bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2803: The role of the sarcosine pathway in prostate cancer progression
Authors: Khan Amjad P. , Rajendiran Thekkelnaycke M. , Ateeq Bushra , Asangani Irfan , Yocum Anastasia K. , Mehra Rohit , Sreekumar Arun , Chinnaiyan Arul M. 
Published: June 2012

Abstract
Differential metabolomic alterations occur during prostate cancer progression. Exploring the metabolome of prostate cancer progression, may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Recently, we have identified sarcosine, an N-methyl derivative of the amino acid glycine, as a key metabolite increased most robustly in metastatic prostate cancer and detectable in the urine of men with organ-confined disease (Sreekumar et al., Nature, 2009). Here, we examined if the proximal regulatory enzymes of sarcosine, glycine-N-methyl transferase (GNMT), sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), play a functional role in prostate cancer progression. By tissue microarray analysis, we observed that GNMT protein levels are strongly associated with prostate cancer aggressiveness. Here, we demonstrate that stable knockdown of GNMT inhibits cell proliferation, induces apoptosis, attenuates cell invasion in Matrigel coated transwells, and blocks the anchorage-independent growth of the cancerous DU145 cells. Overexpression of GNMT in benign RWPE cells showed significantly increased cell invasion and increased sarcosine level. Importantly, knockdown of GNMT in DU145 cells also inhibited intravasation using chick chorioallantoic membrane (CAM) assay and tumor growth in xenograft assays. In contrast, we also showed that while the knockdown of sarcosine degrading enzymes, SARDH and PIPOX, induced invasion and increased sarcosine level in RWPE cells, the overexpression of these enzymes attenuated invasion and decreased sarcosine level. Further, overexpression of SARDH inhibited cell proliferation, blocked the anchorage-independent growth and also inhibited intravasation using CAM assay. Taken together, this study shows that the components of the sarcosine pathway may have potential as biomarkers of prostate cancer progression and serve as new avenues for therapeutic intervention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2803. doi:10.1158/1538-7445.AM2011-2803
Abstract 2809: Pathway dependence on the tyrosine kinase TYK2 in T-cell acute lymphoblastic leukemia
Authors: Sanda Takaomi , Tyner Jeffrey W. , Gutierrez Alejandro , Ngo Vu N. , Moriggl Richard , Ahn Yebin , Glover Jason , Chang Bill H. , Willis Stephanie G. , Zhou Wenjun , Gray Nathanael S. , Staudt Louis M. , Druker Brian J. , Look A Thomas 
Published: June 2012

Abstract
To identify novel oncogenic pathways that are dysregulated in T-cell acute lymphoblastic leukemia (T-ALL), we carried out an RNA interference (RNAi) screen using a retroviral library of inducible short-hairpin RNAs (shRNAs) in T-ALL cell lines. We found that loss of TYK2, a JAK family tyrosine kinase, was lethal in each of three T-ALL cell lines that we tested in this screen. An independent RNAi screen using a small-interference RNA (siRNA) library that individually silences each member of the tyrosine kinase gene family in primary T-ALL cells from a pediatric T-ALL specimens also demonstrated a dependence on TYK2 for cell viability. We confirmed by targeted knock-down analysis with multiple independent shRNAs that the loss of TYK2 induces apoptosis in T-ALL cells, whereas knock-down of other JAK proteins (JAK1, JAK2 or JAK3) had no effect. The TYK2 protein is constitutively phosphorylated on tyrosine residues in many T-ALL cell lines, and sequence analysis of the TYK2 gene in T-ALL cell lines and patient samples revealed a diversity of TYK2 point mutations in the FERM domain (V15A), pseudo-kinase domain (V731I) and kinase domain (E957D and R1027H). TYK2 cDNAs harboring each of these mutations, but not wild-type TYK2 cDNA, could transform Ba/F3 cells to factor-independent growth, and TYK2 was heavily phosphorylated in the Ba/F3 cell lines transformed with mutant cDNAs, indicating that these mutations activated the TYK2 kinase. TYK2-dependent T-ALL cell lines and the transformed Ba/F3 cells were sensitive to small-molecule JAK/TYK2 inhibitors. Moreover, we identified that inhibition of TYK2 induces downregulation of STAT1 phosphorylation, and that loss of STAT1 inhibits the growth of TYK2-dependent T-ALL cells, indicating that this transcription factor is involved in the TYK2 pathway and required for cell survival. Gene expression analysis after TYK2 or STAT1 knock-down in TYK2-dependent T-ALL cell lines revealed that BCL2 is upregulated by this pathway. In conclusion, our results establish a requirement for the TYK2-STAT1 pathway to promote T-ALL cell the survival, and establish TYK2 as a novel therapeutic target for this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2809. doi:10.1158/1538-7445.AM2011-2809
Abstract 2813: Serum biomarker panel detects lung cancer in never smokers
Authors: Birse Charlie , Laiger Robert , Bruce Robert , Tomic Jennifer , Ruben Steve , Lenk Thomas 
Published: June 2012

