bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B115: Use of a genome-wide loss-of-function screen to identify novel mechanisms of resistance to TRAIL induced apoptosis.
Authors: Dimberg Lina Y. , Cabrera Joshua , Menke Christina , Kim Jihye , Porter Christopher C. , Tan Aik-Choon , Behbakht Kian , Thorburn Andrew , Ford Heide L. 
Published: August 2014

Abstract
A biological approach to combat cancer is to define and specifically target signaling pathways involved in tumor progression and metastasis. One such target is the TNF-Related Apoptosis Inducing Ligand (TRAIL) signaling pathway. Importantly, TRAIL kills tumor cells selectively without inducing apoptosis in normal tissue. Recombinant TRAIL and agonistic antibodies against the receptors DR4 and DR5 are in early-phase clinical trials as an anti-cancer treatment in breast cancer. However, since cancer cells must evade tumor surveillance, it is not surprising that many tumors are TRAIL-resistant. We are interested in the molecular basis of acquired resistance to TRAIL induced apoptosis as a result of long-term exposure to the drug. Our goal is to gain an increased understanding of how cancer cells can become resistant to TRAIL and how this resistance can be predicted and circumvented, ultimately leading to more efficient TRAIL-based therapy. To this end, we utilized the Burkitt's lymphoma cell line BJAB-LexR that has been made naturally resistant to TRAIL through long-term culture in the presence of increasing concentrations of the drug Lexatumumab, an anti-DR5 antibody. We performed a genome wide loss-of-function screen using the GeneNet lentiviral shRNA library containing 200 000 shRNAs with sequencing tags, allowing for high throughput deep sequencing. After selection for a particular phenotype, in this case TRAIL resistance, the shRNAs that promote or prevent this phenotype can be deduced from the frequency in which the shRNA is present in the selected (TRAIL-treated) population versus the unselected population. Bioinformatic analysis yielded a list of putative resistance genes that were validated in the BJAB system and also in other cell lines that have been made resistant to TRAIL in a similar fashion. With this unbiased approach, we have identified novel genes associated with TRAIL resistance that may provide targets for combination therapy that could improve the response to TRAIL.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B115.
Citation Format: Lina Y. Dimberg, Joshua Cabrera, Christina Menke, Jihye Kim, Christopher C. Porter, Aik-Choon Tan, Kian Behbakht, Andrew Thorburn, Heide L. Ford. Use of a genome-wide loss-of-function screen to identify novel mechanisms of resistance to TRAIL induced apoptosis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B115.
Abstract B121: Ligand-independent AXL diversification of ErbB signaling and ErbB-targeted drug response mitigation in triple negative breast carcinoma cells.
Authors: Meyer Aaron S. , Gertler Frank B. , Lauffenburger Douglas A. 
Published: August 2014

Abstract
The relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Recently, activation of alternative RTKs as an important resistance process has been identified, although underlying mechanisms are not well understood. Amplification of the targeted signal can also confer resistance, particularly in vivo, where access to the tumor site by therapeutics may be limited. AXL is an RTK linked to secondary resistance in a variety of solid cancers, including those of the breast, lung, glioma, prostate, and colon. Though AXL-mediated resistance is well appreciated, the most effective means of targeting the receptor and basic mechanisms of activation have not been elucidated.
Using ligand-blocking antibodies, siRNA-mediated ligand knockdown, and ligand binding-incompetent mutants, we show ligand-independent activation of AXL is present in a subset of cell lines and that this form of activation is actively regulated by ectodomain interactions. With this in mind, we hypothesized ligand-independent mechanisms of activation may be predominant in particular contexts. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET, and PDGFR but not IGF1R or INSR. Activation of EGFR transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification amplified a subset of downstream signaling and was required for EGF-elicited motility responses in AXL-positive TNBC (triple-negative breast cancer) cells.
This alternative mechanism of receptor activation may limit the utility of ligand-blocking therapeutic approaches and indicate against therapy withdrawal after acquired resistance. Inhibiting ligand-independent activation, in contrast, may provide more specific efficacy on cancer cells. Moreover, sub-additive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR principally yields transactivation-mediated signaling.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B121.
Citation Format: Aaron S. Meyer, Frank B. Gertler, Douglas A. Lauffenburger. Ligand-independent AXL diversification of ErbB signaling and ErbB-targeted drug response mitigation in triple negative breast carcinoma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B121.
Abstract B13: Salmonella typhimurium A1-R targets human pancreatic cancer patient-derived orthotopic xenograft (PDOX) in nude mice.
Authors: Hiroshima Yukihiko , Zhao Ming , Maawy Ali , Zhang Yong , Katz Matthew H.G. , Fleming Jason B. , Uehara Fuminari , Miwa Shinji , Yano Shuya , Momiyama Masashi , Suetsugu Atsushi , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: August 2014

