bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4182: Bioinformatic analysis identifies polo-like kinase as a therapeutic target in small-cell lung cancer
Authors: Wildey Gary , Chen Yanwen , Lent Ian , Stetson Lindsay , Pink John , Barnholtz-Sloan Jill , Dowlati Afshin 
Published: May 2015

Abstract
Small cell lung cancer (SCLC) represents 15% of all lung carcinomas and is typically diagnosed when the disease has metastasized. Although most SCLC is initially sensitive to chemotherapy regimens, relapse is common and the survival benefit of second-line therapies, such as topotecan, is also limited. There are currently no molecular targeted approaches to treat SCLC similar to those used successfully against non-small-cell lung cancer (NSCLC). This failure is partly attributable to the empiric nature of these efforts. Thus, a more systematic approach to drug discovery for SCLC may lie in mining available databases on the drug sensitivities of SCLC cell lines. In this regard, two comprehensive studies recently published in Nature, the Cancer Cell Line Encyclopedia (CCLE) and the Cancer Genome Project (CGP), examined the drug sensitivities of cancer cell lines and attempted to link these to their genomic profiles. In the present study we have extracted data on SCLC cell lines from these two studies and mined it for new, promising therapeutic agents for SCLC. Our analyses demonstrate that the drug sensitivity of the SCLC cell lines reflects what is observed clinically for metastatic SCLC tumors. That is, most cells were extremely sensitive to topoisomerase (camptothecin) and microtubule (vinblastine and docetaxel) inhibitors, by contrast many tyrosine kinase inhibitors (erlotinib, sorafenib and imatinib) were ineffective. Importantly, we identified heat shock proteins (HSP), cyclin-dependent kinases (CDK) and polo-like kinases (PLK) as attractive molecular targets that have received little/no attention in clinical trials of SCLC. We further developed a gene signature for PLK inhibitor sensitivity and validated it in untested SCLC cell lines. This gene signature was incorporated into circos plots to yield a comprehensive view of how transcriptional, copy number and mutational elements affect PLK sensitivity in SCLC cell lines.
Citation Format: Gary Wildey, Yanwen Chen, Ian Lent, Lindsay Stetson, John Pink, Jill Barnholtz-Sloan, Afshin Dowlati. Bioinformatic analysis identifies polo-like kinase as a therapeutic target in small-cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4182. doi:10.1158/1538-7445.AM2014-4182
Abstract 419: The role of histone methyltransferase G9a in chemotherapeutic drugs-induced DNA damage
Authors: Liu Chia-Wen 
Published: May 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the serious life-threatening diseases in the world. In addition to surgery, the conventional treatments for oral cancer includes radiation and chemotherapy, which usually act by induction of DNA damage. However, approximately one-third of treated patients will experience local or regional recurrence. G9a is a histone methyltransferase responsible for mono- or di-methylation of lysine 9 in histone H3. Our recent work has demonstrated that G9a level is highly correlated with aggressiveness and poor prognosis of lung, ovarian and colon cancer patients in Taiwanese population. Here, we found that G9a expression in HNSCC is upregulated and positively correlated with poor prognosis. Moreover, knockdown of G9a resulted in decrease cell survival and cologenic capacity following treating with chemotherapeutic drug, hydroxyurea and etoposide. Futhermore, depletion of G9a caused sustained phosphorylation of γ-H2AX after etoposide treatment. Together, We suggest that G9a may contribute to HNSCC proliferation by improvement of DNA double break repair. Our study paves the way for exploring the blockade of G9a overexpression as a novel approach for the prevention and treatment of HNSCC.
Citation Format: Chia-Wen Liu. The role of histone methyltransferase G9a in chemotherapeutic drugs-induced DNA damage. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 419. doi:10.1158/1538-7445.AM2014-419
Abstract 4194: Gliomaspheres mimic the hypoxia-Notch signaling axis of glioblastoma tumors
Authors: Irshad Khushboo , Mohapatra Saroj Kant , Garg Harshit , Mishra Seema , Sarkar Chitra , Gupta Deepak , Chattopadhyay Parthaprasad , Sinha Subrata , Chosdol Kunzang 
Published: May 2015

Abstract
Background and objectives: Notch signaling plays an oncogenic role during gliomagenesis. Synergism of hypoxia with Notch pathway is known to aggravate different cancers. We studied the association between Notch signaling and hypoxia in human glioblastoma (GBM) samples which are characterized by intratumoral hypoxia. We also carried out in-vitro analysis in U87MG cell line enriched in stem cells under low oxygen conditions. The study aimed at identifying a modular gene subset that might be a characteristic of the Notch pathway response in hypoxic GBM tumors and GBM gliomaspheres; which might assist in individualized therapeutics.
