tbuckley/cabot-search huggingface dataset:
Abstract 1466: QKI, a miRNA-200 target gene, suppresses epithelial-to-mesenchymal transition in oral squamous cell carcinoma cells
Authors: Yoon Ho Ko, Eun Ju Kim, Der Sheng Sun, Hye Sung Won, Young-Ho Ahn
Journal: Cancer Research (2017)

Abstract Objectives: The microRNA (miR)-200 family plays a major role in specifying the epithelial phenotype by preventing expression of the transcription repressors, ZEB1 and ZEB2, which are well-known regulators of epithelial-to-mesenchymal transition (EMT) in epithelial tumors including oral squamous cell carcinoma (OSCC). Here, we elucidated whether the miR-200 family members control RNA-binding protein quaking (QKI) which is a newly identified tumor suppressor and is regulated during EMT. Methods: We predicted that miR-200a and miR-200b could recognize QKI 3’-UTR by analyzing TargetScan and TCGA head and neck SCC dataset. To further verify the role of miR-200 on QKI in HNSCC, we carried out the functional study in CAL27 and HSC3 cells. Results: Forced expression of miR-200b/a/429 inhibited the expression of ZEB1 and ZEB2, and decreased cell migration in CAL27 and HSC3 cells. QKI expression was also suppressed by miR-200 over-expression, and the 3’-UTR of QKI mRNA was directly targeted by miR-200 in luciferase reporter assays. Interestingly, shRNA-mediated knockdown of QKI led to pronounced EMT and pro-tumor effects in vitro and in vivo studies of OSCC. Conclusion: QKI increases during EMT and is targeted by miR-200; while, it suppresses EMT and tumorigenesis, contradictorily. We suggest that QKI and miR-200 could form a balancing feedback loop maintaining homeostatic responses to EMT-inducing signals. Citation Format: Yoon Ho Ko, Eun Ju Kim, Der Sheng Sun, Hye Sung Won, Young-Ho Ahn. QKI, a miRNA-200 target gene, suppresses epithelial-to-mesenchymal transition in oral squamous cell carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1466. doi:10.1158/1538-7445.AM2017-1466
Abstract LB-317: Identification of a novel preclinical candidate for CDK7 inhibition
Authors: Leena K. Satyam, Ramulu Poddutoori, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Aravind Basavaraju, Lakshmi Narayana Kaza, Manoj Kumar Pothuganti, Shilpa Nayak, Nandish C, Amith A, Ravindra MV, Dabbeeru Madhu Babu, Nagaraju A, Suraj Tgore, Thomas Antony, Chetan Pandit, Murali Ramachandra, Shekar Chelur, Girish Daginakatte, Susanta Samajdar
Journal: Cancer Research (2017)

Abstract Cyclin-dependent kinase 7 (CDK7) is an important constituent of the cellular transcriptional machinery, where it phosphorylates the C-terminal domain (CTD) of RNAP polymerase II (RNAPII). Because many tumor types are critically dependent on transcription for maintenance of their oncogenic state, pharmacological modulation of CDK7 kinase activity is considered as an approach to treat cancer. Multiple series of covalent CDK7 inhibitors were identified by iterative medicinal chemistry efforts and SAR based approach. These compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile to achieve anti-tumor activity. We have now identified a pre-clinical candidate AU-BGB-002 which is highly potent in inhibiting CDK7 in biochemical as well as cellular assays while fully efficiently engaging the target. In a panel of kinases, AU-BGB-002 shows selectivity for CDK7. A panel of cell lines derived from a diverse set of indications are sensitive to AU-BGB-002. AU-BGB-002 exhibits excellent drug-like characteristics including solubility, permeability, metabolic stability and good oral bioavailability. When tested in a xenograft model, AU-BGB-002 treatment resulted in dose dependent tumor growth inhibition in AML xenograft model with tumor stasis at a dose of 10 mg/kg. Potent inhibiton of tumor growth was accompanied by complete target engagement and suppression of pS5RNAPII RNAPolII Ser5 phosphorylation in a parallel PK-PD study. Efficacy studies in additional xenograft models, advanced DMPK and toxicity studies are ongoing for this compound. In summary, we have identified a novel and selective CDK7 covalent inhibitor candidate with desirable drug-like properties that shows excellent efficacy in an AML xenograft model. Findings presented here support further development of AU-BGB-002 for the treatment of cancer. Citation Format: Leena K. Satyam, Ramulu Poddutoori, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Aravind Basavaraju, Lakshmi Narayana Kaza, Manoj Kumar Pothuganti, Shilpa Nayak, Nandish C, Amith A, Ravindra MV, Dabbeeru Madhu Babu, Nagaraju A, Suraj Tgore, Thomas Antony, Chetan Pandit, Murali Ramachandra, Shekar Chelur, Girish Daginakatte, Susanta Samajdar. Identification of a novel preclinical candidate for CDK7 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-317. doi:10.1158/1538-7445.AM2017-LB-317
Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPβ Signaling
Authors: Jinlong Yin, Young Taek Oh, Jeong-Yub Kim, Sung Soo Kim, Eunji Choi, Tae Hoon Kim, Jun Hee Hong, Nakho Chang, Hee Jin Cho, Jason K. Sa, Jeong Cheol Kim, Hyung Joon Kwon, Saewhan Park, Weiwei Lin, Ichiro Nakano, Ho-Shin Gwak, Heon Yoo, Seung-Hoon Lee, Jeongwu Lee, Jong Heon Kim, Soo-Youl Kim, Do-Hyun Nam, Myung-Jin Park, Jong Bae Park
Journal: Cancer Research (2017)

Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. ©2017 AACR.
Abstract 4382: Genomic events associated with metastasis of colorectal cancer by whole-genome sequencing
Authors: Yi Pan, Joanna Tong, Johnny Kwan, Kwok Wai Lo, Anthony Chan, Ka Fai To
Journal: Cancer Research (2017)

Abstract Background: The diversity of the genomic landscape in colorectal cancer (CRC) is under active investigation. Concordance in molecular events between primary CRC and metastatic tumors is a subject of debate. Understanding the genetic background of metastatic CRC facilitates personalized therapies that target specific molecular events associated with the tumor. Methods: We performed whole genome sequencing in matched primary, metastasis and normal tissues from 3 patients with RAS/NRAS/BRAF wild types and microsatellite stable CRC. We implemented an analysis pipeline that integrated the genetic lesions to characterize somatic single nucleotide variations (SNVs), short insertions and deletions (indels), structural variations including fusions and copy number alterations. Results: Both primary and metastatic tumors showed a predominant mutational signature of C: G →T: A transition. A total of 282 non-silent mutations were identified in 3 pairs of CRC (median 63 per tumor, range 42 to 98). There were 148 (52.5%) variants shared in matched primary and metastatic tumors, 63 (22.3%) were found unique to primary and 71 (25.2%) were unique to the metastases. Only common well known genes (APC and TP53) and TTN mutations were found to be recurrent in the 3 patients. A total of 609 (range 33-171 per tumor) structural variants were discovered with 44.1% concordance between primary and metastasis pairs. We also identified 6 novel candidate fusions shared in primary and metastases and 2 private to the primary tumors. Consistent with the result of previous studies, copy loss at chromosome 17p and 18, and gain at chromosome 5, 8 and 13 were the common events both in the primary and metastatic tumor. Discussion and conclusions: Our data demonstrated a considerable difference in mutational landscape between primary CRCs and their matching metastatic tumors. The result suggested that the metastasis might originate from a distinct subclone from a heterogeneous primary tumor, or additional gain or loss of function via mutation to permit tumor invasion and spreading is necessary to facilitate metastasis. Each of the two models is complicated by the possibility of tumor heterogeneity within the primary tumor. In conclusion, comprehensive analysis and assessment for the genomic events is a powerful approach to delve deeper into the internal relations and contradictions between primary and paired metastases, helping to identify novel genomic events associated with metastasis of CRC. Citation Format: Yi Pan, Joanna Tong, Johnny Kwan, Kwok Wai Lo, Anthony Chan, Ka Fai To. Genomic events associated with metastasis of colorectal cancer by whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4382. doi:10.1158/1538-7445.AM2017-4382
Abstract 4018: Identifying allosteric modulators of KRas using second harmonic generation
Authors: Elizabeth Donohue Vo, Gabriel Besserer Mercado, Patrick Alexander, Ben Moree, Que Van, Andrew G. Stephen, Joshua Salafsky, Frank McCormick
Journal: Cancer Research (2017)

