisashi Tanaka. Replication-associated DNA double-strand breaks and checkpoint abrogation promote gene amplification. [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 LB-126. doi:10.1158/1538-7445.AM2013-LB-126