Abstract
The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R (A1-R) on pancreatic cancer patient-derived orthotopic xenografts (PDOX) in nude mice compared to standard chemotherapy. The pancreatic cancer PDOX was orthotopically implanted in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX acquire RFP-expressing stroma for the purposes of imaging the tumor in non-colored nude mice in order to non-invasively image tumor growth and drug response. The nude mice were treated with A1-R or standard chemotherapy including gemcitabine (GEM). Histopathological response to treatment was defined according to Evans's criteria. A1-R treatment significantly reduced tumor weight as well as tumor fluorescence area compared to untreated control (p=0.011), with comparable efficacy to GEM, CDDP and 5-FU. A1-R had the highest efficacy compared to any of the chemotherapy drugs tested based on Evan's histological response criteria. Salmonella typhimurium A1-R was effective on a human pancreatic PDOX and is a promising therapy for this disease in the clinic.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B13.
Citation Format: Yukihiko Hiroshima, Ming Zhao, Ali Maawy, Yong Zhang, Matthew H.G. Katz, Jason B. Fleming, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Atsushi Suetsugu, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Salmonella typhimurium A1-R targets human pancreatic cancer patient-derived orthotopic xenograft (PDOX) in nude mice. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B13.
Abstract B132: Next generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA).
Authors: Churi Chaitanya R. , Rashid Asif , Shroff Rachna , Mishra Lopa , Zuo Mingxin , Kaseb Ahmed , Janku Filip , Aloia Thomas A. , Vauthey Jean-Nicholas , Curley Steven , Ali Siraj , Palmer Gary , Javle Milind 
Published: August 2014

Abstract
Background: The incidence of CCA is rising and the clinical efficacy of systemic therapy is suboptimal. Next generation sequencing (NGS) technology offers potential for targeted therapeutics against genetically heterogenous solid tumors including cholangiocarcinoma (CCA).
Methods: DNA was extracted from biopsy specimens of 56 patients of CCA seen at MD Anderson Cancer Center Houston, TX. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform.Results: 162 genomic variations (GV) were identified from 56 patient samples with an average of 2.89 GVs/patient (range 0-10). GVs identified were mutations (72%), amplifications (17%), loss/deletions (7%) and others (4%). 6 (11%) tumors showed no GVs. Most frequent GVs were TP53 (35%), KRAS (31%), ARID1A (16%), PBRM1 (11%), BAP1 (9%), ERBB2 (9%), FBXW7 (9%), SMAD4 (9%) and IDH1 (7%). ERBB2 GVs included 4 mutations and 1 amplification. KRAS mutation was associated with a statistically significant reduction in overall survival (OS). Mean OS in patients with KRAS mutation was 32 weeks vs. 63 weeks in KRAS wt (t = -2.126, p = 0.039). Ingenuity Pathway Analysis indicated disruption in cell cycle, proliferation, development, death and DNA repair pathways. Targetable signaling pathways from this study are described in Table 1. Targetable GVs were noted in 59% of patients. These are potentially targetable by inhibitors to ERBB2, FGF, mTOR, MEK, BRAF and PARP-1.
Conclusion: These data are the single largest compilation of NGS analysis on CCA patients and demonstrate the range of GVs that are eligible for investigational targeted therapies. These results can be used as a basis to develop personalized treatments for CCA patients based on individual genetic profiles.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B132.
Citation Format: Chaitanya R. Churi, Asif Rashid, Rachna Shroff, Lopa Mishra, Mingxin Zuo, Ahmed Kaseb, Filip Janku, Thomas A. Aloia, Jean-Nicholas Vauthey, Steven Curley, Siraj Ali, Gary Palmer, Milind Javle. Next generation sequencing yields promising targets in advanced cholangiocarcinoma (CCA). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B132.
Abstract B141: Molecular imaging of DNA damage and repair in cancer.
Authors: Wang Yanming , Wu Chunying , Condie Allison , Zhu Junqing , Gerson Stanton 
Published: August 2014