Abstract The Ras protein family consists of small GTPases that are critical signaling transducers regulating cellular processes including proliferation, differentiation, and survival. As monomeric GTPases, Ras proteins cycle between an inactive GDP-bound state and an active GTP-bound state. Oncogenic mutations in one of the Ras isoforms, H-, N-, and K-Ras, impair GTP hydrolysis, thus de-regulating Ras signaling. Ras mutations are found in one-third of human cancers, and tumors bearing these mutations are notoriously difficult to treat. Conventional approaches to inhibit Ras with small molecules have been largely unsuccessful leading many to characterize the Ras family as an “undruggable” target. However, there is renewed enthusiasm towards Ras drug discovery in response to a recent surge of reports revealing structural complexities to Ras proteins that provide opportunity for innovative drug discovery efforts. In light of findings suggesting KRas contains transient and dynamic binding pockets, many of which are undetectable with traditional structural techniques, we used a second harmonic generation (SHG) platform to screen a ~2700 chemically diverse fragment collection for allosteric modulators of KRas. This high throughput SHG platform enables real-time measurement of protein conformational change under physiological conditions. We selected ~50 fragments for validation by SPR, and positive binders will be selected for structural and biochemical characterization. Another advantage of the SHG platform is that we can monitor the conformational dynamics of fully processed, farnesylated KRas bound to a phosphatidylserine-enriched membrane that mimics KRas’ physiological interaction with the plasma membrane. No other biophysical method is suitable to monitor the real-time interactions of small molecules or proteins with membrane-bound KRas. This analysis may reveal surface contacts unavailable in solution-based assays. We have successfully implemented SHG as a drug discovery platform against KRas, and we aim to utilize selected KRas conformational modulators towards the identification of novel binding pockets and towards the development of targeted KRas therapies. Citation Format: Elizabeth Donohue Vo, Gabriel Besserer Mercado, Patrick Alexander, Ben Moree, Que Van, Andrew G. Stephen, Joshua Salafsky, Frank McCormick. Identifying allosteric modulators of KRas using second harmonic generation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4018. doi:10.1158/1538-7445.AM2017-4018
Abstract 5357: OncoGxSelectTM- a beneficial supplement to comprehensive cancer genetic test
Authors: Yang Han, Pengfei Yu, Qingxuan Song, Min Wei, Guanghui Hu
Journal: Cancer Research (2017)

Abstract Genetic profiling of tumor has been widely accepted both in oncology research and clinical field. However, clinical doctors are sometimes overwhelmed by tremendous and complicated information provided by comprehensive genetic tests, although they are welcomed by research-oriented oncologists. In order to provide accurate key findings to aid diagnosis and treatment in clinical practice, a careful tailored NGS based test - OncoGxSelectTM was developed and validated. Targeting 7 popular cancer types (NSCLC, Colorectal cancer, Breast cancer, Melanoma, Thyroid cancer, Esophageal and GIST cancer), OncoGxSelectTM detects all 4 types of genomic alterations including single nucleotide mutation, insertion/deletion, copy number variation and gene rearrangement in tumor tissue for 12 well-characterized clinical actionable genes strictly following NCCN (National Comprehensive Cancer Network) guidelines. OncoGxSelectTM offers high sensitivity and specificity greater than 99%, low cost and fast turnaround time using both DNA and RNA as starting material from FFPE samples with as low as 10% tumor cell content. This CLIA certified and CAP accredited genetic test panel is a valuable supplement to clinical oncologists to further facilitate diagnosis and treatment choosing. Citation Format: Yang Han, Pengfei Yu, Qingxuan Song, Min Wei, Guanghui Hu. OncoGxSelectTM - a beneficial supplement to comprehensive cancer genetic test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5357. doi:10.1158/1538-7445.AM2017-5357
Abstract LB-323: Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2
Authors: Noriaki Sakuragi, Mohamed Kamel Farah, Zeinab Mohamed, Safwat Okasha, Hidemichi Watari, Takashi Mitamura, sherif El Khamisy, Yusuke Ohba
Journal: Cancer Research (2017)

