bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5389: Novel inhibitors of nicotinamide phosphoribosyl transferase (NAMPT).
Authors: Ramachandra Murali , Pandit Chetan , Subramanya Hosahalli , Chikkanna Dinesh , Lakshminarasimhan Anirudha , Khairnar Vinayak , Panigrahi Sunil , Ramanathan Anuradha , Satyanandan Aparna , Rao Narasimha , Bera Arnab , Narayanan Kishore , Gopinath Sreevalsam , Ramachandra Raghuveer 
Published: August 2014

Abstract
Nicotinamide phosphoribosyl transferase (NAMPT) is the enzyme that catalyzes the rate limiting step in the salvage pathway of Nicotinamide Adenine Dinucleotide (NAD) biosynthesis. NAMPT is reported to be overexpressed in a number of cancer and inflammatory indications. Because of the requirement of NAD as a co-factor or substrate for a number of key biochemical pathways including those catalyzed by PARP1, Sirtuins and ADP-ribosyl cyclase, inhibition of NAMPT has been shown to result in anti-tumor efficacy in preclinical models. Two NAMPT Inhibitors FK866/APO866 and GMX1778 are currently in clinical trials for oncology indications. In the presence of these clinical agents, cultured cell lines show development of resistance due to mutations underscoring the potential need for inhibitors from distinct chemical series.
Here, we report a structure-guided drug design based approach for identification of lead compounds from two chemical series selectively targeting NAMPT. Determination of co-crystal structures with several de novo designed hits greatly aided in the identification of lead compounds that exhibited potent inhibition of NAMPT against both wild type and resistance mutants (G217R and H191R) Lead compounds were highly active in inhibiting proliferation that correlated well with cellular NAD depletion in several cancer cell lines. Normal cells and selected cancer cell lines have an NAMPT independent salvage pathway for biosynthesis of NAD, which is dependent on nicotinic acid phosphoribosyltransferase (NAPRT) and Nicotinic acid (NA). The anti-proliferative activities were fully rescued in NAPRT- proficient cell lines with the addition of NA, confirming the mechanism of action through specific NAD depletion. Lead compounds from both series exhibited excellent drug-like properties including solubility, metabolic stability and permeability, and desired exposure in pharmacokinetic studies. Anti-tumor activities of these compounds including NA rescue in NAPRT-proficient tumor models are currently being evaluated in preclinical models.
Citation Format: Murali Ramachandra, Chetan Pandit, Hosahalli Subramanya, Dinesh Chikkanna, Anirudha Lakshminarasimhan, Vinayak Khairnar, Sunil Panigrahi, Anuradha Ramanathan, Aparna Satyanandan, Narasimha Rao, Arnab Bera, Kishore Narayanan, Sreevalsam Gopinath, Raghuveer Ramachandra. Novel inhibitors of nicotinamide phosphoribosyl transferase (NAMPT). [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 5389. doi:10.1158/1538-7445.AM2013-5389
Abstract 54: Marked reduction of sequence artifacts in massively parallel sequencing of formalin-fixed paraffin-embedded DNA by depletion of uracil containing templates.
Authors: Do Hongdo , Wong Stephen Q. , Li Jason , Dobrovic Alexander 
Published: August 2014

