bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 487: MicroRNA regulation of oral squamous cell carcinoma
Authors: Xiao Gary Guishan , Cao Min 
Published: August 2018

Abstract
Oral squamous cell carcinoma (OSCC) remains the sixth most common human cancer with high mortality rate worldwide. Understanding the molecular mechanisms is important for development of an effective treatment for the disease. MicroRNA is a short, noncoded nucleotide playing an important role in tumorigenesis and metastasis. This study is to identify novel microRNAs and their targets in order to understand the molecular mechanisms underlying OSCC and metastasis using label-free proteomics and microRNA microarray techniques. Human oral tissue biopsies from three groups of subjects who had benign, localized carcinoma and distal carcinoma were collected from the archived tissue bank at Pathology in Creighton University. Total RNA and proteins were extracted from the core biopsy of the same subject. MicroRNA identification was performed by using Affymetrix GeneChip miRNA arrays and comprehensive data analysis. Protein was analyzed by using label-free LTQ orbit trap mass spectrometry. Forty-four miRNAs were upregulated significantly, including let-7b, miR-720, miR-21, and miR-1274b, while 41 miRNAs were remarkably downregulated, including miR-195, and miR-932, at localized and distal carcinoma compared to benign tissues. Additionally, as compared to benign, 38 miRNAs upregulated at local carcinoma were downregulated significantly at distal carcinoma, while other 17 miRNAs downregulated significantly at localized carcinoma were upregulated gigantically at distal carcinoma. Those miRNAs were further validated by qRT-PCR and FISH. Among those upregulated at both local and distal, miR-720 was further studied, and tryptase alpha-1 as its target was identified. MicroRNA-720 mimics suppressed significantly the expression of tryptase alpha-1 in cultured human OSCC stem cell lines. Results from miR-720 tissue microarray analysis showed that 98.8% of sensitivity and 100% of specificity for OSCC detection were achieved, suggesting that miR-720 may be developed as a novel biomarker for detection of human OSCC.
Citation Format: Gary Guishan Xiao, Min Cao. MicroRNA regulation of oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 487.
Abstract 4872: ONC201 induction of apoptosis in hPheo1 cell line supports use of this oral agent in ongoing phase 2 clinical trial against neuroendocrine tumors (NCT03034200)
Authors: Proudfit Austin M. , Anderson Peter M. , Gupta Neetu 
Published: August 2018

Abstract
ONC201 is an imipridone that induces TRAIL and causes apoptosis in cancer cell lines, but not normal cells. Recent data shows the dopamine-like DRD2 receptor binds ONC201 and pheochromocytoma-paragangliomas (PC-PG) have &gt;10x more DRD2 than any other human cancer (TCGA data). We present pre-clinical data on dose response and time course of ONC201 against hPheo1, a PC-PG cell line, that support a recently opened phase 2 clinical trial of weekly oral ONC201 in neuroendocrine tumors (NETs) including PC-PG. The human pheochromocytoma cell line, hPheo1, was treated with ONC201 and studied for in vitro anti-cancer activity. Effects on cell viability/proliferation were measured via cell counting with trypan blue exclusion. Post-treatment target-protein levels were assessed via western blotting. Additionally, cells were stained with Annexin V and analyzed using flow cytometry for markers of apoptosis. Upon treatment with ONC201, hPheo1 cells experienced a dose-dependent decrease in cell viability and proliferation with peak effect at 72 h post-treatment (GI50=3.2 μM). Substantial inhibition of pro-survival kinases, Akt and ERK, were confirmed at 72 hours to further support the drug's efficacy and elucidate on a corresponding mechanism of action. The anti-proliferative effects of the drug were gradual over a 96 h time period, rather than an abrupt, intense response. In addition, apoptosis was confirmed at 24 and 96 h, with Annexin V+ cells detectable by FACS. Pre-clinical data show excellent anti-cancer efficacy of ONC201 against PC-PG cells at concentrations achievable in vivo. These findings suggest both anti-proliferative effects and induction of apoptosis lead to anti-cancer activity. The gradual influence of ONC201 on PC-PG cells, rather than rapid cell destruction argues against a scenario where immediate catecholamine release could result in severe hypertension. These pre-clinical data support safe use of ONC201 against PC-PG in vivo and other NETs in our ongoing Phase 2 clinical trial (NCT03034200; investigator-initiated IND132665).
Citation Format: Austin M. Proudfit, Peter M. Anderson, Neetu Gupta. ONC201 induction of apoptosis in hPheo1 cell line supports use of this oral agent in ongoing phase 2 clinical trial against neuroendocrine tumors (NCT03034200) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4872.
Abstract 4879: Mutation selectivity of the allosteric SHP2 inhibitor SHP099
Authors: Sun Xiaojun , Ren Yuan , Gunawan Steven , Teng Peng , Chen Zhengming , Lawrence Harshani R. , Cai Jianfeng , Lawrence Nicholas J. , Wu Jie 
Published: August 2018

