bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5041: Translational pharmacokinetic-pharmacodynamic xenograft model for TAK-931, a small molecule cell division cycle 7 (CDC7) kinase inhibitor
Authors: Locuson Charles , Patel Mayank , Ohashi Akihiro , Iwai Kenichi , Nambu Tadahiro , Takeuchi Toshiyuki , Kogame Akifumi , Bowman Douglas , Tirrell Stephen , Niu Huifeng , Xia Cindy 
Published: July 2017

Abstract
TAK-931 is a small molecule inhibitor of the cell division cycle 7 (CDC7) kinase. As a serine/threonine kinase that contributes to DNA replication and the DNA damage response, CDC7 is hypothesized to be a promising cancer drug target. CDC7 inhibition with TAK-931 has demonstrated antiproliferative activity with cancer cell lines and tumor growth inhibition (TGI) in murine ectopic xenograft models. Herein, the analysis of multiple models to characterize pharmacokinetic (PK) and pharmacodynamic (PD) relationships with xenograft TGI is described. TAK-931 treatment-induced TGI was dose schedule-independent and could be described using plasma drug concentrations or tumor PD inhibition. However, the efficacious doses were at least 10-fold higher for the PK-TGI relationship than for the PD-TGI relationship. This discrepancy was used to select a dynamic PK-PD-TGI modeling approach to project the minimal efficacious dose (MED) and minimal biological active dose (MBAD) for TAK-931 due to the large differences in time-concentration profiles predicted for humans versus mice. The Phase I human trial is on-going and will be used to verify the dynamic PK-PD-driven modeling approach for the CDC7 inhibitor.
Citation Format: Charles Locuson, Mayank Patel, Akihiro Ohashi, Kenichi Iwai, Tadahiro Nambu, Toshiyuki Takeuchi, Akifumi Kogame, Douglas Bowman, Stephen Tirrell, Huifeng Niu, Cindy Xia. Translational pharmacokinetic-pharmacodynamic xenograft model for TAK-931, a small molecule cell division cycle 7 (CDC7) kinase inhibitor [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 5041. doi:10.1158/1538-7445.AM2017-5041
Abstract 505: Somatic and inherited riboSnitches in TPT1 and LCP1 mRNA secondary structures
Authors: Lackey Lela L. , Coria Aaztli , Tolson Chanin , McArthur Evonne , Laederach Alain 
Published: July 2017

Abstract
RiboSnitches are single nucleotide variants that change the secondary structures of RNA. These structural changes can have a regulatory or functional impact on the RNA. Many inherited single nucleotide variants function as riboSNitches. We wanted to investigate the potential of somatic mutations to act as riboSNitches. We determined the secondary structure of two cancer-associated mRNAs, TPT1 and LCP1, using the chemical probing SHAPE-Map technique. Both of these mRNAs are highly structured and have similar folds in vivo and in vitro. We analyzed the structural impact of all the synonymous somatic mutations identified in the COSMIC cancer sequencing database for both TPT1 and LCP1 mRNAs. In TPT1 we also tested several inherited variants. We found that both somatic and inherited variants can be riboSNitches, at approximately the same ratio. Our results are in accord with previous work indicating that ~15% of SNVs are capable of acting as riboSNitches. Although the impact of non-coding and synonymous somatic mutations are difficult to measure, it is becoming clear that these mutations can contribute to cancer progression and phenotype. The majority of our identified riboSNitches are detrimental according to FATHMM-MKL functional impact prediction. Our experiments indicate that a substantial fraction of somatic mutations can cause a measurable change to RNA structure, potentially changing the regulatory or functional behavior of that mRNA.
Citation Format: Lela L. Lackey, Aaztli Coria, Chanin Tolson, Evonne McArthur, Alain Laederach. Somatic and inherited riboSnitches in TPT1 and LCP1 mRNA secondary structures [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 505. doi:10.1158/1538-7445.AM2017-505
Abstract 506: The role of Nek2 in hepatocellular carcinoma
Authors: Vincent Chan Shing Ho 
Published: July 2017

