bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA28: Preclinical strategies to target resistance in colorectal cancer: Opportunities and challenges
Authors: Trusolino Livio , Sassi Francesco 
Published: May 2016

Abstract
More than ten years after completion of the Human Genome Project, genetic alterations with causative roles in cancer have been identified. Inhibitors that target druggable mutant gene products have been developed. Finally, a number of these drugs have entered the clinic and are now used in patients.
Some fundamental issues need to be addressed before the informative potential of genome-wide molecular surveys is translated into clinical benefit. First, given the heavy mutational load accrued during neoplastic progression, driver alterations are difficult to distinguish from passenger events. Second, next-generation approaches are likely to identify previously neglected small subsets of very rare variants, which requires population-scale studies for statistically solid genotype/response correlations. Third, not always does the presence of an oncogenic driver predict response. Therefore, treatment paradigm may not be decided on the sole basis of the mutational status of a single gene with potential cancer-causing function, but rather on the basis of the heterogeneous context in which that mutation is found (precision medicine).
All these challenges also apply to metastatic colorectal cancer (mCRC). Less than 20% of mCRC patients respond to anti-EGFR antibodies, the gold standard targeted therapy, which calls for the identification of novel predictive biomarkers and suggests that uncharacterized drivers other than EGFR can sustain the growth of different CRC subsets. The categorization of tumor subpopulations featuring specific driver lesions, the validation of such lesions as targets, and the need for discrimination between “actionable” opportunities and those with weak clinical transferability require reliable preclinical models. The scope of our research is to refine genetic, mechanistic and therapeutic annotation of mCRC subsets using predictive in vivo models as a means to systematically increase the success rate of rationally based clinical trials that emanate from preclinical findings.
Citation Format: Livio Trusolino, Francesco Sassi. Preclinical strategies to target resistance in colorectal cancer: Opportunities and challenges. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA28.
Abstract IA31: Mechanisms of resistance to EGFR inhibitors in lung cancer
Authors: Jänne Pasi 
Published: May 2016

Abstract
Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs), including geftinib, erlotinib and afatinib are the standard of care for patients with advanced EGFR mutant non-small cell lung cancer. Treatment with an EGFR TKI leads to a response rate of ~60% and a median progression free survival ranging from 9 to 11 months. Acquired drug resistance inevitably develops in most of not all EGFR mutant lung cancer patients treated with EGFR inhibitors. The most common mechanism of acquired resistance is the development of a secondary EGFR T790M mutation. Other mechanism of resistance include activation of bypass signaling pathways (such as MET or HER2) and histological transformation. Over the last few years a series of new structurally distinct EGFR inhibitors have been identified and entered the clinic that are capable of inhibiting EGFR T790M. This class of mutant selective EGFR TKIs are effective both against the activating EGFR mutation and the drug resistant T790M but spare inhibition of wild type (WT) EGFR. This has enormous potential therapeutic implications as the side effects of all approved EGFR inhibitors is derived from inhibition of WT EGFR. Several of these agents, including AZD9291 and rociletinib (CO-1686) are in advanced stage clinical development. Both agents have been granted FDA’s breakthrough designation. In EGFR inhibitor resistant patients who have developed resistance to current clinical EGFR inhibitors through T790M, the response rates to either AZD9291 or rociletinib is over 60% with median progression free survivals of ~ 10 months. Current research efforts and clinical studies are focusing on a.) understanding mechanisms of drug resistance to this new class of EGFR inhibitors, b.) the development of rationale combination therapies and c.) use of these agents as initial treatment (instead of currently approved EGFR inhibitors) for patients with advanced EGFR mutant NSCLC.
Citation Format: Pasi Jänne. Mechanisms of resistance to EGFR inhibitors in lung cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA31.
Abstract PR01: Oncogenic Kras-induced mitochondrial oxidative stress in pancreatic acini modulates the formation of precancerous lesions through autocrine EGFR signaling
Authors: Liou Geou-Yarh , Doeppler Heike , DelGirono Kathleen E. , Crawford Howard C. , Murphy Michael P. , Storz Peter 
Published: May 2016