Abstract
Introduction: Lung cancer is the leading cause of cancer mortality worldwide with more than 1 million deaths each year. Although most lung cancers are attributable to smoking tobacco, it is estimated that as many as 25% of all lung cancer cases are in subjects who have never smoked. A number of clinical, epidemiological, and molecular variations suggest that lung cancers that arise in smokers and non-smokers are significantly different. Biomarker panels may have considerable value when combined with imaging protocols in detecting and diagnosing lung cancer. We previously employed a novel mass spectrometry-based approach to identify serum biomarkers which we have previously shown to detect non-small cell lung cancer (NSCLC) in a smoking population representing all 4 stages of disease. In this study we extend these findings to a cohort of lung cancer subjects who have never smoked.
Methodology: Initially 9 biomarkers were assayed in serum collected from smoking subjects with NSCLC and appropriate controls. More than 600 specimens collected from 4 independent sites were employed in the study. Samples were randomly divided into a training set (NSCLC n=128, controls n = 191) and a testing set (NSCLC n=141, controls n=175) and used to develop a regression-based algorithm for lung cancer detection. Subsequently, an independent validation study was undertaken in cohort of lung cancer subjects who had never smoked (interview questionnaire). All stages of cancer (stage I n = 8, stage II n = 4, stage III n = 17, stage IV n = 11) and all major histological cell types (adenocarcinoma n = 21, squamous n = 7, bronchioloalveolar = 8, others n=4) were included. Controls were matched on age/gender (n=40).
Results: A global 6-marker regression model identified smoking associated cancer cases with good performance (Training AUC=0.877; Testing AUC=0.868). All stages of cancer were distinguished as well as all of the major histological cell types. Fitting of the model to data from the never smoker cohort revealed that the algorithm again discriminated the malignant cases with strong performance AUC=0.906 (sensitivity = 83% at specificity = 83%).
Conclusion: Lung cancer biomarkers identified initially through proteomic analysis have shown robust performance in a study cohort of lung cancer subjects who have never smoked. The findings from these studies suggest that these biomarkers may provide suitable performance across all lung cancer populations to design tests for a variety of diagnostic applications. For example, it is possible that these biomarkers could be employed to enhance the discrimination of malignant nodules identified by radiologic imaging.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2813. doi:10.1158/1538-7445.AM2011-2813
Abstract 2832: Development of AGS-22M6E, a novel antibody drug conjugate (ADC) targeting Nectin-4 for the treatment of solid tumors
Authors: Satpayev Daulet , Torgov Michael , Yang Peng , Morrison Karen , Shostak Yuriy , Raitano Art , Liu Wendy , Lortie Dawn , An Zili , Capo Linnette , Leavitt Monica , Perez Myra , Verlinsky Alla , Shirasuna Kenna , Avina Hector , Guevara Claudia , Morrison Kendall , Challita-Eid Pia , Jia Xiao-Chi , Gudas Jean , Stover David 
Published: June 2012