Abstract
Cancer is a disease of aging. Among different types of cancer, liver cancer is one of the most prevalent cancers over the world and particularly affects people in some East Asia countries such as Korea, Japan and China. The NIMA-related kinase 2 (Nek2), which regulates centrosome cohesion, is a potential player in carcinogenesis. Our evidence showed Nek2 mRNA and protein levels are overexpressed in liver cancer cells and promotes HCC cell growth. Since Nek2 is pertinent to centrosome, we speculated that it might take part in centrosome regulation. To study the effect of Nek2 in chromosomal instability, centrosome splitting and cell cycle, a stable isoform Nek2A overexpression inducible system was generated in different Hepatocellular Carcinoma cell lines for investigations through immunofluorescent staining and cell-cytometry. For the study of centrosome, we observed that higher proportion of cells with centrosome splitting occurred in the Nek2A overexpressing cells in both HepG2 and SMMC-7721 inducible cell lines. Moreover, cell cycle analysis showed an increased content of DNA when Nek2A is overexpressed, suggesting that Nek2A induces more aneuploidy cells. To conclude, overexpression of Nek2 exacerbates chromosomal instability. Dysregulation of centrosome may be the key for understanding of regulatory mechanism of chromosomal instability by Nek2.
Citation Format: Chan Shing Ho Vincent. The role of Nek2 in hepatocellular carcinoma [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 506. doi:10.1158/1538-7445.AM2017-506
Abstract 5061: TET inhibits prostate cancer tumor growth, progression and metastasis in TRAMP mice
Authors: Koul Hari K. , Shanmugam Prakash Srinivasan Timiri , Jaiswal Praveen K. , Koul Sweaty 
Published: July 2017

Abstract
Introduction: Prostate cancer (PCa) is the 2nd most common malignancy in USA. Novel agents for treatment of advanced PCa are warranted. Transgenic adenocarcinoma of the mouse prostate (TRAMP) is an autochthonous mouse model exhibits both histological and morphological features that mimic human prostate carcinogenesis. Herein, for the first time, we evaluated the in vivo effects of TET, a derivative of Tetrandrine in TRAMP model.
Methods: Beginning 12 weeks of age, male TRAMP mice were administrated with TET (30 mgm/kg body weight, orally, alternative days) in PBS or PBS alone (Control) till 30 weeks of age. Body weight (B) of animals was recorded weekly. At various time points animals were euthanized, genitourinary tract (G) were weighed. Prostate tissue was subjected to immunohistochemical analyses for SV40-TAg, epithelial-mesenchymal transition (EMT), proliferation, neuroendocrine differentiation (NED) and apoptosis. Multiple organs were examined for drug toxicity and lungs were analyzed for metastasis.
Results: TRAMP mice exhibit to high-grade prostatic intraepithelial neoplasia (PIN) by 12 weeks and progresses to poorly differentiated adeno-carcinoma by 30 weeks with distant metastasis to lungs. TET feeding did not show any considerable difference body weight loss profiles during the entire treatment regimen. At the time of necropsy, there was no evidence of edema, abnormal organ size or appearance in non-target organs. TET gavage group showed (p&lt;0.005) lower G/B ratio compared to the PBS treated group. These findings clearly indicate that TET dosing is non-toxic and restricts the abnormal growth of the prostate in TRAMP mice. TET repress the EMT as well as NED transition and inhibits cell proliferation (p&lt;0.005) by Ki-67 staining. Oral administration of TET inhibits PCa growth and progression by increases (p&lt;0.005) apoptosis in tumor tissues. Further, TET inhibited metastasis as there was significant (p&lt;0.005) decrease in metastasis to lungs in TET treated animals.
Conclusion: Human achievable dose of TET treatment to TRAMP mice bearing prostate tumor, exhibited no-observed-adverse-effect-level in toxicology evaluations and also significantly inhibited tumor growth, progression, local invasion and distant metastasis involving suppression of tumor, and thus could have potential against human PCa.
Citation Format: Hari K. Koul, Prakash Srinivasan Timiri Shanmugam, Praveen K. Jaiswal, Sweaty Koul. TET inhibits prostate cancer tumor growth, progression and metastasis in TRAMP mice [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 5061. doi:10.1158/1538-7445.AM2017-5061
Abstract 5065: Harnessing epigenetic reprogramming by histone deacetylase inhibitor MS275 for pancreatic cancer therapy
Authors: Liang Gaoyang , Yu Ruth , Liddle Christopher , Truitt Morgan , Antal Corina , Atkins Annette , Banayo Ester , Downes Michael , Evans Ronald 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 85% of pancreatic cancer and is one of the most lethal malignancies with limited therapeutic options. Chromatin-modulating small molecules, or epigenetic drugs, have the ability to reprogram cell fate and alter disease phenotypes. The potential of these drugs for PDAC therapy remains to be fully investigated. Screening a panel of epigenetic drugs identified MS275 (MS, also called entinostat), a histone deacetylase inhibitor, as capable of suppressing PDAC cell proliferation and inhibiting stromal fibrosis. Genome-wide expression analysis revealed that MS extensively reprograms the transcriptomes of tumor cells and cancer-associated fibroblasts (CAFs). In tumor cells, MS downregulates genes important for cell cycle progression inducing cytostasis. In CAFs, MS specifically represses the profibrotic transcription program responsive to TGF-beta, effectively inhibiting the fibrotic response. Consistent with this, MS blocks the activation of pancreatic stellate cells, the primary source for CAFs in PDAC, to repress the fibroblast-like phenotypes in these cells. Using an orthotopic transplantation model, we confirmed that MS treatment reduces tumor cell proliferation and decreases intratumoral fibrotic content. Importantly, we showed that MS substantially enhances chemocytotoxicity, synergizing with gemcitabine to reduce tumor burden in PDAC mouse models. Our study establishes a novel therapeutic strategy for PDAC based on epigenetic reprogramming induced by HDAC inhibition.
Citation Format: Gaoyang Liang, Ruth Yu, Christopher Liddle, Morgan Truitt, Corina Antal, Annette Atkins, Ester Banayo, Michael Downes, Ronald Evans. Harnessing epigenetic reprogramming by histone deacetylase inhibitor MS275 for pancreatic cancer therapy [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 5065. doi:10.1158/1538-7445.AM2017-5065
Abstract 5074: Therapeutic targeting of bromodomain and extra-terminal proteins degradation in triple-negative breast cancer
Authors: Bai Longchuan , Zhou Bing , Yang Chao-Yie , Ji Jiao , McEachern Donna , Przybranowski Sally , Wang Shaomeng 
Published: July 2017