Methods: Expression of Notch receptors, Dll/Jag ligands, Hes/Hey targets and hypoxia markers was analyzed in 35 GBMs by q-PCR and immunohistochemistry. Spearman's test, clustering and statistical analyses were applied to assess the correlation between hypoxia and Notch pathway upregulation. Expression analysis was also done in U87MG cells grown in stem cell culture conditions under hypoxia using q-PCR and western blot.
Results: Using various statistical analyses, we found HIF-1α to be correlated with the expression of maximum number of Notch pathway genes, followed by PGK1, OPN and VEGF. Well-segregated tumor clusters accounting for differential Notch genes' expression were produced using gene clustering and principal components analysis by ordering the GBMs in decreasing levels of HIF-1α/PGK1. By logistic regression, a five hypoxia marker combination (HIF-1α/PGK1/VEGF/CA9/OPN) was determined as the best predictor for Notch signaling augmentation in GBM. A similar Notch-axis (Notch1/Dll1/Hes1/Hes6/Hey1/Hey2) was activated in U87MG gliomaspheres under hypoxia.
Interpretation and conclusions: The hypoxia markers most associated with Notch signaling upregulation in resected GBM were identified. Similar components of the Notch pathway were also found to be activated in hypoxia-exposed gliomaspheres, supporting them as an in-vitro model for studying the perturbations of hypoxia-Notch signaling axis.
Citation Format: Khushboo Irshad, Saroj Kant Mohapatra, Harshit Garg, Seema Mishra, Chitra Sarkar, Deepak Gupta, Parthaprasad Chattopadhyay, Subrata Sinha, Kunzang Chosdol. Gliomaspheres mimic the hypoxia-Notch signaling axis of glioblastoma tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4194. doi:10.1158/1538-7445.AM2014-4194
Abstract 4208: Suppressor of Cytokine Signaling (SOCS)-3 and the C-X-C chemokines CXCL1 and CXCL2 promote tumor aggessiveness and radiation resistance in pancreatic cancer
Authors: Jiang Sisi , Mose Evangeline , Coppola Giovanni , Lowy Andrew , Jamieson Christina , Cacalano Nicholas A. 
Published: May 2015

Abstract
Despite recent advances in our understanding of pancreatic ductal adenocarcinoma (PDA), it remains a poorly understood, devastating disease that is largely resistant to all standard treatment modalities. Much effort has been made to identify novel tumor suppressor genes, biomarkers of metastatic behavior, and targets for molecular therapeutics that can improve prognosis and quality of life for PDA patients. Despite the finding that the pro-inflammatory C-X-C family chemokines CXCL1 and CXCL2 are expressed in a significant fraction of human PDA tissues and are known to promote metastasis in bladder and breast cancer, very little is known of its regulation and its role in the progression of PDA. Our laboratory has identified a mechanism by which CXCL1 expression is regulated in human PDA. CXCL1/2 expression is repressed by the Signal Transducer and Activator of Transcription (STAT)-3 and conversely, the Suppressor of Cytokine Signaling (SOCS)-3, a STAT3 inhibitor, promotes CXCL1/2 gene activation and pro-inflammatory signaling in murine embryonic fibroblasts (MEFs) and human PDA cell lines. Ectopic expression of SOCS3 in the ASPC1 PDA cell line induces CXCL1 and CXCL2 expression and drives resistance to radiation and gemcitibine treatment. Further, using an orthotopic xenograft model of human PDA in immunodeficient mice, we demonstrated the in vivo relevance of this pathway. We found that mice injected with human SOCS3-positive human PDA cells have a survival time compared and develop more aggressive disease compared to mice injected with control cells. We hypothesize that CXCL1and CXCL2 promote human PDA pathogenesis by two mechanisms: (i) autocrine activation of the CXCR2 receptor expressed on human pancreatic cancer cells and (ii) pro-inflammatory recruitment of neutrophils to the tumor microenvironment.