Abstract
Formalin-fixed and paraffin-embedded (FFPE) tissues are commonly used for the detection of mutational biomarkers in cancer patients. One of the challenges associated with FFPE DNA in genetic testing is its high number of sequence artefacts, thus increasing the risk of false positive results particularly for low level mutations. We have previously shown that uracil lesions in FFPE DNA due to deamination of cytosines are the major cause of C:G&gt;T:A sequence artefacts and pretreatment of damaged FFPE DNA with uracil-DNA glycosylase (UDG) prior to PCR amplification markedly reduces the C:G&gt;T:A sequence artefacts using methodologies suitable for the testing of limited numbers of genomic loci. As the number of cancer associated mutations increases, massively parallel sequencing (MPS) approaches are increasingly necessary. In particular, the use of targeted amplicon based strategies is being implemented in many laboratories. We set out to test whether sequence artifacts were a serious problem and whether the UDG pretreatment strategy is also applicable to a amplicon based targeted MPS approach (Truseq Cancer Panel).
Samples not treated with UDG showed multiple sequence artefacts with a significant portion of changes greater than background sequencing error, with C:G&gt;T:A changes forming the vast majority of artefacts. Treatment of the samples with UDG prior to sequencing dramatically reduced the majority of C:G&gt;T:A changes without affecting the detection of known SNPs and somatic mutations. Elimination of artefactual changes by UDG treatment also improved the accurate detection of low-level sequence variants. Interestingly, most C:G&gt;T:A changes that occurred in the context of CpG dinucleotides were resistant to the UDG treatment as a likely consequence of 5-methyl cytosine being deaminated to thymine.
This approach will greatly facilitate accurate detection of mutations in FFPE samples using amplicon-based approaches which is imperative for personalised cancer medicine, especially when working with samples of low tumour purity. This work also has implications for choice of tissue and protocols for the assessment of heterogeneity in tumours.
Citation Format: Hongdo Do, Stephen Q. Wong, Jason Li, Alexander Dobrovic. Marked reduction of sequence artifacts in massively parallel sequencing of formalin-fixed paraffin-embedded DNA by depletion of uracil containing templates. [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 54. doi:10.1158/1538-7445.AM2013-54
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5413: Role of NANOG in modulating cancer cell metabolism.
Authors: Yang Lifeng , Zhao Hongyun , Marini Juan C. , Jeter Collene , Tang Dean , Nagrath Deepak 
Published: August 2014

Abstract
Tumors and cancer cell lines are both heterogeneous populations and contain a sub-population of undifferentiated cells known as cancer stem cells (CSCs) that are able to renew, proliferate and differentiate into tumor cells. Recent studies have shown that transcription factors (TFs) that are implicated in the pluripotency maintenance of embryonic stem cells (ESCs) are over-expressed in many tumors. Origin and progression of cancer is the result of a complex network of communication between tumor initiating cells also known as cancer stem cells (CSCs) and epithelial cells. Despite the knowledge about involvement of NANOG in modulation of cancer progression, oncogenic signaling, and tumorigenesis, it is not known about how NANOG regulates metabolic fluxes and alter cancer cell's metabolism. Here, we show that NANOG can shift cancer cells metabolism from oxidative phosphorylation to glycolysis, to meet cancer cell's energy needs, redox balance, proliferation, and invasion. Our findings are based on the quantification of metabolites, related to glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and amino acids and nucleotide metabolism, and comparison of these pathways fluxes under induced and uninduced NANOG expression. Our results demonstrate the metabolic targets of NANOG on cancer progression. These insights will present a unique opportunity for diagnosing and treating cancer through CSCs.
Citation Format: Lifeng Yang, Hongyun Zhao, Juan C. Marini, Collene Jeter, Dean Tang, Deepak Nagrath. Role of NANOG in modulating cancer cell metabolism. [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 5413. doi:10.1158/1538-7445.AM2013-5413
Abstract 5414: AMPK regulates HER2/EGFR activity in HER2-positive breast cancer.
Authors: Jhaveri Teraneh , Woo Ju Hyung , Gabrielson Edward 
Published: August 2014