Abstract
The development of pancreatic cancer requires both obtain of oncogenic Kras mutations and up-regulation of growth factor signaling. However, how oncogenic Kras regulates growth factor signaling in pancreatic cancer development is still unclear. Using a transgenic mouse model harboring an oncogenic Kras mutation and a 3D organoid explant culture of primary pancreatic acini, we here show that expression of mutant Kras in pancreatic acinar cells alters their mitochondrial metabolism, resulting in increased generation of mitochondrial reactive oxygen species (mROS). We further demonstrate that mROS induced by oncogenic Kras is required for transdifferentiating acinar cells to a duct-like phenotype and eventually progression to pancreatic intraepithelial neoplasia (PanIN), the most common precursor lesions of pancreatic ductal adenocarcinoma (PDAC). This transdiffentiation process is mediated by increased levels of epidermal growth factor receptor (EGFR) as well as its ligands, EGF and TGFα, through activation of the ROS-receptive transcription factors, NF-κB1 and NF-κB2. In Kas transgenic mice, the interception of KrasG12D-mediated generation of mROS significantly reduced the formation of pre-neoplastic lesions. Hence, our data provide mechanistic insight of how oncogenic Kras mutant crosstalks with growth factor signaling to cause the formation of pancreatic cancer.
Citation Format: Geou-Yarh Liou, Heike Doeppler, Kathleen E. DelGirono, Howard C. Crawford, Michael P. Murphy, Peter Storz. Oncogenic Kras-induced mitochondrial oxidative stress in pancreatic acini modulates the formation of precancerous lesions through autocrine EGFR signaling. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr PR01.
Abstract PR08: Macrophage-mediated trogocytosis leads to death of antibody-opsonized tumor cells
Authors: Velmurugan Ramraj , Challa Dilip K. , Ram Sripad , Ober Raimund J. , Ward E. Sally 
Published: May 2016

Abstract
The interplay between innate immune cells and antibodies to control cancerous growth is of central importance for mediating direct anti-tumor effects and the induction of long-lived anti-tumor immunity. Phagocytosis of antibody-opsonized cells by macrophages through Fcgamma receptor interactions is well characterized and leads to cell death through target cell engulfment into phagosomes. By contrast, the contribution of the related process called trogocytosis, involving the ingestion of limited amounts of the target cell by phagocytic cells, to cell attrition is less certain. In the current study we have developed a high throughput, quantitative assay to distinguish whole cell phagocytosis (WCP) and trogocytosis for different macrophage:breast cancer cell combinations. These analyses, combined with long term microscopic imaging, demonstrate that trogocytosis leads to target cell death. The implementation of multifocal plane microscopy to investigate trogocytic events at high spatiotemporal resolution reveals that these processes involve tubular extensions of opsonized tumor cells that are subsequently pinched off by the recipient macrophage. Of relevance to the design of second generation antibodies with improved efficacy, antibody engineering to enhance Fcgamma receptor interactions results in increased trogocytic activity. Collectively, these studies have significance to the rapidly expanding use of antibodies to treat cancer.
Citation Format: Ramraj Velmurugan, Dilip K. Challa, Sripad Ram, Raimund J. Ober, E. Sally Ward. Macrophage-mediated trogocytosis leads to death of antibody-opsonized tumor cells. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr PR08.
Abstract A04: LINC00467 regulates the autophagy signaling pathway STK11/AMPK
Authors: Guo Sujuan , Pridham Kevin , Sheng Zhi 
Published: May 2016