Abstract
Objectives: To directly assess apurinic/apyrimidinic (AP) sites induced by DNA-targeted chemotherapeutic agents for in vivo studies of DNA damage and repair.
Background: Current cancer treatments rely heavily on chemotherapeutic agents to induce cytotoxic DNA damages and programmed cell death in ancer cells. However, the efficacy of DNA-targeted agents such as temozolomide are often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway results in formation of abasic or AP sites and inhibition of AP sites leads to significant reduction of drug resistance and enhancement of drug sensitivity. Thus, AP-site formation has been identified as an important biomarker in DNA-targeted chemotherapies.
Methods: Design, synthesis, and evaluation of small molecular probes used in combination with positron emission tomography (PET) that allows for quantification of AP sites in vivo.
Results: To date, we have design and synthesized a series of AP-binding agents for PET imaging studies. Following radiolabelling, microPET studies have been conducted to evaluate their pharmacokinetic profiles in melanoma and glioma xenograft tumor mouse models that are pre-treated with temozolomide to induce AP-site formation. Subsequent quantitative analysis showed that the radioactivity concentration were higher in tumor regions pre-treated with temozolomide relative to tumor regions without any treatment, indicating that AP-site formation was elevated following temozolomide treatment. In vivo blocking studies based on microPET also showed that the agents bound to AP sites with high specificity.
Conclusion: Our studies have proved the concept that PET imaging agents can be developed to monitor BER pathway and demonstrate the feasibility for future clinical applications in cancer research.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B141.
Citation Format: Yanming Wang, Chunying Wu, Allison Condie, Junqing Zhu, Stanton Gerson. Molecular imaging of DNA damage and repair in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B141.
Abstract B15: Increased clinical relevance of orthotopic glioma models through bioluminescence and MR imaging.
Authors: Lister Deanne , Meade Mary Anne , Woolliscroft Tracey , Balagurunathan Deepa , Trachet Erin , Leopold Wilbur , McConville Patrick 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most common and most aggressive form of malignant primary brain tumors, affecting nearly 35,000 people in the United States. Most preclinical studies in glioma utilize survival as the primary endpoint to study, which provides limited information about disease progression, tumor burden response to treatment (a primary clinical end point). We have characterized two human glioma cell lines, Gli36 and LN827 that were modified to express luciferase in order to enable in vivo monitoring of disease progression and response to treatment using bioluminescence imaging (BLI). Anatomical magnetic resonance imaging (MRI) was also performed to directly correlate bioluminescence signal with tumor volume. Both models exhibited &gt;90% tumor take-rate and responded to treatment with temozolomide, a clinical standard of care. Analysis of lifespan, tumor volume doubling times, and tumor growth delay all indicated that BLI is a reliable indicator of disease progression and response to treatment. BLI-based endpoints also showed good correlation with MR-based endpoints. These results support the use of in vivo imaging in these modified cell lines for longitudinal monitoring of tumor progression and response to therapy. Imaging was not only a reliable method for quantifying tumor burden, but enabled clinically relevant end points that could not be accessed through non-imaging means or lifespan determination alone. Further utility can be driven in these models through the use of other functional imaging end points.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B15.
Citation Format: Deanne Lister, Mary Anne Meade, Tracey Woolliscroft, Deepa Balagurunathan, Erin Trachet, Wilbur Leopold, Patrick McConville. Increased clinical relevance of orthotopic glioma models through bioluminescence and MR imaging. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B15.
Abstract B153: sVEGFR-1 functionalized nanoparticles for diagnosis of cancer using magnetic resonance imaging.
Authors: Ozgurtas Taner , Yesildal Fatih , Aydin Fevzi Nuri , Sardan Melis , Uzunalli Gozde , Kocaoglu Murat , Tekinay Ayse Begum , Guler Mustafa Ozgur , Genc Rukan , Deveci Salih 
Published: August 2014

Abstract
Cancer is considered to be an important public health problem throughout the world. Early diagnosis of cancer and recurrent tumors are extremely important for reducing mortality rates and also for following up the response to treatment. The increased need of oxygen leads to new vascular structures in and around the tumor. The most important components of this angiogenic process are vascular endothelial growth factor (VEGF) and its receptors which are overexpressed in tumor cells. The aim of this study is to develop soluble VEGF receptor-1 (sVEGFR-1) functionalized iron oxide nanoparticles for diagnosis of early stages of tumors or metastases by MRI. A single dose of N-nitroso-N-methylurea (NMU) at a concentration of 50 mg/kg was injected to inbred rats intraperitoneally on the 21st day of their birth to create breast cancer. In this study, in vivo characteristics of functionalized nanoparticles were studied by comparing rats with tumors and the healthy controls. Approximately 70 days later, tumor formed rats were administered with nanoparticles functionalized with sVEGFR-1, intravenously and scanned with MRI. MR images were taken before the treatment with nanoparticles (0 minute), and at 30th and 60th minutes after treatment. The evaluation of MRI data revealed that the images of metastases were hypointense at 30th minute with respect to the 0 minute and 60th minute images (p&lt;0.05). Nanoparticles were observed to localize at the tumoral regions and there were significant contrast intensity differences in rats with tumor. These results showed that our sVEGFR-1 functionalized nanoparticles were localized at tumoral regions including metastasis. This method can be useful in diagnosis of early tumors, metastasis, and recurrencies. Further molecular and histological studies are necessary to explain the efficacy of these nanoparticles for tumor diagnosis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B153.
Citation Format: Taner Ozgurtas, Fatih Yesildal, Fevzi Nuri Aydin, Melis Sardan, Gozde Uzunalli, Murat Kocaoglu, Ayse Begum Tekinay, Mustafa Ozgur Guler, Rukan Genc, Salih Deveci. sVEGFR-1 functionalized nanoparticles for diagnosis of cancer using magnetic resonance imaging. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B153.
Abstract B157: Understanding the role of transcription factor ETV1 in metabolic reprogramming of prostate cells as a route to novel therapeutics.
Authors: Baena Esther , Mamoor Shahan , Li Zhe , Orkin Stuart H. 
Published: August 2014