Abstract
The AMP-activated Protein Kinase (AMPK) is a master regulator of cell metabolism, controlling fatty acid synthesis, protein synthesis and carbohydrate metabolism. Physiological states with increased AMPK activity are associated with decreased cancer incidence, leading to interest in AMPK as a potential target for cancer therapy and prevention. To explore a possible role of AMPK modulation in breast cancer therapy, we investigated how activation of AMPK affects breast cancer cell signaling and survival. Initial experiments found that breast cancer cell lines with amplification and over-expression of HER2 (BT474, HCC1419, and SKBR3) are 2-fold to 5-fold more sensitive to cytotoxic effects of AICAR, a canonical pharmacological activator of AMPK, than breast cancer cell lines that lack HER2 amplification (MCF7 and MDA231). In parallel to this activation of AMPK, we observed dose- and time-dependent inhibitory effects on phosphorylation and activity of HER2 and EGFR in these AICAR-treated, HER2-amplified breast cancer cells, with activation of AMPK and suppression of HER2/ EGFR activity preceding commitment to cell death. To further explore how AMPK activity affects HER2/ EGFR, we stably transfected HER2-amplified breast cancer cells with constitutively active AMPKα and observed that AMPK activated by this genetic manipulation also leads to decreased HER2 and EGFR phosphorylation and associated downstream signaling as well as reduced cell growth. Finally, we found that morin, a flavinoid compound previously found to inhibit fatty acid synthesis, also activates AMPK and inhibits HER2 and EGFR signaling in parallel, further supporting the link across these pathways. Our results lead us to postulate that AMPK regulates HER2 and EGFR activity in HER2-amplified breast cancer cells, and activation of AMPK might provide therapeutic benefit in such cancers.
Citation Format: Teraneh Jhaveri, Ju Hyung Woo, Edward Gabrielson. AMPK regulates HER2/EGFR activity in HER2-positive breast 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 5414. doi:10.1158/1538-7445.AM2013-5414
Abstract 5427: Increased glycolysis by 14-3-3ζ-mediated LDHA up-regulation contributes to transformation of early mammary epithelial cells.
Authors: Chang Chia-Chi , Xu Jia , Wang Hai , Zhang Chenyu , Zhang Jian , Rehman Sumaiyah K. , Li Ping , Yu Dihua 
Published: August 2014

Abstract
The Warburg effect is a distinct cancer hallmark that shifts the metabolic pathway in cancer cells through elevated aerobic glycolysis for energy supply and biomass. However, the mechanism of early stage metabolic dysregulation still remains unclear. 14-3-3ζ was found to be over-expressed in the early stages of breast disease and cancer (Atypical ductal hyperplasia and Ductal carcinoma in situ) and in &gt;40% of breast cancer patients, correlating with poor patient prognosis. We found that 14-3-3ζ over-expression in non-transformed human mammary epithelial cells (HMECs), MCF10A and MCF12A, positively correlated with changes in the cellular glycolytic activity (increased glucose uptake, increased lactate production and reduced oxygen consumption). Additionally, 14-3-3ζ over-expression in HMECs induced soft agar colony formation and disorganized acini in three dimensional (3D) culture. Interestingly, we identified that lactate dehydrogenase A (LDHA) was up-regulated in these 14-3-3ζ overexpressing HMECs. LDHA knockdown in 14-3-3ζ overexpressing cells reduced aerobic glycolysis, decreased soft agar colonies and partially rescued the abnormal acinar structures, indicating LDHA upregulation contributed to 14-3-3ζ-mediated aerobic glycolysis and early transformation. Taken together, our data provide new insight into metabolic deregulation during the early stages of breast cancer transformation.
Citation Format: Chia-Chi Chang, Jia Xu, Hai Wang, Chenyu Zhang, Jian Zhang, Sumaiyah K. Rehman, Ping Li, Dihua Yu. Increased glycolysis by 14-3-3ζ-mediated LDHA up-regulation contributes to transformation of early mammary epithelial 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 5427. doi:10.1158/1538-7445.AM2013-5427
Abstract 543: A loss of function Cbl-c mutation in a murine breast cancer model.
Authors: Kales Stephen C. , Ryan Philip E. , Nau Marion , Green Jeffrey E. , Lipkowitz Stanley 
Published: August 2014