Abstract
Mounting evidence has established a fundamental role of autophagy (a self-digestion process) in tumor initiation and progression. Hence, targeting autophagy is a promising strategy for developing effective therapies to treat cancer. In our previous genome-wide RNA interference screen, we identified a set of genes that regulate autophagy in human chronic myeloid leukemia K562 cells. One of the candidates is LINC00467 (long intergenic noncoding RNA 00467), a long non-coding RNA (LncRNA) known for apoptosis regulation in neuroblastoma. LncRNA is a new RNA species with important role in gene expression regulation. Although the role of LncRNAs in apoptosis has been extensively studied. Whether or how LncRNA regulate autophagy has not yet been explored. Our previous work has established that LINC00467 regulates autophagy in different types of cancers. However, how LINC00467 regulates autophagy is largely unknown. To address this question, we first determined the stage of autophagy LINC00467 targets using a combination treatment of LINC00467 depletion and chloroquine and measuring the protein level of p62. We then monitored the activity of STK11/AMPK and MTOR, two autophagy signaling pathways, in K562 cells upon inhibition of LINC00467. We found that shRNA knockdown of LINC00467 in conjunction with chloroquine treatment significantly induced the formation of autophagic compartments manifested by the increase of Cyto-ID fluorescence. Moreover, LINC00467 knockdown substantially decreased the protein level of P62. These results indicate that Linc00467 suppresses the initiation of autophagy. To further probe the mechanism, we measured the activity of autophagy-promoting kinases STK11/AMPK, and autophagy-inhibiting kinase MTOR. Our results showed that Linc00467 knockdown substantially enhanced the activity/expression of STK11/AMPK while inhibiting that of MTOR, consistent with the inhibition of BCR-ABL using imatinib. Furthermore, We showed that LINC00467 inhibition led to a delayed degradation of STK11 mRNA. Taken together, our data demonstrates that LINC00467 suppresses autophagy through blocking STK11/AMPK. These results not only reveal a new LINC00467/STK11/AMPK pathway in autophagy regulation but also provide a basis for future therapeutic development.
Citation Format: Sujuan Guo, Kevin Pridham, Zhi Sheng. LINC00467 regulates the autophagy signaling pathway STK11/AMPK. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A04.
Abstract A07: Long noncoding RNA PANCRNA1 is a novel regulator of cell growth and motility in pancreatic ductal adenocarcinoma
Authors: Karaboga Husna , Jonsson Philip , Liu Yu , Lin Chin-Yo 
Published: May 2016

Abstract
Recent advances in sequencing technology have been increasing our understanding of non-protein coding regions in the mammalian genome. There is growing recognition that the majority of mammalian genome produces long non-coding RNA (lncRNA). Generally, their expression is lower than protein-coding genes and they are strikingly tissue-specific. Several studies have shown that they function in various aspects of cell biology. Abnormal expression and dysregulation of lncRNAs are associated with various types of cancer including pancreatic ductal adenocarcinoma (PDAC), which has the worst prognosis of the major cancers, with a 5-year survival rate of 5%, due to difficulties in early detection and limited therapeutic options. Although lncRNAs play important roles in cancer, they have not been extensively studied in PDAC. The goal of this study is to identify PDAC-related lncRNAs and characterize their functions in pancreatic cancer cells. Recently, we identified a potentially important lncRNA, PANCRNA1 (pancreatic cancer RNA 1), in PDAC progression through re-annotation of whole genome transcript RNA sequencing data of PDAC tissue samples from sequence read archive (SRA). Overexpressed candidates were determined in both early stage and metastatic PDAC tissue samples. PANCRNA1 shows a statistically significant higher expression profile in PDAC tissue samples. Its expression in different pancreatic cancer cell lines was confirmed (BxPC-3, MiaPaca-2 and Panc-1) by RT-qPCR. In order to investigate the effect of PANCRNA1 on pancreatic cancer cells, its expression was transiently knocked down using targeting siRNA. Statistically significant changes were reported on cell phenotype by measuring the rate of cell proliferation and motility. PANCRNA1 knock down reduced proliferation and cell motility in wound healing assays as compared to scrambled siRNA controls. To determine potential mechanisms underlying the observed effects of PANCRNA1 on pancreatic cancer cells, changes in epidermal growth factor receptor (EGFR) signaling, which contributes to pancreatic tumor cell proliferation, evasion of apoptosis, angiogenesis and metastasis were investigated. Knock down of PANCRNA1, decreased both EGFR transcript and protein levels. These results provide the first evidence for the expression and the function of PANCRNA1 in pancreatic cancer and the motivation for future studies to further elucidate its mechanisms of action and determine its possible application as a marker and target.
Citation Format: Husna Karaboga, Philip Jonsson, Yu Liu, Chin-Yo Lin. Long noncoding RNA PANCRNA1 is a novel regulator of cell growth and motility in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A07.
Abstract A08: A novel lncRNA RGMB-AS inhibit NSCLC metastasis via upregulating the expression of target gene RGMB
Authors: Li Jin , Xiaoshun Shi , Jianxing He 
Published: May 2016