Abstract
SHP2 (PTPN11) mediates oncogenic signaling and gain-of-function (GOF) SHP2 mutations are associated with leukemias and other types of cancer. Recently, SHP099 was identified as a novel allosteric SHP2 inhibitor that displayed high potency and selectivity to the wildtype SHP2 in vitro and inhibited protein tyrosine kinase oncogene-driven cancer cells. However, it was unclear whether SHP099 inhibits SHP2 mutants. Using SHP2 mutant-dependent TF-1 leukemia cells, we determined sensitivities of four common oncogenic SHP2 mutants to SHP099. SHP2D61Y-, SHP2A72V-, and SHP2E76K-expressing TF-1 cells were resistant, whereas SHP2E69K-expressing TF-1 cells were sensitive to SHP099 with a potency similar to that of cytokine-stimulated TF-1 cells expressing the wildtype SHP2. Consistently, SHP099 reduced active ERK1/2 and Bcl-XL and induced apoptosis of SHP2E69K-dependent TF-1 cells, but had no effects on the other SHP2 mutant cell lines. SHP2 knockout cells were unresponsive to SHP099, demonstrating specificity. Like the wildtype SHP2, SHP2E69K PTP was inhibited by SHP099 in vitro with a sub-micromolar IC50, whereas micromolar IC50s of SHP099 were observed against SHP2D61Y, SHP2A72V, and SHP2E76K. These results indicate that SHP2D61Y, SHP2A72V, and SHP2E76K mutants are resistant to SHP099 and that SHP2E69K is a SHP099-sensitive oncogenic mutant.
Citation Format: Xiaojun Sun, Yuan Ren, Steven Gunawan, Peng Teng, Zhengming Chen, Harshani R. Lawrence, Jianfeng Cai, Nicholas J. Lawrence, Jie Wu. Mutation selectivity of the allosteric SHP2 inhibitor SHP099 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4879.
Abstract 4880: Novel nano-molar small-molecule STAT3 inhibitor series with antitumor activities against human breast cancer
Authors: Yue Peibin , Lopez-Tapia Francisco , Brotherton-Pleiss Christine , Kubota Casie , Chen Jasmine , Tius Marcus , Turkson James 
Published: August 2018

Abstract
Constitutively-active Signal transducer and activator of transcription (STAT) 3 has been well validated as a significant mechanistic underpinning of many human cancers and a target for anticancer therapy. To date, no small molecule STAT3 inhibitor has been successfully developed for clinical application as a therapeutic agent, despite the discovery of many molecular entities that inhibit the protein. To advance the therapeutic development of small molecule STAT3 inhibitors, we focused on the existing lead compounds, BP-1-102, SH4-54, and SH5-07 (all three showing IC50 of 4-7 μM). All three leads are based on an N-methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. Intensive medicinal chemistry campaign was directed towards understanding and optimizing the molecular determinants critical for enhanced STAT3-inhibitory potency and strong antitumor effects. We report the development of nanomolar potent inhibitors of STAT3 DNA-binding activity. Most notably, the analogs H127, H145, H171, H174, H181, and H182 preferentially inhibit STAT3 activity in DNA-binding assay in vitro, with IC50 of 300 - 800 nM, compared to little or no observed effect on STAT1 and STAT5 DNA-binding activity at concentrations up to 20 μM. Treatment of human breast cancer MDA-MB-231 and MDA-MB-468 cells with H171, H174 or H182 inhibited constitutive STAT3 DNA-binding activity and phosphorylation at Tyr705 in both time- and dose-dependent manner. H171, H174 or H182 further blocked the growth and viability, colony formation, and oncogenic transformation of the human breast cancer cells that harbor persistently active STAT3, with IC50 of 1.0 - 1.9 μM, compared to the IC50 of 3.8 - 8.1 μM against the viability of the immortalized breast epithelial cells that do not harbor persistently active STAT3. These compounds represent some of the first nanomolar potent small molecules observed to directly inhibit STAT3 activity, with potent antitumor cell effects.
Citation Format: Peibin Yue, Francisco Lopez-Tapia, Christine Brotherton-Pleiss, Casie Kubota, Jasmine Chen, Marcus Tius, James Turkson. Novel nano-molar small-molecule STAT3 inhibitor series with antitumor activities against human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4880.
Abstract 4883: Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152
Authors: Kim Hyejin , Dong Jiabin , Xu Jimin , Li Dengfeng , Zheng Zhi , Ye Na , Zhang Ziwei , Chen Haiying , Zhou Jia , Shen Qiang 
Published: August 2018