Abstract
Receptor Tyrosine Kinase (RTK) signaling is essential for normal biological processes and inappropriate RTK activity can result in malignant transformation. Cbl proteins are a family of RING finger ubiquitin ligases that negatively regulate a variety of RTKs, including EGFR, MET, RET and components of the TCR pathway and disruption of this negative regulation can lead to tumor initiation and progression. Recent studies have identified a growing number of Cbl mutations associated with human myeloid neoplasias and epithelial tumors. Cbl-c is the most recently identified human Cbl protein and is expressed exclusively in epithelial cells. Recently, a novel Cbl-c cDNA has been isolated from a ductal carcinoma which developed in a C3(1)SV40Tag mouse, a murine model of breast cancer driven by Large T antigen. This mutant cDNA encodes a Cbl-c protein which lacks the catalytic domain of Cbl-c, thereby resembling known Cbl family mutations associated with myeoloid neoplasias. Genomic analysis of both parental and transgenic lines shows no evidence of germline mutation indicating that this mutation is likely somatic and may contribute to malignant transformation in this animal model. In overexpression studies, this mutant Cbl-c protein fails to mediate ubiquitination and degradation of activated EGFR and acts as a dominant negative protein, preventing ubiquitination of the EGFR by wild type Cbl proteins. The mutant Cbl-c protein also enhances transformation of NIH 3T3 cells by SV40 Large T antigen and through subsequent analysis of transforming capacity and signal pathway regulation, we are assessing interacting partners of Cbl-c and the potential role of this mutation in tumorigenesis. This mutant Cbl-c protein is the first functional evidence for the involvement of Cbl-c in transformation.
Citation Format: Stephen C. Kales, Philip E. Ryan, Marion Nau, Jeffrey E. Green, Stanley Lipkowitz. A loss of function Cbl-c mutation in a murine breast cancer model. [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 543. doi:10.1158/1538-7445.AM2013-543
Abstract 5469: SAR650984, an anti-CD38 antibody, shows anti-tumor activity in a preclinical model of multiple myeloma.
Authors: Hann Byron , Cai Ti , Wang Donghui , Hom Yun-Kit , Aftab Blake T. , Martin Tom , Wolf Jeffrey 
Published: August 2014

Abstract
Multiple myeloma (MM) is the second most common cancer of the blood and one that is difficult to treat. Although survival has greatly improved over the past decade, MM remains fatal, necessitating development of novel therapies. CD38 is a promising target for antibody therapeutics for the treatment MM and various other hematological malignancies. CD38 is a type II transmembrane glycoprotein with ectozyme activity that has been implicated in Ca2+ mobilization and is found highly expressed on malignant plasma cells of MM. CD38 expression correlates with poor disease prognosis in a subset of hematological malignancies, including MM, where CD38 expression in circulating cells is associated with decreased progression free survival. Previous studies have identified several potential mechanisms of action in the context of anti-myeloma activity, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and pro-apoptotic activity in cancer cell lines.
To determine the potential therapeutic value of targeting CD38 in the context of MM, a humanized anti-CD38 antibody, SAR650984, was generated and evaluated for anti-tumor activity. We evaluated anti-tumor activity of SAR650984 in xenograft-based models of multiple myeloma . SAR650984 demonstrated potent anti-tumor activity in NCI-H929 and RPMI-8226 MM xenograft models.
These results strongly support continued clinical examination of the therapeutic potential for SAR650984 in the treatment of MM and further demonstrates that targeting CD38 with SAR650984 has potential to impact MM disease.
Citation Format: Byron Hann, Ti Cai, Donghui Wang, Yun-Kit Hom, Blake T. Aftab, Tom Martin, Jeffrey Wolf. SAR650984, an anti-CD38 antibody, shows anti-tumor activity in a preclinical model of multiple myeloma. [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 5469. doi:10.1158/1538-7445.AM2013-5469
Abstract 5473: Anti-EGFR monoclonal antibody nimotuzumab enhances temozolomide-induced growth suppression of mutant EGFR expressing glioma xenografts.
Authors: Nagane Motoo , Nitta Yusuke , Shimizu Saki , Shishido-Hara Yukiko , Shiokawa Yoshiaki 
Published: August 2014