Abstract
Triple negative breast cancer represents the most clinically challenging subtypes of breast cancer for which targeted therapeutics are still lacking. BET proteins have emerged as new therapeutic targets for human cancer and other diseases.We have developed a highly potent BET degrader, BETd-246, with an exceptional selectivity based upon a new class of BET inhibitor, BETi-211, and investigated its therapeutic potential and mechanisms of action in TNBC. BETd-246 induces degradation of BET proteins at low nanomolar concentrations within 1 hour, leading to potent anti-proliferative activity and strong apoptosis induction in the majority of TNBC cell lines, and is much more effective than the BETi-211 treatment. RNA-seq analysis reveals that degradation of BET proteins by BETd-246 elicits distinct transcriptional response than BET BD inhibition in TNBC cell lines. Transcriptomic analysis also shows a number of proliferation and survival-related genes were differentially regulated by BETd-246 and BETi-211 which were confirmed by quantitative RT-PCR. Mechanistically, down-regulation of MCL1 by BETd-246 plays a key role in the robust apoptosis induction in TNBC cell lines. In in vivo models, BETd-246 effectively degrades BET proteins and suppresses MCL1 expression in xenograft tumor tissues and exhibits a strong antitumor activity at well-tolerated dose-schedules in mice. Our data strongly suggest that targeting BET protein degradation is an exciting therapeutic strategy for TNBC.
Citation Format: Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Shaomeng Wang. Therapeutic targeting of bromodomain and extra-terminal proteins degradation in triple-negative breast 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 5074. doi:10.1158/1538-7445.AM2017-5074
Abstract 5078: EZH2 methyltransferase regulates disseminating tumor cells in breast cancer metastasis
Authors: Yomtoubian Shira , Ryu Seongho , Lee Sharrell , Markowitz Geoff , Gao Dingcheng , Mittal Vivek 
Published: July 2017