Abstract Ovarian cancer is the most aggressive female reproductive tract tumours. Taxane (TX) is widely used for ovarian cancer treatment. However, ovarian cancer often acquire chemoresistance. MicroRNAs (miR) have been reported to regulate many tumours’ chemoresistance. Here, we investigated the comparative microRNA expression profile between the ovarian cancer cells and their taxane-resistant counterpart, KF-TX to get novel markers for taxane resistance in ovarian cancer. The array data revealed that miR-486, miR143,miR145 and miR363 are the most upregulated miRNAs in association with TX resistance. However, miR-155, miR-100, miR-31 and miR-629 are the most significantly downregulated miRNAs after resistance development. We then focused on the role of miR-363 in chemoresistance of the ovarian cancer. qRT-PCR indicated that miR-363 was upregulated in KF-TX cells, confirming the array data, and introduction of miR-363 into sensitive ovarian cancer cells confers TX-resistance and significantly inhibited the expression of the Hippo member, LATS2, as indicated by viability, clonogenic assays and expression analysis. Furthermore, we validated the role of LATS2 in the TX-response by sh-based silencing, which also confers TX-resistance in the responsive ovarian cancer cells. On the other hand, specific inhibitor against miR-363 restored the response to TX. In addition, miR-363 was found to bind to the 3′-UTR of LATS2 mRNA, confirming that miR-363 directly targets LATS2 as indicated by dual luciferase assay. RT-PCR-based evaluation of miR-363 in a panel of human ovarian tumours revealed its upregulation in most of the tumour tissues identified as resistant while downregulation of the same gene in most of the tissues identified as sensitive ones. Moreover, higher levels of miR-363 in human ovarian cancer specimens were significantly correlated with TX chemoresistance and poor prognosis. Taken together, our study reveals the involvement of miR-363 in chemoresistance by targeting LATS2 in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance. Note: This abstract was not presented at the meeting. Citation Format: Noriaki Sakuragi, Mohamed Kamel Farah, Zeinab Mohamed, Safwat Okasha, Hidemichi Watari, Takashi Mitamura, sherif El Khamisy, Yusuke Ohba. Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-323. doi:10.1158/1538-7445.AM2017-LB-323
Abstract 3498: Characterization of a novel metastatic lung cancer associated lncRNA
Authors: Nicole M. White, Emily B. Rozycki, Ha X. Dang, Christopher A. Maher
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of death worldwide with the majority of patients presenting with metastasis and moreover, developing resistance to current treatments. One promising therapeutic area is the novel class of long noncoding RNAs (lncRNAs). While emerging evidence implicates them in cancer, lncRNA biology is still largely unexplored in tumor metastasis. To elucidate the function of lncRNAs in lung cancer, our lab used transcriptome sequencing (RNA-Seq) to discover 120 long non-coding RNAs (lncRNAs) that are enriched in metastatic tumors compared to their corresponding primary lung tumors, which we have named Metastasis Associated Lung cancer LncRNAs (MALLs). Notably, metastatic tumors were enriched for differentially expressed protein-coding genes targeted by Polycomb Repressive Complex 2 (PRC2). In lung cancer studies show that the catalytic subunit of PRC2, EZH2 (an H3K27 methylase), is overexpressed, associates with poor prognosis, promotes tumor progression, and epigenetically represses genes to promote metastasis. Specifically, we have found MALL-1 to be (i) highly up-regulated in lung cancer; (ii) promotes proliferation and migration/invasion, hallmarks of oncogenic phenotypes; (iii) binds to EZH2; and (iv) cooperatively represses well-known PRC2 target genes associated with metastasis in patients. Further, we found MALL-1 to be altered in multiple solid tumors thus suggesting a critical conserved oncogenic role of MALL-1 in solid tumor progression. We believe MALL-1 promotes aggressive disease through its interactions with, and recruitment of the PRC2 complex to chromatin, to epigenetically modify genes associated with metastasis. Citation Format: Nicole M. White, Emily B. Rozycki, Ha X. Dang, Christopher A. Maher. Characterization of a novel metastatic lung cancer associated lncRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3498. doi:10.1158/1538-7445.AM2017-3498
Abstract 4550: IODNE: an integrated optimization method for identifying the deregulated sub-network for precision medicine in cancer
Authors: Lijun Cheng, Sai Mounika Inavolu, Milan Radovich, Varshini Vasudevaraja
Journal: Cancer Research (2017)

Abstract Background and Purpose: Sub-network analysis can explore complex patterns of the entire molecular pathways and networks for the drug target identification, and therefore drug selection. Computational algorithms are needed to optimize the sub-network search for molecular pathways and networks under certain conditions. Materials and Methods: In the paper, the gene expression profile of a cohort breast cancer patients and protein-protein interaction (PPI) network are integrated with edge score and node score simultaneously. A novel optimization algorithm, IODNE, is developed to search for the optimal de-regulated subnetwork of merging gene and protein network. The application of IODNE is demonstrated for a sub-network of drug target selection in breast cancer subtypes Luminal-A/Luminal-B data from Cancer Genome Atlas (TCGA). Where, the PPI networks data selected from Pathway Commons. Results: IODNE selects sub-networks, which contain ER1/PR and HER2, the well-known targets in clinic Luminal-A/Luminal-B breast cancer subtypes. This validates the utility of IODNE. When applying IODNE to the triple-negative breast cancer subtype data, we identify sub-networks that contain genes such as ERBB2, HRAS, PGR, CAD, POLE and SLC2A1. Conclusion: Using the known drug targets in breast cancer subtypes, we demonstrate that IODNE is a robust and powerful algorithm to identify sub-networks for drug target identification. Based on the gene expression profiles and protein interaction networks, it detects the optimum deregulated subnetwork for the candidate drug target selection. The IODNE is promising tool for the precision medicine. Citation Format: Lijun Cheng, Sai Mounika Inavolu, Milan Radovich, Varshini Vasudevaraja. IODNE: an integrated optimization method for identifying the deregulated sub-network for precision medicine in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4550. doi:10.1158/1538-7445.AM2017-4550