Abstract
ETV1 is the second most frequently rearranged ETS transcription factor gene in human prostate cancer. It is widely believed that ectopically expressed ETV1 (due to gene fusions) plays a similar role in prostate tumorigenesis to that of ERG. However, further analysis of clinical data revealed that high levels of ETV1 expression are often found in more advanced prostate cancers, whereas ERG overexpression is mainly associated with localized prostate cancer and elevated androgen receptor signaling. High expression of ETV1, rather than ERG, in the prostate has been associated with disease recurrence in some patients. Interestingly, many metabolic pathways often associated with cancer cells are enriched in the prostates of mice engineered to carry a Tmprss2-ETV1 knockin allele and ETV1-expressing human prostate cancer samples. To determine the dominant metabolic programs that accompany ETV1 expression, we have performed metabolic profiling, and integrated the data with human prostate cells and mouse transcriptome data. Our analyses have identified ETV1 as a regulator of lipid metabolism, glycolysis and glutamine metabolism. Of note, ETV1 expression reprograms the steroid biosynthesis pathway, leading to an increase in testosterone production at least in part through 17-β hydroxysteorid dehydrogenases activation. Indeed, one of the main causes of prostate cancer recurrence is local androgen production due to metabolic changes in prostate cancer cells. This novel finding may explain, at least in part, how ETV1 expression promotes castration-resistant disease, opening a new path to the development of novel therapies directed to progressive and lethal prostate cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B157.
Citation Format: Esther Baena, Shahan Mamoor, Zhe Li, Stuart H. Orkin. Understanding the role of transcription factor ETV1 in metabolic reprogramming of prostate cells as a route to novel therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B157.
Abstract B158: Transcriptional profile of NAMPTi unveils modulation of Tankyrase and Wnt/B-catenin pathway.
Authors: Shomali Maysoun , McGlynn Patrick , Wiederchain Dmitri , August Paul , Adrian Francisco , Garcia-Echeverria Carlos , Theilhaber Joachim , Bouaboula Monsif 
Published: August 2014

Abstract
The coenzyme, NAD, is as an essential redox factor in cellular biochemical processes such as respiration and metabolism. NAD is also a substrate for cellular enzymes including sirtuins and poly (ADP ribose) polymerases. NAMPT, which catalyzes the rate limiting step of NAD biosynthesis, has been considered as promising cancer target for more than a decade. NAMPT inhibitors profoundly inhibit tumor cell growth; however, the mechanism that leads to the tumor cell growth inhibition is not understood.
In this work, we report the results of our exploration of the metabolic and transcriptional alterations post-NAMPT inhibition in HCT116 cell line. Our results show that NAMPTi induces a time-dependent modulation of tumor metabolism which in turn induces the reprogramming of tumor cell transcriptome concomitant with cell growth inhibition. The transcriptional profile revealed different metabolic and oncogenic signaling pathways are modulated by NAMPT inhibition. The wnt/b-catenin pathway was highlighted as one of the most modulated pathways by NAMPTi.
We indeed confirmed that the NAMPTi induces the inhibition of b-catenin/TCF reporter system transfected in HCT116 cells or in HEK293 cells constitutively expressing Wnt3A. NAMPT inhibition induces a strong decrease of cyclinD1 and c-myc expression in agreement with the modulation of Wnt/b-catenin pathways.
The NAMPTi impact on Wnt/b-catenin pathways can be seen in CRC cell lines bearing APC wt or APC mut and in cell lines with heterozygote but not homozygote b-catenin mutation suggesting that the effect of NAMPTi effect is upstream b-catenin. Our studies highlighted two potential mechanisms that contribute to wnt/b-catenin pathway modulation by NAMPTi. First, we observed an inhibition of disheveled activation and secondly, a decrease in the activity of tankyrase.
The results obtained from these studies highlight the key role of NAMPT in tumor metabolism and the wnt/b-catenin oncogenic pathway. This suggests that modulation of wnt /b-catenin contributes to the antitumor activity of NAMPTi.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B158.
Citation Format: Maysoun Shomali, Patrick McGlynn, Dmitri Wiederchain, Paul August, Francisco Adrian, Carlos Garcia-Echeverria, Joachim Theilhaber, Monsif Bouaboula. Transcriptional profile of NAMPTi unveils modulation of Tankyrase and Wnt/B-catenin pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B158.