Abstract
Most mammalian cells use glucose as the primary fuel source. Glucose is metabolized via glycolysis to pyruvate, which is further transferred into mitochondria for generation of ATP through the Krebs cycle in normal condition. However, metabolism is characteristically reprogrammed and cancer cells or highly proliferative cells preferably generate ATP through lactate production by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward anaerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, and disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. HJC0152, a novel small-molecule glucose metabolism modulator, was developed using structure-/fragment-based drug design strategies and molecular modeling techniques. Aggressively growing and metastatic breast cancer cells of triple-negative subtype (MDA-MB-231) treated with HJC0152 showed inhibited cell growth. Intriguingly, HJC0152 decreased activity and protein level of LDHA, which resulted in a decrease of lactate production in breast cancer cells. In addition, these cells also exhibited a decrease of glucose uptake by reducing Glut1 and HK2 protein level and modulation of the expression of glycolytic enzymes. Furthermore, HJC0152 treatment causes decreased mitochondrial membrane energy potential, resulting in significantly reduced level of intracellular ATP in MDA-MB-231 cells. Our findings suggest that HJC0152 is capable of reprogramming caner metabolism by modulating glucose metabolism and ATP production. These results may provide a rationale to develop HJC0152 as an effective therapeutics for cancer and other metabolic diseases with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors responsible for developing breast cancer and other metabolic diseases.
Citation Format: Hyejin Kim, Jiabin Dong, Jimin Xu, Dengfeng Li, Zhi Zheng, Na Ye, Ziwei Zhang, Haiying Chen, Jia Zhou, Qiang Shen. Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4883.
Abstract 4891: Co-inhibition of AXL and FN14 by pharmacologic inhibitors or genetic inhibition in NSCLC mice models
Authors: Suresh Dhananjay , Mukherjee Soumavo , Zambre Ajit , Ghoshdastidar Shreya , Yadavilli Sairam , Upendran Anandhi , Kannan Raghuraman 
Published: August 2018

Abstract
Non-small Cell Lung Cancer (NSCLC) patients who express EGFR activating mutations are treated with tyrosine kinase inhibitors (TKI) and have a median overall survival time of 22 months. TKI therapy showed only moderate success with poor (37%) survival rate. On the other hand, TKI therapy is ineffective in patients with active KRAS mutation. Acquired drug resistance is one of the major reasons for the failure of the TKI therapy. Studies have shown that overexpression of AXL is one of the possible reasons for the drug resistance. In our previous studies, we have shown that AXL inhibition in NSCLC drug-resistant cells resulted in FN14 survival activation. Subsequently, we have demonstrated that co-inhibition of both AXL and FN14 resulted in increased therapeutic efficacy. Based on these studies, we recognize that both AXL and FN14 play important role in proliferation, invasion and survival pathways. Therefore, synergistic co-inhibition of AXL-FN14 is a viable therapeutic strategy for treating NSCLC. In the present study, we compared the efficacy of inhibition of AXL and FN14 by siRNA (using nanoparticle delivery vehicles) and small-molecule inhibitors in A549 mouse xenografts. Our data further confirms that co-inhibition is effective and results in tumor volume reduction. The details of this study provide a rationale for enhanced treatment of drug resistant NSCLC.
Citation Format: Dhananjay Suresh, Soumavo Mukherjee, Ajit Zambre, Shreya Ghoshdastidar, Sairam Yadavilli, Anandhi Upendran, Raghuraman Kannan. Co-inhibition of AXL and FN14 by pharmacologic inhibitors or genetic inhibition in NSCLC mice models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4891.
Abstract 4904: PD-L1 pathway activation as an escape mechanism of resistance to MEK inhibitor treatment in human colorectal cancer models
Authors: Napolitano Stefania , Matrone Nunzia , Belli Valentina , Falco Vincenzo De , Martinelli Erika , Kopetz Scott , Ciardiello Fortunato , Troiani Teresa 
Published: August 2018