Citation Format: Sisi Jiang, Evangeline Mose, Giovanni Coppola, Andrew Lowy, Christina Jamieson, Nicholas A. Cacalano. Suppressor of Cytokine Signaling (SOCS)-3 and the C-X-C chemokines CXCL1 and CXCL2 promote tumor aggessiveness and radiation resistance in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4208. doi:10.1158/1538-7445.AM2014-4208
Abstract 4212: ADAM10/Kuzbanian is upregulated during neuroendocrine prostate carcinogenesis
Authors: Shannon Brian D. , Littlepage Laurie E. 
Published: May 2015

Abstract
Prostate cancer (CaP) is the second leading cause of cancer death in men. Advanced prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Currently, androgen deprivation is the first line of therapy for metastatic CaP. However, CaP often progresses to an androgen-independent bone-metastatic stage, at which point chemotherapy and radiotherapy become the primary therapeutic options. Despite recent advances in therapeutic strategies, many cancers still develop resistance to radiation and therapies, making the identification of new therapies essential to improve the lives and survival rates of patients.
We have studied neuroendocrine cancer progression in the cryptdin-2 SV40-TAg (CR2-TAg) mouse model of CaP. Since these cancers do not express androgen receptor, they are refractory to androgen therapy. Therefore, we sought new potential targets. We previously found that matrix metalloproteinases (MMPs), which are capable of degrading many extracellular matrix proteins and cell surface receptors, are upregulated during CR2-Tag tumor progression. In the present study, we examined expression of a family of a disintegrin and metalloproteinases (ADAMs) that is actively involved in these signaling pathways due to their role in releasing the extracellular domain of transmembrane proteins. ADAMs contain features of both adhesive proteins and proteinases. ADAM10 activates the epidermal growth factor receptor (EGFR) and NOTCH signaling systems controlling cell growth, invasion, and metastasis. We found that ADAM10 expression increased during tumor progression and was highly penetrant. We are quantifying the expression levels and localization patterns of ADAM10 in these samples over time. Since MMPs, like ADAMs, are capable of degrading many extracellular matrix proteins and cell surface receptors, we determined if MMPs (MMP 2, 7, and 9) contribute to ADAM10 expression or localization in aggressive hormone refractory CaP. We have stained for ADAM10 in tissue sections from the CR2-TAg mice that are each missing expression of MMPs to determine if that particular MMP contributes to ADAM10 expression or localization. Our research using ADAM10 localization as a potential biomarker and therapeutic target has potential clinical value to identify aggressive CaP earlier in patients. Our study of MMPs and their role in ADAM10 expression will offer insight into the mechanisms of advanced prostate tumor progression.
Note: This abstract was not presented at the meeting.
Citation Format: Brian D. Shannon, Laurie E. Littlepage. ADAM10/Kuzbanian is upregulated during neuroendocrine prostate carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4212. doi:10.1158/1538-7445.AM2014-4212
Abstract 4214: Antitumoral effects of orexins and their receptors OX1R in pancreatic ductal adenocarcinomas (PDAC)
Authors: Voisin Thierry , Speisky Daniela , Couvelard Anne , Couvineau Alain 
Published: May 2015

Abstract
Orexins A and B were identified as hypothalamic ligands for two serpentine G protein-coupled receptors, OX1R and OX2R. Aberrant expression of OX1R was detected in colonic cancer cells and hepatic metastasis. Orexins induce apoptosis in human colon cancer cell lines and in mice models, resulting in massive reduction of tumor cell growth. Pancreatic ductal adenocarcinomas (PDAC) are highly malignant neoplasms with poor prognosis. Chemotherapy treatment shows a poor response rate. Our previous data suggested the expression of OX1R in 98% of tested PDAC.
The aims of this study were 1) to investigate the presence of OX1R in human PDAC cell lines and to analyse orexin-A (OX-A) effects in relation to apoptosis and 2) to develop an in vivo heterotopic xenografted model from the cell lines expressing OX1R, for the study of tumor growth in response to OX-A.
The expression of OX1R was studied at mRNA (RT-PCR), proteins (immunocytochemistry) and functional levels (number of viable cells after OX-A treatment), in 3 PDAC cell lines (AsPC-1, HPAF-II and SW 1990). The development of an animal model (heterotopic xenograft) from the cell line expressing OX1R, has allowed studying the effect of OX-A in tumor growth. Resected tumors were analyzed by immunohistochemistry.
