bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4355: Inhibition of RNA Polymerase I as a strategy to treat cancer.
Authors: Bywater Megan J. , Hannan Katherine M. , Poortinga Gretchen , Devlin Jennifer R. , Cullinane Carleen , Drygin Denis , Rice William G. , Von Hoff Daniel , Johnstone Ricky W. , McArthur Grant A. , Hannan Ross D. , Pearson Richard B. 
Published: August 2014

Abstract
Abnormalities of the nucleolus, the site of transcription of the ribosomal genes (rDNA) by RNA Polymerase I (Pol I), have been recognized as diagnostic for cancer for more then a century. However, a critical, unresolved question has been whether the accelerated ribosome biogenesis responsible for the nucleolar changes is required for malignancy.
Here we show that the PI3K/AKT pathway, deregulated in a high proportion of human tumours, is a critical regulator of ribosome biogenesis. Active AKT is sufficient to drive rRNA synthesis and ribosome biogenesis. Furthermore, AKT cooperates with c-MYC to drive these processes identifying the AKT//MYC network as a master controller of cell growth. Consistent with this concept, AKT activity is required for maximal activation of rRNA synthesis and tumour formation in the Eμ-Myc mouse model of Burkitt's lymphoma (1). Our findings raise the possibility that cancers characterized by unrestrained cellular growth may be vulnerable to therapeutic strategies that target ribosome biogenesis.
To directly test this hypothesis, we used a novel selective small molecule inhibitor of Pol I transcription (CX-5461) (2), to show that Pol I can be targeted in vivo to treat tumors in mouse models of lymphoma and leukemia through the activation of p53-dependent apoptosis, while sparing normal hematologic cells. Thus, selective inhibition of Pol I transcription can serve as a novel therapeutic strategy for the treatment of cancer (3). A Phase 1 trial of this first-in-class molecule begins in 2013 at the Peter MacCallum Cancer Centre for patients with haematologic malignancies. Strikingly, allosteric inhibitors of AKT suppress rRNA synthesis independent of p53 and cooperate with CX-5461 in killing Eμ-Myc lymphomas providing a clear rationale for combining these agents in future trials.
Citation Format: Megan J. Bywater, Katherine M. Hannan, Gretchen Poortinga, Jennifer R. Devlin, Carleen Cullinane, Denis Drygin, William G. Rice, Daniel Von Hoff, Ricky W. Johnstone, Grant A. McArthur, Ross D. Hannan, Richard B. Pearson. Inhibition of RNA Polymerase I as a strategy to treat 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 4355. doi:10.1158/1538-7445.AM2013-4355
Abstract 4360: Involvement of intermediate filament nestin in cell growth of small-cell lung cancer.
Authors: Kunii Eiji , Takakuwa Osamu , Maeno Ken , Oguri Tetsuya , Yokoyama Midori , Hijikata Hisatoshi , Uemura Takehiro , Kasai Daishi , Ohkubo Hirotsugu , Miyazaki Mikinori , Niimi Akio 
Published: August 2014

Abstract
Small-cell lung cancer (SCLC) represents 13% of all newly diagnosed cases of lung cancer. Clinical progression of SCLC is rapid and aggressive. Unfortunately, 70% of SCLC cases have already metastasized at the time of diagnosis, and the recent median survival time and two-year survival rate in SCLC patients with extensive-stage disease is only 8-13 months and 5%, respectively. Clinical trials of SCLC treatments have been conducted since the mid-1980s, but have not achieved prolonged survival; this lack of success is likely due to a lack of appropriate target molecules. To improve outcomes for SCLC patients, new therapeutic strategies including novel molecular targets for SCLC are desired. Nestin is a class VI intermediate filament protein expressed in stem/progenitor cells during the development of the central nervous system. Nestin is detected in various types of tumors and reported to be involved in malignant phenotypes. Here, we investigated the expression and function of nestin in SCLC. At the beginning, protein expression of nestin and achaete-scute homolog 1 (ASH1) was studied in 21 lung cancer cell lines. Nestin was expressed in 9 of 10 SCLC cell lines. The nestin expression level in SCLC cell lines was significantly higher than that in non-small-cell lung cancer (NSCLC) cell lines (P&lt;0.01). There was a statistically significant positive correlation between the expression levels of nestin and ASH1 in SCLC cell lines, but not in NSCLC cell lines. To assess the function of nestin, we transfected a short hairpin RNA (shRNA) targeting nestin into two SCLC cell lines, DMS53 and SBC3, and then obtained cloned cells that showed apparent down-regulation of nestin. Nestin knock-down cells created by transfection with shRNA exhibited decreased invasion and cell proliferation capabilities. In conclusion, Nestin is expressed in SCLC in association with neuro-endocrine feature and participates in malignant phenotypes including cell growth. Therefore, nestin may be a novel therapeutic target of SCLC. Additional in vivo study will be needed.
Citation Format: Eiji Kunii, Osamu Takakuwa, Ken Maeno, Tetsuya Oguri, Midori Yokoyama, Hisatoshi Hijikata, Takehiro Uemura, Daishi Kasai, Hirotsugu Ohkubo, Mikinori Miyazaki, Akio Niimi. Involvement of intermediate filament nestin in cell growth of small-cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4360. doi:10.1158/1538-7445.AM2013-4360
Abstract 4364: Copy number gain of PTK2 and PIK3CA mutations are common genetic alterations in ovarian clear cell carcinoma.
Authors: Yoon Heejei , Choi Yoon-La , Song Ji-Young , Do Ingu , Kang So Young , Ko Young-Hyeh , Song Sangyong , Kim Byong-Gie 
Published: August 2014