Abstract
Triple negative breast cancer (TNBC, ER-, PR-, HER2-) exhibits the worst outcome due to higher rates of metastasis compared to non TNBC subtypes. Despite this clinical significance, there is a conspicuous lack of FDA approved molecularly targeted anti-metastatic therapies for TNBC. The enhancer of zeste homolog 2 (EZH2), a catalytic core subunit of the Polycomb repressive complex 2 (PRC2) with histone methyltransferase (HMT) activity is associated with the worst clinical outcome in breast cancer patients. Using a combination of genetic and pharmacological approaches, we show that EZH2 HMT blockade did not impact primary tumor growth, but significantly reduced distal metastases. Metastasis suppression was associated with a marked reduction of tumor-initiating cells (TICs) in primary tumor, circulating tumor cells (CTCs) in the blood and impaired lung colonization. Using a SOX2/OCT4 promoter reporter system, we identified EZH2-sensitive metastatic cells with GATA3 low luminal progenitor phenotypes in the primary tumor, and EZH2 HMT blockade restored GATA3 expression, promoted differentiation of luminal progenitors and impaired metastasis. These key preliminary findings have led to the hypothesis that EZH2 promotes metastasis, and that inhibition of EZH2 HMT may constitute a viable anti-metastatic approach. We will also discuss the potential of EZH2 inhibition in combination with chemotherapy as an effective strategy against TNBC metastasis.
Citation Format: Shira Yomtoubian, Seongho Ryu, Sharrell Lee, Geoff Markowitz, Dingcheng Gao, Vivek Mittal. EZH2 methyltransferase regulates disseminating tumor cells in breast cancer metastasis [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 5078. doi:10.1158/1538-7445.AM2017-5078
Abstract 5096: Targeted ablation of essential oncogenes in rhabdomyosarcoma with CRISPR/Cas9 gene therapy
Authors: Phelps Michael , Yang Heechang , Chen Eleanor 
Published: July 2017

Abstract
Targeted therapy seeks to exploit unique vulnerabilities in cancer cells not present in normal tissue. The development of effective therapies targeting essential tumor proteins has had significant challenges particularly for tumor oncogenes many of which have proven “undruggable”. Targeting these critical tumor oncogenes has been one of the foremost challenges in cancer research. Current sequencing technology facilitates rapid identification of novel cancer mutations yet there are no effective therapeutic strategies aimed at targeting essential cancer genes at the genome level. To overcome the challenges associated with targeting “undruggable” cancer proteins, we have employed high efficiency CRISPR/Cas9 genome editing technology to destroy cancer cells by directly targeting the genomic DNA of essential cancer genes. We used pediatric rhabdomyosarcoma to demonstrate the potential of CRISPR/Cas9 gene therapy in solid tumor preclinical xenograft mouse models. Rhabdomyosarcoma is an aggressive pediatric sarcoma characterized by myogenic differentiation arrest. The two major subtypes of rhabdomyosarcoma (RMS), embryonal (ERMS) and alveolar (ARMS) are defined largely by either activation of the RAS pathway (ERMS) or the presence of a fusion oncogene between PAX3 and FOXO1 (ARMS). CRISPR/Cas9 was first used to target critical exons in the activated RAS or PAX3/FOXO1 oncogenes unique to each RMS subtype, using inducible or viral CRISPR delivery systems. Targeting these essential genes resulted in significant regression of tumor xenografts due to a combination of cell death and differentiation. By precisely targeting the activating mutations in the RAS oncogene or the fusion site in the PAX3/FOXO1 fusion gene we further demonstrate that tumor-specific CRISPR/Cas9-mediated gene therapy can also be achieved. This strategy disrupts the essential cancer oncogenes with minimal impact to normal cells that do not harbor the unique cancer mutations. Our results highlight the utility of exploiting essential cancer genetic mutations for personalized therapy. This novel approach to cancer therapy provides a potential alternative strategy for targeting “undruggable” oncogenes while establishing a foundation for further development of CRISPR/Cas9 gene therapy for cancer treatment
Citation Format: Michael Phelps, Heechang Yang, Eleanor Chen. Targeted ablation of essential oncogenes in rhabdomyosarcoma with CRISPR/Cas9 gene therapy [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 5096. doi:10.1158/1538-7445.AM2017-5096
Abstract 5108: Potent small molecule compounds that selectively inhibit proliferation of ABC-DLBCL cell lines
Authors: Satyam Leena Khare , Chikkanna Dinesh , Khairnar Vinayak , Pothuganti Manoj , Panigrahi Sunil , Lakshminarasimhan Anirudha , Rao Narasimha , Balasubramanian Wesley , Patil Sandeep , Gopinath Sreevalsam , Upendra Gunta , Nagaraj Jwala , Aithal Kiran , Ahuja Vijay , Giri Sanjeev , Pandit Chetan , Ramachandra Murali 
Published: July 2017