Only AsPC-1 cell line expresses OX1R. The treatment with OX-A promoted a 32% cell growth inhibition. OX-A injection in nude mice xenografted with AsPC-1 cells, has declined 49% of tumor progression in treated cases. This effect was dose-dependent and more important in weekly or twice-weekly treatments. All the tumors corresponded to poorly differentiated adenocarcinomas expressing OX1R. Induction of apoptosis was observed in OX-A treated tumors (activated caspase-3). To generalize further the role of OX1R in inhibition of cell growth and induction of apoptosis, we considered HPAF-II cells expressing the recombinant hOX1R. Orexin-A strongly inhibited HPAF-II/OX1R cell growth in vitro and tumor growth in vivo, whereas no effect of orexins could be detected in the parental HPAF-II cell line. The role of OX1R in controlling apoptosis is directly demonstrated by the expression of recombinant OX1R in HPAF-II cells that confers the ability of orexins to promote apoptosis in this cell line.
This work has demonstrated the antitumor and proapoptotic effect of orexins in PDAC, using in vitro and in vivo models. In this context, orexines receptors may establish a new therapeutic target in pancreatic antineoplastic therapies.
Citation Format: Thierry Voisin, Daniela Speisky, Anne Couvelard, Alain Couvineau. Antitumoral effects of orexins and their receptors OX1R in pancreatic ductal adenocarcinomas (PDAC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4214. doi:10.1158/1538-7445.AM2014-4214
Abstract 4221: HSP90 as a therapeutic target in colorectal cancer
Authors: Nagaraju Ganji Purnachandra , Willingham Field F. , Woods Kevin E. , Sullivan Patrick , Landry Jerome C. , Diaz Roberto , El-Rayes Bassel F. 
Published: May 2015

Abstract
Purpose/Objectives: Activation of PI3K /Akt/ NF-κB and MAPK signaling pathway contributes to colorectal cancer cell growth, survival and resistance to therapy. HSP90 is required for PI3K/Akt and MAPK stability, folding and trafficking. Ganetespib is a potent functional inhibitor of HSP90 currently under evaluation in clinical trials. We tested the hypothesis that HSP90 functional inhibition by ganetespib can inhibit PI3K/Akt/ NF-κB and MAPK signaling pathways in colorectal cell lines.
Methods: Two colorectal cancer (CRC) cell lines were used, HCT-116 and HT-29. Cells were either untreated (control) or treated with ganetespib at 50nM for 24 hours. Western blot and RT-PCR analyses were carried out to determine the effect of ganetespib on protein molecules involved in cell survival and proliferation. Electrophoretic mobility shift assay (EMSA) was performed in CRC cells to evaluate the effects of ganetespib on NF-κB activity. A subcutaneous xenograft mouse model was used to evaluate the in vivo effects of ganetespib.
Results: Treatment of HCT-116 and HT-29 CRC cell lines with ganetespib inhibited survival signaling (PI3K/Akt) and proliferative signaling (MAPK) at the transcriptional and translational level. As validation, HSP90 knockdown similarly inhibited PI3K/Akt and MAPK protein and mRNA levels in both cell lines. Functional inhibition of HSP90 resulted in inhibition of PI3K/Akt and MAPK transcription. Functional inhibition or down regulation of HSP90 was associated with inhibition of NF-κB trafficking (downregulation of NF-κB in nucleus). Ganetespib sensitized colon cancer cell lines to the effects of oxaliplatin and 5FU. Similar effects were also observed in tumors from animals treated with ganetespib. Conclusion: In this study, we present in vitro and animal data supporting the targeting of HSP90 as a method to inhibit the PI3K/Akt/ NF-κB and MAPK signaling pathways in colorectal cancer. We demonstrate that inhibition of HSP90 downregulates PI3K/Akt/ NF-κB and MAPK leading to a decrease in colon cancer cell survival and proliferation, as well as sensitization to chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in colorectal cancer.