Abstract
Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer and accounts for 5-25% of ovarian cancers. OCCC has shown higher resistance to first-line platinum and taxane-based chemotherapy, resulting in worse prognosis. Most common mutations occur in the genes ARID1A (46%) and PIK3CA (33%). Using array comparative genomic hybridization (aCGH), we previously identified frequent chromosomal gain at 8q24, which includes the encoding sequence for focal-adhesion kinase (FAK)/Protein Tyrosine Kinase 2 (PTK2), a protein that provides signaling and scaffolding functions at sites of integrin adhesion. To validate the copy number gain of PTK2 and correlate the copy number variations with PIK3CA mutations, we analyzed the copy number gain and protein expression levels of PTK2, and examined the PIK3CA mutations in 67 OCCC samples. We found that PTK2 copy number gain and loss were at a frequency of 23% and 25%, respectively. PTK2 gain significantly correlated with the strong expression of PTK2. PIK3CA mutations were found in 20% of the samples. About 40% of the tested samples showed PTK2 gain or PIK3CA mutation. PIK3CA mutations are not strictly mutually exclusive to PTK2 gain, but are more likely to occur in samples with PTK2 copy number normal or loss. Genetic alterations in OCCC mainly activate the PTK2/PI3K/AKT signaling pathway, which makes the pathway an attractive candidate for targeted therapeutics. We, therefore, treated OVMANA, OVISE and OVTOKO OCCC cell lines with PTK2 inhibitors (PF-562271 or PF-573228), or a combination of PF-562271 with a PI3K/mTOR dual inhibitor (BEZ235). Copy number variations of PTK2 were not related to the drug sensitivity of the OCCC cell lines. Drug sensitivity of most of the cells was enhanced toward PF-562271 than PF-573228. OVMANA cells with PIK3CA mutations were more sensitive to a combination of PI3K/mTOR and PTK2 inhibitor than the cells without PIK3CA mutations. Our findings thus suggest that the PTK2/PI3K/AKT signaling pathway is frequently activated in OCCC, and a combination of inhibitor drugs would prove to be necessary to enhance the overall drug efficacy in treating OCCC.
Citation Format: Heejei Yoon, Yoon-La Choi, Ji-Young Song, Ingu Do, So Young Kang, Young-Hyeh Ko, Sangyong Song, Byong-Gie Kim. Copy number gain of PTK2 and PIK3CA mutations are common genetic alterations in ovarian clear cell carcinoma. [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 4364. doi:10.1158/1538-7445.AM2013-4364
Abstract 4366: ShRNA-based cellular proliferation signaling analysis revealed DRD2 as a novel therapeutic target for glioblastoma.
Authors: Li Jie , Zhu Shan , Kozono David , Futulan Diahnn , Gonda David , Kushwaha Deepa , Kahle Kristopher , Elledge Stephen , Chen Clark C. 
Published: August 2014