Abstract
Nectin-4 is a type I transmembrane antigen identified by Agensys to be highly expressed at the RNA level in a significant number of bladder and breast cancer specimens. Analysis of protein expression carried out in an extensive panel of tumor specimens by immunohistochemistry confirmed strong to moderate expression levels of Nectin-4 in bladder, breast and pancreatic cancers (40-60%). A subset of lung and ovarian cancers (up to 30%) also showed significant expression levels of this protein. We have generated an antibody-drug conjugate (ADC) targeting Nectin-4, AGS-22M6E. The highly potent microtubule disrupting drug monomethyl auristatin E (MMAE) was conjugated via valine-citrulline cleavable linker to a fully human IgG1k antibody specific for Nectin-4. AGS-22M6E was characterized for binding affinity, species crossreactivity and cytotoxicity in vitro. AGS-22M6E binds to cell surface Nectin-4 with high affinity and crossreacts with Nectin-4 orthologs of cynomolgus monkey, rat and murine origin. Upon binding to its target on the cell surface AGS-22M6E is internalized and induces cell death in vitro in a dose dependent manner. In vivo efficacy of AGS-22M6E was tested in SCID mice on xenograft models of breast, bladder, pancreatic and lung cancers in subcutaneous and orthotopic modalities. Treatment of well established tumor xenografts with the ADC resulted in significant growth inhibition or complete eradication of tumors in various models covering multiple cancer indications. Pharmacokinetics of AGS-22M6E in non-tumor bearing mice was also evaluated and will be discussed. Overall, these data validate AGS-22M6E as an attractive therapeutic drug candidate for multiple solid tumor indications and support further clinical investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2832. doi:10.1158/1538-7445.AM2011-2832
Abstract 2840: Efficacy of radiation therapy in mammary carcinomas is regulated by macrophages
Authors: Shiao Stephen L. , DeNardo David G. , Fujikawa Kerri A. , Faddegon Bruce A. , Park Catherine C. , Coussens Lisa M. 
Published: June 2012

Abstract
In patients with locally advanced breast cancer, radiation therapy (RT) and chemotherapy following surgery has been a mainstay of treatment with demonstrated survival advantage in numerous randomized trials. However, despite recent advances in treatment, many women still ultimately succumb to disease highlighting the need to improve therapeutic strategies. Results from several groups have recently revealed that the therapeutic effects of RT are in part dependent on activation of immune-mediated mechanism(s); however, little is known regarding the mechanistic details of this activation. To address this, we examined changes in the immune microenvironment of mammary carcinomas following RT. We found that following RT (5 Gy), the density of infiltrating macrophages was significantly increased (20 vs 35%, p = 0.02) as compared to mammary tumors in mice not receiving RT. When macrophages were depleted following RT, via use of a CSF-1 antagonist, a significant delay in tumor growth, as compared to tumors treated with RT alone was observed. Since this data indicated that macrophage infiltration blunted RT responsiveness, we hypothesized that reprogramming tumor-infiltrating macrophages more towards a classical cytotoxic phenotype would result in enhanced RT response and delayed tumor re-growth. Thus, we treated tumor-bearing mice with anti-IL-4 neutralizing mABs in combination with RT, and evaluated tumor re-growth, as compared to tumor-bearing mice treated with either RT or anti-IL4 mAB alone, and found that indeed, reprogramming tumor-infiltrating macrophages to favor classical (M1)-type activity significantly enhanced RT response and delayed tumor re-growth. Together these studies indicate that: 1) RT induces macrophage infiltration into mammary tumors, 2) protumor-type macrophages infiltrating mammary carcinomas blunt response to RT, and 3) reprogramming of tumor-infiltrating macrophages to favor a cytotoxic phenotype improves efficacy of RT.
This work was supported by grants from the NIH/NCI, and Era of Hope (W81XWH-06-1-0416), and Program in Mesothelioma (PR080717) grants from the Department of Defense to LMC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2840. doi:10.1158/1538-7445.AM2011-2840
Abstract 2848: SHLP6: A naturally occurring mitochondrial-derived peptide has therapeutic potential in prostate cancer
Authors: Cobb Laura J. , Nakamura Hiromi , Cohen Pinchas 
Published: June 2012