Citation Format: Ganji Purnachandra Nagaraju, Field F. Willingham, Kevin E. Woods, Patrick Sullivan, Jerome C. Landry, Roberto Diaz, Bassel F. El-Rayes. HSP90 as a therapeutic target in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4221. doi:10.1158/1538-7445.AM2014-4221
Abstract 4226: B-thujaplicin suppressed estrogen dependent breast cancer via regulating estrogen receptor signaling
Authors: Ko Jiwon , Bao Cheng , Lee Jaehoo , Park Hyun-Chang , Lee Hong Jin 
Published: May 2015

Abstract
B-thujaplicin (Hinokitiol), a natural monoterpenoid found in the family of Chamaecyparis obtusa, has been demonstrated to exert anti-fungal, anti-bacterial, and anti-oxidant properties. However, the role of β-thujaplicin in mammary carcinogenesis has not been extensively studied. Here, we investigated the effect of β-thujaplicin on cell proliferation and underlying mechanisms in estrogen-dependent MCF-7 breast cancer cells and N-nitroso methy urea (NMU)-induced animal model. We first found that β-thujaplicin inhibited cell proliferation in a dose dependent manner, where the IC50 was 7.5 μM. The protein and mRNA expression of estrogen receptor (ER)-α was suppressed by β-thujaplicin, without affecting the level of ER-β. One of the target genes of estrogen signaling, cyclin D1 was also significantly inhibited by β-thujaplicin treatment. In animal study of NMU-induced breast cancer model, β-thujaplicin at 7.5mg/kg body weight significantly suppressed tumor growth and tumor multiplicity from 3.1 g in the control to 1.8 g in the β-thujaplicin treatment group, and from 2.9 tumor/rat to 1.7 tumor/rat, respectively. The ER-α expression and cyclin D1 in tumor tissues were also reduced by β-thujaplicin treatment. Taken together, β-thujaplicin suppressed ER-positive breast carcinogenesis through suppressing the ER-α expression and its target gene cyclin D1, and it suggests that β-thujaplicin may be a potent phytochemical in inhibiting breast cancer development.
Citation Format: Jiwon Ko, Cheng Bao, Jaehoo Lee, Hyun-Chang Park, Hong Jin Lee. B-thujaplicin suppressed estrogen dependent breast cancer via regulating estrogen receptor signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4226. doi:10.1158/1538-7445.AM2014-4226
Abstract 4235: Anti-proliferative effect of (19Z)-halichondramide from the sponge Chondrosia corticata via G2/M cell cycle arrest and suppression of mTOR signaling in human lung cancer cells
Authors: Bae Song Y. , Song Jayoung , Shin Yoonho , Kim Won Kyung , Oh Jedo , Choi Tae Joon , Jeong Eun Ju , Park So Hyun , Jang Eun Jeong , Kang Ji In , Park Hyen Joo , Hong Ji-Young , Kim Gi Dae , Jeon Ju-eun , Shin Jongheon , Lee Sang Kook 
Published: May 2015

Abstract
Five oxazole-containing macrolides isolated from the marine sponge Chondrosia corticata were evaluated for their anti-proliferative activity in a panel of human solid cancer cell lines. (19Z)-Halichondramide ((19Z)-HCA), a novel trisoxazole-containing macrolide, exhibited the highest potency among the macrolides, with IC50 values in the submicro-molar ranges. Prompted by the high potency of growth inhibition of cancer cells, we investigated the mechanism of action of the anti-proliferative activity of (19Z)-HCA in human A549 lung cancer cells. (19Z)-HCA induced cell cycle arrest in the G2/M phase, and this event was highly correlated with the expression of checkpoint proteins, including the up-regulation of p53 and GADD45α and the down-regulation of cyclin B1, cyclin A, CDC2, and CDC25C. In addition, the growth inhibition by (19Z)-HCA was associated with the suppression of mTOR and its downstream effector molecules 4EBP1 and p70S6K. The modulation of mTOR signaling by (19Z)-HCA was found to be mediated by the regulation of upstream proteins, including the down-regulation of Akt and p38 MAPK and the up-regulation of AMPK. These data suggest the potential of (19Z)-HCA to serve as a candidate for cancer chemotherapeutic agents derived from marine organisms by virtue of arresting the cell cycle in the G2/M phase and the modulation of mTOR/AMPK signaling pathways. [Acknowledgements: This work was supported by the MarineBio Research Program (NRF-2013045101) of the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MEST).]
Citation Format: Song Yi Bae, Jayoung Song, Yoonho Shin, Won Kyung Kim, Jedo Oh, Tae Joon Choi, Eun Ju Jeong, So Hyun Park, Eun Jeong Jang, Ji In Kang, Hyen Joo Park, Ji-Young Hong, Gi Dae Kim, Ju-eun Jeon, Jongheon Shin, Sang Kook Lee. Anti-proliferative effect of (19Z)-halichondramide from the sponge Chondrosia corticata via G2/M cell cycle arrest and suppression of mTOR signaling in human lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4235. doi:10.1158/1538-7445.AM2014-4235