Abstract
Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within one year of diagnosis. Our best current understanding of its etiology is that glioblastoma involves genetic and epigenetic changes that subvert the inherent molecular circuitry of glial cells to drive uncontrolled cellular proliferation. Unfortunately, this molecular circuitry in glioblastoma appears sufficiently complex and redundant that disruption at any particular point tends to redirects signaling through the remaining circuit. In this context, meaningful therapeutic gains will require the identification of therapeutic agents that target critical nodes within this circuit. To identify novel therapeutic agents that target critical nodes which regulate cellular proliferation, a genome-wide retroviral shRNA library screen was conducted in two glioblastoma cell lines (U87MG and A172) and two lung carcinoma lines (A549 and NCI-H460). Pathway analysis of the pro-proliferative genes using both PANTHER and Ingenuity software revealed an over-representation of G-protein coupled neurotransmitter receptors (GPCR), including dopamine receptor subtype 2 (DRD2), which was also highly expressed in glioblastoma specimens relative to the matched normal parentchymal. Further investigation demonstrated that DRD2 signal regulates cell growth by GNAI2-induced ERK activation. Moreover, Haloperidol, one of DRD2 antagonists, enhances significantly anti-tumor efficacy of EGFR inhibitor AG1478 using U87 and mesenchymal neuroshpere xenografy mouse models. Given that both AG1478 and DRD2 antagonists have been approved for the treatment of glioblastoma and psychotics, separtately, Haloperidol combined with chemotherapy represents a novel and likely conducted strategy for the treatment of glioblastoma.
Citation Format: Jie Li, Shan Zhu, David Kozono, Diahnn Futulan, David Gonda, Deepa Kushwaha, Kristopher Kahle, Stephen Elledge, Clark C. Chen. ShRNA-based cellular proliferation signaling analysis revealed DRD2 as a novel therapeutic target for glioblastoma. [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 4366. doi:10.1158/1538-7445.AM2013-4366
Abstract 4367: Differential contribution of chromatin remodeling complex components to the protection from cytotoxic stress.
Authors: Freeman Miles D. , Mazu Tryphon , Flores-Rozas Hernan 
Published: August 2014

Abstract
Anthracyclines are among the most common chemotherapeutic agents used to-date. Although effective, resistance to this agent usually develops in the course of treatment and serious dose-related toxicity, namely chronic cardio-toxicity, limits its use. In patients suffering from triple negative breast cancer (TNBC) cytotoxic agents such as anthracyclines are some of the only therapeutic alternatives. To increase our knowledge of the pathways that protect cells from anthracyclines we carried out a genome-wide genetic screening in the eukaryotic model organism S. cerevisiae to identify gene defects that generate cells hypersensitive to doxorubicin. A total of 71 deletion strains displayed varying levels of sensitivity to anthracylcines. Of these, 11 genes are involved in chromatin remodeling. The most sensitive mutations corresponded to swi3, snf2 and arp8, which are components of the SWI/SNF complex. Deletion of SNF2 resulted in sensitivity to doxorubicin of 100,000-fold higher than wild type cells. Further analysis of the SNF2 defective strain revealed that it is also sensitive to daunorubicin and cisplatin, as well as to other DNA damaging agents such as alkylating agents, the topoI inhibitor campthotecin or replication blocks from hydroxyurea. Our results indicate that the SWI/SNF complex plays a critical role in protecting cells from exposure to anthracyclines and other DNA damaging agents. Targeting these genes may provide a useful alternative to hypersensitize cancer cells to chemotherapy and provide a therapeutic alternative to TNBC. Research supported by NIH/NCRR RCMI grant #RR03020 at Florida A&M University.
Citation Format: Miles D. Freeman, Tryphon Mazu, Hernan Flores-Rozas. Differential contribution of chromatin remodeling complex components to the protection from cytotoxic stress. [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 4367. doi:10.1158/1538-7445.AM2013-4367
Abstract 4368: Cathepsin B is a potential therapeutic target in pancreatic and gastric cancer .
Authors: Wang Mei , Huang Chunlei , Dong Harvey , Qian Ziliang , Fan Shuqiong , Su Xinying , Zheng Li , Ji Qunsheng , Yu De-Hua 
Published: August 2014