Abstract
Mitochondrial DNA (mtDNA) mutations have been demonstrated in prostate cancer, particularly at the 16S rRNA region; and abnormal mRNA transcripts from that locus have been described. We and others showed that a novel open reading frame (ORF) within the mitochondrial 16S rRNA region, encoding for a 24 AA peptide called humanin, is a potent cell-survival and metabolic factor.
Hypothesizing that additional bioactive peptides may be encoded from this region we identified an additional six ORFs that encode peptides transcribed from within the 16s rRNA gene in the mtDNA, which we have named small humanin-like peptides, or SHLPs. SHLP1-5 are functionally analogous to humanin, and act as potent survival factors.
Intriguingly an additional peptide, SHLP6, functions in a completely opposing manner. We demonstrate that endogenous SHLP6 is expressed in serum and in multiple tissues, including the prostate, and that its expression declines with age. In addition, the addition of exogenous SHLP6 promotes apoptosis in prostate cancer cell lines including 22RV1, LNCaP and DU145. To assess the in vivo potency of SHLP6, we treated 22RV1 xenografts in SCID mice with SHLP6 for 1 week, and observed a potent inhibition of CaP xenograft growth and angiogenesis in vivo. In addition, we show that SHLP6 expression is decreased in preliminary staining of human prostate cancer, compared with normal prostate tissue.
Analysis of gene and protein expression of SHLP6 treated cells reveals modulation of cell cycle and apoptosis genes and a dramatic inhibition of VEGF expression. Importantly, treatment of prostate cells with siRNA against SHLP6 leads to a dramatic increase in VEGF expression, suggesting that endogenous SHLP6 plays a role in the regulation of VEGF levels. We therefore propose the revolutionary concept that a previously unrecognized family of peptides is produced from the mitochondria and that one of these, SHLP6, plays a key role in regulating angiogenesis, is altered in prostate cancer, and may serve as a novel therapeutic and diagnostic agent in this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2848. doi:10.1158/1538-7445.AM2011-2848
Abstract 2864: Targeting cathepsin S induces tumor cell autophagy via the EGFR-ERK signaling pathway
Authors: Chen Kuo-Li , Chang Wun-Shaing Wayne , Lin Chun-Cheng , Cheung Chun-Hei Antonio , Kuo Chang-Po , Kuo Ching-Chuan , Chang Yi-Hsun , Liu Ko-Jiunn , Chang Jang-Yang 
Published: June 2012

Abstract
Cathepsin S is a vital cellular cysteine protease that is frequently amplified and over-expressed in various human cancers. In this study, we report that targeting cathpesin S could induce tumor cell autophagy via the EGFR-ERK signaling pathway. Cancer cells treated with cathepsin S inhibitors [α-ketoamide inhibitor (6r), Z-FL-COCHO (ZFL)] and cathepsin S-specific siRNA induced autophagy as indicated by an increase in the cleavage of the microtubule-associated protein light chain 3B (LC3B) and the formation of membrane-bound autophagic vacuoles (AVOs). In addition, co-treatment of a specific inhibitor of autophagy, 3-methyladenine (3MA), inhibited the 6r-induced autophagy in cancer cells. Further Western blot analysis revealed that targeting cathepsin S induced cancer cell autophagy through the activation of EGF receptor and its downstream MAPK-related signaling pathways. The induction of autophagy by targeting cathepsin S subsequently leads to the activation of apoptosis as indicated by both the up-regulation of caspase-9/3 activity, the down-regulation of Bcl-2, Bcl-XL and the altered mitochondrial membrane retention potential in cells. The application of the autophagy inhibitor, 3MA, was able to inhibit the process of apoptosis induced by the cathepsin S inhibitor 6r in cancer cells. In conclusion, the current study reveals that cathepsin S inhibitor is able to induce cancer cell autophagy through the EGF receptor signaling pathways, which may provide therapeutic benefit in cancer patients who are less sensitive to apoptosis-inducing agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2864. doi:10.1158/1538-7445.AM2011-2864
Abstract 2867: Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling in human cancer cells
Authors: Jing Kiapeng , Song Kyoung-Sub , Shin Soyeon , Kim Kim Nayeong , Jeong Soyeon , Heo Jun-Young , Park Ji-Hoon , Seo Kang-Sik , Kwon Hyun-Joo , Park Hae-Duck , Han Chang , Wu Tong , Park Jong-Il , Park Seung-Kiel , Kweon Gi-Ryang , Yoon Wan-Hee , Hwang Byung-Doo , Lim Kyu 
Published: June 2012