Abstract
Background: The relationships between long noncoding RNA (lncRNAs) and tumors have currently become one of the focuses on cancer studies. Our previous studies found repulsive guidance molecule b (RGMB) was downregulated in lung cancer which is associated with poor prognosis and cancer metastasis.The present study investigated the regulation of RGMB expression by lncRNA RGMB-AS and its role in lung cancer progression.
Methods: The expression of lncRNA RGMB-AS and RGMB were detected in 56 paired NSCLC tissues and adjacent normal tissues by qRT-PCR assay. The relations of lncRNA RGMB-AS and RGMB expression with clinicopathological factors of NSCLC patients were explored. The lncRNA RGMB-AS was downregulated and overexpressed in A549 and H1299 cells, and its role in lung cancer was further investigated in vitro and in vivo.
Results: The results of qRT-PCR showed that lncRNA RGMB-AS expression was significantly downregulated in NSCLC tissues than in adjacent normal tissues (P &lt; 0.05). Correlation analysis indicated that the expression of lncRNA RGMB-AS and RGMB mRNA were positively correlated (P &lt; 0.05). The downregulation of lncRNA RGMB-AS in NSCLC tissues were associated with poor overall survival status(P &lt; 0.05). Downregulation of lncRNA RGMB-AS in A549 and H1299 cells subsequently results in reduced RGMB mRNA and protein expression. The downregulation/overexpression of lncRNA RGMB-AS significantly promoted/inhibited NSCLC cells metastasis in vitro and in vivo.
Conclusion: We identified lncRNA RGMB-AS which was downregulated in NSCLC patients and thereby to reduce RGMB expression. lncRNA RGMB-AS might inhibit lung cancer metastasis via the regulation on RGMB and other tumor suppressors.
Citation Format: Jin Li, Shi Xiaoshun, He Jianxing. A novel lncRNA RGMB-AS inhibit NSCLC metastasis via upregulating the expression of target gene RGMB. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A08.
Abstract A10: LncRNA MIR222HG transcribed from the miR-221/222 promoter are associated with the development of castration resistant prostate cancer
Authors: Qu Fangfang , Sun Tong , Wang Xiaodong , Lee Gwo-Shu Mary , Kantoff Philip W. 
Published: May 2016

Abstract
We previously found that microRNA-221 and 222 play a crucial role in regulating the AR function during the castration resistant prostate cancer (CRPC) development. We further investigated mechanisms involved in the differential expression of miR-221/222 in prostate cancer cell lines. Based on transcriptome and histone modification data, we recognized a putative promoter region located at 23.3 kb upstream of the miR-221/222. By further characterizing transcriptional events occurred in this promoter region, we identified a two- exonic, polyadenylated long non-coding RNA (lncRNA), MIR222HG. Forced over-expression MIR222HG significantly increased androgen-independent cell growth and repressed DHT induced PSA expression in LNCaP cells, a hallmark of CRPC phenotype. Expression level of MIR222HG is significantly associated with human prostate cancer progression from localized hormone sensitive prostate cancer (HSPC) to CRPC. Taken together, lncRNA MIR222HG, which is co-transcribed from miR-221/222 promoter region, mediated AR transcriptional regulation and may involved in transformation process from HSPC to CRPC. Further study on MIR222HG may help understand the CRPC development processes.
Citation Format: Fangfang Qu, Tong Sun, Xiaodong Wang, Gwo-Shu Mary Lee, Philip W. Kantoff. LncRNA MIR222HG transcribed from the miR-221/222 promoter are associated with the development of castration resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A10.
Abstract A26: Importance of long noncoding RNAs in human papillomavirus-related cancers
Authors: Barr Jamie A. , Hayes Karen E. , Martinez Ivan 
Published: May 2016