Abstract
Proteases are critical in tumorigenesis by facilitating rapid cell cycling, mediating local invasion, fueling angiogenesis, and promoting metastasis. Cathepsin B (CTSB), a member of papain subfamily of lysosomal cysteine proteases, is involved in tumor cell invasion, metastasis, and angiogenesis. Emerging evidence indicated that CTSB is up-regulated in many cancer nodes and metastatic lesions and functions to protect tumor cells from apoptosis. Hererin, we have performed microarray-based comparative hybridization (aGCH) to screen gene copy number variations in primary tumor samples and found CTSB gene is amplified in 13% (14/107) of Chinese gastric cancer and 2% (1/54) of Chinese pancreatic samples. Theses amplifications were confirmed by fluorescence in situ hybridization (FISH) analysis. By using siRNA-mediated gene silencing, we demonstrated for the first time a role of CTSB in cancer cell proliferation. Down-regulation of CTSB by siRNA interference resulted in significantly reduced cell proliferation and increased cell death in HupT4, a CTSB amplified human pancreatic cancer cell line, but not in the non-amplified cell lines. Together, our results suggest that CTSB is a potential therapeutic target for pancreatic and gastric cancer with CTSB amplification.
Citation Format: Mei Wang, Chunlei Huang, Harvey Dong, Ziliang Qian, Shuqiong Fan, Xinying Su, Li Zheng, Qunsheng Ji, De-Hua Yu. Cathepsin B is a potential therapeutic target in pancreatic and gastric 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 4368. doi:10.1158/1538-7445.AM2013-4368
Abstract 4371: Anti-leukemia effect of Casein Kinase II (CK2) inhibitors in vivo is mediated by the Ikaros tumor suppressor.
Authors: Dovat Sinisa , Song Chunhua , Payne Kimberly J. 
Published: August 2014

Abstract
An increase in the expression and activity of pro-oncogenic Casein Kinase II (CK2) is associated with the development of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in humans. The mechanism by which CK2 promotes leukemogenesis is unknown. Previously, we demonstrated that CK2 kinase phosphorylates the Ikaros tumor suppressor in vivo and that phosphorylation of Ikaros at specific amino acids interferes with the normal function of the Ikaros protein. We hypothesized that CK2 exerts its pro-oncogenic effect by reducing the tumor suppressor activity of Ikaros and that inhibition of CK2 could enhance Ikaros tumor suppressor activity in leukemia. Here we show that Ikaros binds to the promoter regions and represses transcription of several genes that promote cell cycle progression in leukemia. Inhibition of CK2 results in: 1) enhanced Ikaros DNA-binding affinity to its target genes as indicated by quantitative chromatin immunoprecipitation (qChIP) assay); 2) increased Ikaros-mediated transcriptional repression of Ikaros target genes as demonstrated by luciferase reporter assay; 3) impaired proliferation of leukemia cells and 4) increased sensitivity of leukemia cells to Doxorubicin. The use of specific CK2 inhibitors in vivo in a human-mouse leukemia xenograft model produced a strong anti-leukemia effect. Functional analysis of leukemia cells from xenografts demonstrated that CK2 inhibition results in strong binding of Ikaros at the promoters of its target genes and reduced transcription of these genes as indicated by quantitative real-time PCR (qRT-PCR). Our results provide evidence that CK2 inhibitors have a potent anti-leukemia effect in vitro and in vivo, and suggest the mechanism through which CK2 inhibitors exert their therapeutic effect. The presented data demonstrate that one of the mechanisms of action for CK2 inhibitors involves increasing Ikaros activity as a transcriptional repressor in leukemia cells, resulting in enhanced tumor suppressor activity. These results provide a rationale for the use of CK2 inhibitors as a novel therapeutic modality for leukemia. Supported by National Institutes of Health R01 HL095120, a St. Baldrick's Foundation Career Development grant, and the Four Diamonds Fund Endowment (to S.D.).
Citation Format: Sinisa Dovat, Chunhua Song, Kimberly J. Payne. Anti-leukemia effect of Casein Kinase II (CK2) inhibitors in vivo is mediated by the Ikaros tumor suppressor. [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 4371. doi:10.1158/1538-7445.AM2013-4371
Abstract 4372: Evaluating TBK1 as a cancer therapeutic target in cancer cell lines with activated IRF3.
Authors: Muvaffak Asli , Pan Qi , Middleton Richard , Morris Erick , Fernandez Rafael , Lim Jonwong , Dolinski Brian , Nguyen Thi T. , Strack Peter , Yan Haiyan , Chung Rossana , Wu Stephen , Zhang Weiqun , Hulton Chris , Hirsch Heather , Nagashimo Kumiko , Wang Yan 
Published: August 2014