Abstract
A mutant form of EGFR, EGFRvIII or ΔEGFR, is common in glioblastoma (GBM) conferring enhanced tumorigenic activity as well as resistance to chemotherapeutic drugs. Nimotuzumab, a humanized monoclonal EGFR antibody, has been shown to exert a modest activity in patients with GBM, but its specific activity against ΔEGFR has not been fully investigated. We treated human glioma cells overexpressing either wild-type (wt) EGFR or ΔEGFR with nimotuzumab with or without temozolomide (TMZ). Nimotuzumab treatment resulted in reduction in tyrosine phosphorylation at C-terminal of ΔEGFR more preferentially than that of wtEGFR, albeit to a lesser extent than tyrosine kinase inhibitor AG1478. Nimotuzumab-induced EGFR tyrosine dephosphorylation was associated with a decrease in AKT phosphorylation, suggesting suppression of downstream signaling pathways. In animal models, growth of subcutaneous xenografts was suppressed by TMZ, but was not affected by nimotuzumab monotreatment. However, antitumor activity was synergistically enhanced when TMZ was combined with nimotuzumab in both U87MG.ΔEGFR and LNZ308.ΔEGFR xenografts, while such an effect was limited in wtEGFR-overexpressing xenografts. Similarly, compared with nimotuzumab or TMZ monotherapy, the combination treatment of TMZ with nimotuzumab significantly elongated survival of mice bearing intracerebral xenografts derived from U87MG.ΔEGFR (p &lt; 0.001, logrank test), and U87MG.wtEGFR to a lesser extent (p = 0.006). These anti-tumor effects by the combination treatment were associated with a decreased proliferation rate and an increase in apoptosis rate in treated xenografts. The U87MG.ΔEGFR intracerebral tumors which had re-grown after the combination treatment with TMZ and nimotuzumab (“escapers”) exhibited an increase expression of MGMT as well as a decrease in mismatch repair (MMR) proteins, MSH6 and MLH1. The reduction of MMR expression was further retained in subcultured escaper cells. These expression changes were not observed in xenografts treated with any of vehicles or monotherapies. These results suggest that nimotuzumab has antitumor activity against mutant EGFR-expressing glioma in vivo when combined with TMZ, and the resistance to this combination treatment might involve expression change of both MGMT and MMR.
Citation Format: Motoo Nagane, Yusuke Nitta, Saki Shimizu, Yukiko Shishido-Hara, Yoshiaki Shiokawa. Anti-EGFR monoclonal antibody nimotuzumab enhances temozolomide-induced growth suppression of mutant EGFR expressing glioma xenografts. [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 5473. doi:10.1158/1538-7445.AM2013-5473
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5489: CRK protein domains diminish cell invasiveness of non-small cell lung cancer.
Authors: Rettig Matthew , Mortazavi Fariborz (Fred) 
Published: August 2014

Abstract
CRK (c-Crk) as an adaptor protein is involved in several oncogenic signal transduction pathways, conveying oncogenic signals to its downstream effectors, and thereby affecting multiple cellular processes including proliferation, differentiation and migration. For example, CRK expression and phosphorylation have been linked to heightened invasiveness of non-small cell lung cancer (NSCLC) cells. In order to intervene in CRK signaling pathway, we examined whether CRK protein domains can be used as a therapeutic tool to interrupt CRK signaling thereby influencing cell invasiveness in NSCLC. For this purpose, Src homology domains of CRK-I (i.e., SH2 and SH3 domains) were overexpressed in H157, Rh2 and A549 cells. CRK-I SH3 domain expression induced epithelial morphology in H157 cells and enhanced epithelial morphology of A549 and Rh2 cells as compared to cells transfected with SH2 domain or control vector. In addition, CRK-I SH3 domain expression induced E-cadherin expression in H157 cells. Furthermore, CRK-I SH3 domain expression significantly decreased the motility of A549 and H157 cells and also decreased the invasiveness of H157 cells. In summary, these data provide evidence that CRK protein domains can be utilized to influence the malignant phenotype of NSCLC cells and also reduce the metastatic potential of these cells.
Citation Format: Matthew Rettig, Fariborz (Fred) Mortazavi. CRK protein domains diminish cell invasiveness of non-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 5489. doi:10.1158/1538-7445.AM2013-5489