Abstract
The objective of this study is to identify the importance of long non-coding RNAs (lncRNAs) in the induction of carcinogenesis by high-risk human papillomavirus (HPV)-16 oncoprotein E6 in HPV-related cancers. Dysregulation of long non-coding RNAs (lncRNAs) occurs in most human cancers, however, there are only a few studies showing dysregulation of specific lncRNAs in human papillomavirus (HPV)-related cancers. High-risk HPV infection (e.g. HPV-16 and HPV-18) is one the most common causes of cervical cancer, as well as a subset of head and neck squamous cell carcinoma (HNSCC). It is well known that one of the main factors contributing to HPV-related carcinogenesis is the expression of high-risk HPV E6 viral oncoprotein and its interaction with several human proteins, such as the tumor suppressor p53 and the anti-apoptotic protein Bak. It is hypothesized that HPV-16 E6 changes the expression of host lncRNAs to regulate downstream processes important in the induction of carcinogenesis. To test this hypothesis, we stably express high-risk HPV-16 E6 in primary human keratinocytes and conducted high-throughput RNA sequencing analysis to identify HPV-16 E6-mediated changes in lncRNAs expression. Our preliminary data shows over 500 lncRNAs up- or down- regulated by greater than 2-fold with the expression of HPV-16 E6 compared to control. We validated the expression changes of many individual lncRNAs after the expression of HPV-16E6, via q-RT-PCR and Northern blots. In addition we observe similar expression patterns when comparing normal cells to HPV+ cervical cancer cell lines. Currently, we are characterizing specific lncRNAs of interest that are altered with expression of HPV-16 E6 by using 5' and 3' rapid amplification of cDNA ends (RACE) experiments as well as determining certain lncRNA's mechanism of action contributing to cancer by conducting knockdown and rescue experiments followed by behavior assays (e.g. invasion, angiogenesis, and proliferation). To aid in the determination of the function of the lncRNAs, we plan to use Fluorescence in situ Hybridization (FISH) assays to identify their localization. We believe this project will be significant in that it will identify and show the importance of lncRNAs in HPV-related cancers as well as give us new information about a novel mechanism by which high-risk HPV infection contributes to cervical and HNSCC carcinogenesis.
Citation Format: Jamie A. Barr, Karen E. Hayes, Ivan Martinez. Importance of long noncoding RNAs in human papillomavirus-related cancers. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A26.
Abstract A41: A single let-7 microRNA bypasses LIN28-mediated repression
Authors: Triboulet Robinson , Pirouz Mehdi , Gregory Richard I. 
Published: May 2016

Abstract
The let-7 miRNA family members are small non-coding RNAs that function as tumor suppressors and are frequently down-regulated in many different types of cancers upon reactivation of LIN28 oncogenes. Mammalian genomes contain twelve let-7 isoforms that suppress expression of a common set of target mRNAs comprising key oncogenes and mitotic regulators. LIN28 proteins selectively block let-7 biogenesis postranscriptionally. The current model for coordinate let-7 repression involves the LIN28 cold shock domain (CSD) binding the terminal loop and the two CCHC-type zinc fingers recognizing a GGAG sequence motif in precursor let-7 (pre-let-7) RNAs. Here we perform a systematic analysis of all let-7 miRNAs and find that a single let-7 family member, human let-7a-3 (and its murine ortholog let-7c-2), escapes LIN28-mediated regulation. Mechanistically, we find that the pre-let-7c-2 loop precludes LIN28A binding and regulation. These findings refine the current model of let-7 regulation by LIN28 proteins and have important implications for understanding the LIN28/let-7 axis in cancer.
Citation Format: Robinson Triboulet, Mehdi Pirouz, Richard I. Gregory. A single let-7 microRNA bypasses LIN28-mediated repression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A41.