Abstract
TBK1 is a non-canonical IκB protein kinase that phosphorylates and activates downstream targets such as IRF3 and cRel and, reportedly mediates NFkB activation in cancer. We used both genetic and pharmacological approaches to evaluate TBK1 function in cancer cells. In oncogenic KRAS mutant lung cancer cell lines, the TBK1 knockdown did not correlate with reduction in a 2D viability assay. Using TBK1 small molecule inhibitors, we found that the inhibition of cell growth in 2D viability assays did not correlate with Kras dependency or RAS genetic signature. Since the pIRF3(S386) levels in lung lines were too low to assess TBK1 target engagement, we identified cell lines with high pIRF3(S386) levels. We discovered a subset of pancreatic and colorectal cell lines that have high constitutive pIRF3(S386) levels and this correlated with high levels of pTBK1(S172). TBK1 inhibitors were able to dose-dependently inhibit pIRF3S386 in pancreatic & colon lines. These observations indicate that pIRF3(S386) could be used as a biomarker for direct target engagement of TBK1 in cancer cell lines with activated TBK1 pathway. pTBK1(S172), a phosphorylation site within the TBK1 kinase domain activation loop, does not decrease upon inhibition with TBK1 inhibitors but, instead increases. This suggests stimulation of a feedback loop resulting in the activation of an upstream kinase(s) responsible for activating TBK1 in cancer cell lines. Although several pancreatic and colon cell lines were identified to have low μM sensitivity to TBK1 inhibitors, TBK1 shRNA knockdown did not impact proliferation in these cell lines even though pIRF3(S386) levels were reduced. Further studies using knockdown of the related IKKe homolog in cell lines with activated pathway are also being pursued to determine if IKKe knockdown alone or in combination with TBK1 knockdown would result in more substantial growth reduction. It is likely that inhibition of additional nodes in the NF-kB pathway and other pathways are needed to achieve robust anti-tumor efficacy.
Citation Format: Asli Muvaffak, Qi Pan, Richard Middleton, Erick Morris, Rafael Fernandez, Jonwong Lim, Brian Dolinski, Thi T. Nguyen, Peter Strack, Haiyan Yan, Rossana Chung, Stephen Wu, Weiqun Zhang, Chris Hulton, Heather Hirsch, Kumiko Nagashimo, Yan Wang. Evaluating TBK1 as a cancer therapeutic target in cancer cell lines with activated IRF3. [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 4372. doi:10.1158/1538-7445.AM2013-4372
Abstract 4375: Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells.
Authors: Chang Inik , Majid Shahana , Saini Sharanjot , Zaman Mohd S. , Yamamura Soichiro , Chiyomaru Takeshi , Shahryari Varahram , Fukuhara Shinichiro , Deng Guoren , Dahiya Rajvir , Tanaka Yuichiro 
Published: August 2014

Abstract
Prostate cancer is one of the most prevalent cancers in males and ranks the second most common cause of cancer related deaths. 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, is a promising anticancer agent for various types of cancers. Although 2-ME has been shown to activate Jun N-terminal kinase (JNK) and mitochondrial dependent apoptotic signaling pathways, the underlying mechanisms including downstream effectors remain unclear. Here, we report that the human Bcl-2 homology 3 (BH3)-only protein harakiri (Hrk) is a critical effector of 2-ME-induced-JNK dependent apoptosis in prostate cancer cells. Hrk mRNA and protein are preferentially up-regulated by 2-ME, and Hrk induction is dependent on JNK activation of c-Jun. Hrk knockdown prevents 2-ME-mediated apoptosis by attenuating the decrease in mitochondrial membrane potential, subsequent cytochrome c (cyt c) release and caspase activation. Conversely, Hrk over-expression increases caspase-dependent prostate cancer cell apoptosis. Involvement of the pro-apoptotic protein Bak in this process suggested the possible interaction between Hrk and Bak. Thus, Hrk activation by 2-ME or its over-expression displaced Bak from the complex with anti-apoptotic protein Bcl-xL, while deletion of the Hrk BH3 domain abolished its interaction with Bcl-xL, reducing the pro-apoptotic function of Hrk. Finally, Hrk is also involved in the 2-ME-mediated reduction of X-linked inhibitor of apoptosis (XIAP) through Bak activation in prostate cancer cells. Together, our findings suggest that induction of the BH3-only protein Hrk is a critical step in 2-ME activation of the JNK-induced apoptotic pathway targeting mitochondria by liberating pro-apoptotic protein Bak.
Citation Format: Inik Chang, Shahana Majid, Sharanjot Saini, Mohd S. Zaman, Soichiro Yamamura, Takeshi Chiyomaru, Varahram Shahryari, Shinichiro Fukuhara, Guoren Deng, Rajvir Dahiya, Yuichiro Tanaka. Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer 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 4375. doi:10.1158/1538-7445.AM2013-4375