Abstract
Diffuse large B cell lymphoma (DLBCL), which accounts for 25% of all lymphomas cases, has been classified into molecular subtypes including germinal center B cell like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal B cell lymphoma (PMBL). Among these subtypes, patients with ABC-DLBCLs have the worst prognosis because of the high chemo-resistance, and require effective therapies.
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 (MALT1) protease activity is linked to the pathogenesis of ABC-DLBCL. Therefore, a focused library of covalent compounds selected based on molecular docking on the reported crystal structure was screened for selective sensitivity to ABC-DLBCL, but not GCB-DLBCL cell lines. Optimization of initial hits resulted in the identification of lead compounds with an anti-proliferative EC50 of &lt;100 nM selectively in ABC-DLBCL cell lines. Consistent with the previously reported role of MALT1 inhibitors, lead compounds also showed anti-proliferative activity in selected melanoma and NSCLC cell lines. The anti-proliferative activity of the lead compounds correlated well with the inhibition IL-6, a downstream marker of MALT1 signaling, in ABC-DLBCL cell line such as OCI-LY3. The lead compounds exhibited excellent drug-like properties including solubility, metabolic stability, lack of CYP inhibition, permeability and desired dose-dependent oral exposure in pharmacokinetic studies. In a repeated dose MTD study, the lead compounds showed good tolerability with an exposure multiple of &gt;10 over cellular EC50 for up to 8 hours. The lead compounds showed dose-dependent tumor growth inhibition in a xenograft model upon oral dosing.
In summary, we have identified novel and potent MALT1 inhibitors capable of selectively inhibiting proliferation of DLBCL cell lines with optimized drug-like properties including oral bioavailability. The data presented here strongly support further development of these compounds for DLBCL and other indications.
Citation Format: Leena Khare Satyam, Dinesh Chikkanna, Vinayak Khairnar, Manoj Pothuganti, Sunil Panigrahi, Anirudha Lakshminarasimhan, Narasimha Rao, Wesley Balasubramanian, Sandeep Patil, Sreevalsam Gopinath, Gunta Upendra, Jwala Nagaraj, Kiran Aithal, Vijay Ahuja, Sanjeev Giri, Chetan Pandit, Murali Ramachandra. Potent small molecule compounds that selectively inhibit proliferation of ABC-DLBCL cell lines [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 5108. doi:10.1158/1538-7445.AM2017-5108
Abstract 5113: Usnic acid, lichen secondary metabolite, inhibits glioblastoma progression through the reduction of epithelial-mesenchymal transition and glioma stemness factors
Authors: Lee Kyung-Hwa , Oh Se-Jeong , Jung Shin , Kim Kyung-Keun , Lee Jae-Hyuk , Moon Kyung-Sub 
Published: July 2017

Abstract
Background: Usnic acid (UA), an active compound mainly found in lichens, has shown some anti-tumoral activities for lung and breast cancers. The therapeutic role of UA in glioblastoma (GM) have not yet been determined, nor has the definitive relationships of UA with EMT and cancer stem cells.
Methods: We tested the anti-tumoral activities of UA against glioblastoma (GM) progression and further investigated the mechanistic link with epithelial-mesenchymal transition (EMT) and cancer stemness factors. The targeting and anti-tumor effect of UA was also checked in orthotopic mouse glioma model.
Results: In vitro assay, we found that UA increased apoptotic cell death and inhibited the invasion/migration of GM cells. Sphere and colony forming abilities were also decreased in treated GM cells. UA decreased the expression of the EMT markers (N-cadherin, ZEB1, ZEB2, SNAIL and SLUG) and the cancer stemness markers (CD133, ALDH1 and CD44). In orthotopic mouse glioma models, UA localized in GBM and significantly decreased tumor growth and progression to lead longer survival.
Conclusion: Taken together, these findings showed that UA prevent GBM invasiveness and progression, through the down-regulation of EMT and cancer stemness markers.
Citation Format: Kyung-Hwa Lee, Se-Jeong Oh, Shin Jung, Kyung-Keun Kim, Jae-Hyuk Lee, Kyung-Sub Moon. Usnic acid, lichen secondary metabolite, inhibits glioblastoma progression through the reduction of epithelial-mesenchymal transition and glioma stemness factors [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 5113. doi:10.1158/1538-7445.AM2017-5113