Abstract
Although Omega 3-polyunsatuarated fatty acids (Omega 3-PUFAs) induce cytotoxicity in several cancer cell lines, the exact mechanisms are not identified yet. In this study, we showed that autophagy is involved in the Omega 3-PUFAs-induced cytotoxicity in cancer cells. Autophagy is characterized by the sequestration of cytoplasmic material within autophagosomes for bulk degradation by lysosomes. We found that docosahexaenoic acid (DHA), an Omega 3-PUFA, induced not only apoptosis but also autophagy in cancer cells. Autophagy was detected after DHA exposure as indicated by induction of LC3 expression, and formation of autophagic vacuolization. We observed that the DHA-induced autophagy was accompanied by loss of p53. Inhibition of p53 by Pifithrin-α or microRNA-p53 significantly increased the DHA-induced autophagy, suggesting that the DHA-induced autophagy is mediated by downregulation of p53. Further experiments showed that the mechanism of the DHA-induced autophagy associated with p53 attenuation, involved an increase in the active form of AMPK which attenuated the mTOR activity as revealed by p27 sequestration. In addition, compelling evidence for the interplay between autophagy and apoptotic cell death induced by DHA is supported by the findings that autophagy inhibition partially decreased the DHA-induced apoptotic cell death and further autophagy induction by p53 inhibitor enhanced apoptosis in response to treatment with DHA in cancer cells. Our results demonstrate that autophagy may be related to the DHA-induced cytotoxicity in cancer cells. [This work was supported by basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (E00026 and R13-2007-020-01000-0].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2011-2867
Abstract 2873: The pandeacetylase inhibitor panobinostat induces the involvement of autophagy related factors in liver cancer cell death
Authors: Fazio Pietro Di , Montalbano Roberta , Quint Karl , Ocker Matthias 
Published: June 2012

Abstract
Background. Liver cancer still represents an unmet medical need with rising incidence rates also in Western countries. Panobinostat (LBH589, Novartis Oncology), a pandeacetylase inhibitor, represents a new agent with a promising future in liver cancer therapy. We have previously demonstrated that panobinostat is able to induce cell death in two liver cancer cell lines, HepG2 and Hep3B, through activation of ER stress related apoptotic pathways (Cell Oncol 2010;32:285-300). Panobinostat also significantly reduced the growth of HepG2 xenografts in nu/nu mice. We here demonstrate the implication of autophagy mechanisms into cell demise mediated by panobinostat.
Materials and Methods. HepG2 (p53 wt) and Hep3B (p53 null) were treated for 72 hours with panobinostat and cell death was quantified through FACS with propidium ioded staining and CK18 fragmentation staining. Impedance based real-time cell analysis was performed to continuously monitor cell viability after panobinostat treatment. The expression of autophagy related factors was analyzed through RT-qPCR, western blot and immunofluorescence based cytochemistry.
Results. Panobinostat induces cell death in a dose and time dependent manner. Autophagy related factors Atg5, Beclin and its activators Ambra, p62 and UVRAG were up-regulated after 48 hours of treatment. We also observed also significant increase of p73 expression in Hep3B cells after 24 hours of treatment. Immunofluorescence based cytochemistry showed a modification of the ubiquitous cytosolic distribution of Beclin and LC3B in both cell lines to a defined spot formation after treatment with panobinostat, indicating a probable autophagosome formation. Western blot analysis also demonstrated an increase of Beclin and LC3-I and LC3-II.
Conclusion. Panobinostat treatment determines the involvement of autophagy related mechanisms in a ER stress related apoptosis scenario. The wide spectrum of mechanisms of action of panobinostat need to be further investigated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2873. doi:10.1158/1538-7445.AM2011-2873