Abstract
Molecular mechanisms driving acquired resistance to anti-EGFR therapies in mCRC is complex and biochemically converge to activate the EGFR-RAS-MAPK pathway. In order to understand the mechanism underlying MEKi resistance, SW48 MEKi resistant cell lines (SW48-MR) have been established by in vivo selection. To expand our results, another CRC cell line sensitive to MEK blockade, such as HCT116, has been generated: HCT116-MR. Microarray analysis showed that several genes involved in the PD-L1 pathway were up regulated in SW48-MR versus SW48. Moreover, genes overexpressed in MEKi-resistant tumor were related to the gene signature of CMS4 subtype of CRC. In particular all the pathways that were up regulated in CMS4 tumors were up regulated in the resistant cell line, as confirmed by Western blot and Immunofluorescence analysis. The regulation of PD-L1 expression is regulated by multiple signaling pathways, including JAK/STAT. STAT3 gene is also up regulated in MEKi-resistant tumors. Inhibition of STAT3 expression by siRNA reduced PD-L1 expression and restored MEKi sensitivity. Moreover, a direct correlation has been demonstrated between EGFR and PD-L1. Exogenous activation of EGFR by TGFα stimulation in MEKi sensitive HCT 116 cell lines induced PD-L1 overexpression and resistance to MEKi. Once demonstrated the EGFR role in modulation of PD-L1 expression and subsequently development of acquired resistance to MEKi, we further evaluated the potential mechanism(s) responsible for EGFR activation. One major mechanism is the specific ligand stimulation. Gene expressions analysis revealed that all EGFR ligands were up regulated in MEKi resistant tumors compared to parental tumors. Moreover, we will perform an ELISA assay to confirm this data. To extend these in vitro findings, we will perform an in vivo study using MC38 and CT26 MEKi resistant syngeneic models that we have previously generated. These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with other agents and provide an additional therapeutic strategy via modulation of host immune responses in CMS4 CRC tumors.
Citation Format: Stefania Napolitano, Nunzia Matrone, Valentina Belli, Vincenzo De Falco, Erika Martinelli, Scott Kopetz, Fortunato Ciardiello, Teresa Troiani. PD-L1 pathway activation as an escape mechanism of resistance to MEK inhibitor treatment in human colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4904.
Abstract 4912: Targeting cyclin-dependent kinase 7 in gastric cancer
Authors: Huang Jia-Rong , Zhang Wen-Ji , Jiang Qi-Wei , Yang Yang , Wei Meng-Ning , Shi Zhi 
Published: August 2018

Abstract
CDK7 is a member of the cyclin-dependent kinase family, which forms the CDK activating kinase (CAK) complex with Cyclin H and RING finger protein Mat1 to control cell cycle progression and transcription by phosphorylating other CDKs and RNA polymerase II. Upregulation of CDK7 frequently occurs in human gastric cancer (GC). In this study, we demonstrated that inhibition of CDK7 was able to induce cell growth inhibition, cell cycle arrest at G2/M phase and apoptosis with the increasing intracellular reactive oxidative species (ROS) levels. Pretreatment with ROS scavenger N-acety-L-cysteine partly reversed GC cell apoptosis induced by CDK7 inhibition. In the nude mice, inhibition of CDK7 also suppressed the growth of xenograft tumors of GC. Overall, our data showed that inhibition of CDK7 in GC presented outstanding anticancer effect in vitro and in vivo, suggesting that CDK7 is a potential therapeutic target for GC patients.
Citation Format: Jia-Rong Huang, Wen-Ji Zhang, Qi-Wei Jiang, Yang Yang, Meng-Ning Wei, Zhi Shi. Targeting cyclin-dependent kinase 7 in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4912.
Abstract 4914: IFI16 is increased in response to chemotherapeutic agents in breast cancer cells
Authors: Lim Gayoung , Ka Na-Lee , Lee Mi-Ock 
Published: August 2018

Abstract
Breast cancer is the most common cancer in women worldwide and chemotherapy is one of the standard treatment options for breast cancer. Chemotherapeutic agents induce severe DNA damage in cancer cells, which have mutations in genes related with DNA repair, resulting in cancer cell death. Thus, controlling DNA damage response is an important factor in determining outcome upon chemotherapy. In this study, we identified IFN-γ inducible protein 16 (IFI16) as a regulator of DNA damage response in breast cancer cells. First, we found that the expression of IFI16 was increased in response to chemotherapeutic agents such as 5-fluouracil, doxorubicin and cisplatin. However, changes in mRNA level of IFI16 was not observed, suggesting that IFI16 expression could be regulated by post-translation modification. Second, nuclear fractionation and confocal analysis revealed that expression of nuclear IFI16 was increased and cytoplasmic IFI16 was decreased in response to doxorubicin. Taken together, IFI16 could be a possible candidate for regulating factor of DNA damage response upon chemotherapy in breast cancer cells.
Citation Format: Gayoung Lim, Na-Lee Ka, Mi-Ock Lee. IFI16 is increased in response to chemotherapeutic agents in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4914.
Abstract 4927: Plasma and CNS pharmacokinetics of the CHK-1 inhibitor prexasertib (LY-2606368) in mice bearing orthotopic group 3 medulloblastoma
Authors: Maharaj Anil , Davis Abigail , Zhong Bo , Roussel Martine F. , Stewart Clinton F. 
Published: August 2018

Abstract
Many children with brain tumors have limited treatment options and poor long-term survival. A key protein kinase involved in activating and maintaining the S and G2/M checkpoints is CHK1, which when inhibited in the absence of p53 leads to loss of DNA damage checkpoints and can enhance the activity of many DNA-damaging agents. Prexasertib (LY-2606368), a potent and selective small molecule inhibitor of CHK1 protein kinase activity in vitro (IC50 &lt;1 nM), is currently under clinical evaluation for treatment of pediatric malignancies. To evaluate prexasertib in preclinical efficacy studies for pediatric brain tumor models, the ratio of free drug concentrations between the central nervous system (CNS) and plasma (Kpu,u) is typically computed as a surrogate to measure CNS penetration. To facilitate the prospective determination of preclinical CNS Kpu,u values, we evaluated the plasma pharmacokinetic (PK) disposition of prexasertib in a murine model of medulloblastoma. A plasma PK study was performed using CD1 nude mice orthotopically implanted with group 3 medulloblastoma to obtain initial prexasertib PK parameters. Tumor growth was assessed by bioluminescence imaging (D-Luciferin) and mice were enrolled in the study once tumors reached 1x10~8-9 photons/second. Prexasertib mesylate monohydrate was reconstituted in 20% Captisol and administered subcutaneously at a dosage of 10 mg/kg (free base). A population based study design was used in which 3 samples per mouse were obtained. Plasma samples were prepared using a liquid-liquid extraction technique, and analyzed for prexasertib using a validated LC-MS/MS method (LLOQ = 0.2 µg/L). A two-compartment PK model was fit to the prexasertib concentration-time data using nonlinear mixed effects modeling (NONMEM 7.3, ICON Development Solutions). Plasma PK parameters from this model were used with the D-optimality criterion as implemented in ADAPT (D'Argenio, 1981) to derive a limited sampling model (LSM) for use in upcoming cerebral microdialysis studies. The results of our plasma PK studies showed a Cmax, terminal half-life, and AUC in CD1 nude mice bearing group 3 medulloblastoma of 1015 µg/L, 4.5 hours, and 1773 µg*hr/L, respectively. The LSM for plasma PK that will be used in the cerebral microdialysis studies include the time points of 0.25, 6.6, and 24 hours. Now that the plasma PK and a LSM are defined, we are poised to begin cerebral microdialysis studies in CD1 nude mice bearing group 3 medulloblastoma.
Citation Format: Anil Maharaj, Abigail Davis, Bo Zhong, Martine F. Roussel, Clinton F. Stewart. Plasma and CNS pharmacokinetics of the CHK-1 inhibitor prexasertib (LY-2606368) in mice bearing orthotopic group 3 medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4927.