bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5373: AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells
Authors: CHEON MIN GYEONG , Kim Ja-Eun 
Published: August 2015

Abstract
SIRT2, a member of the sirtuin family, is involved in the regulation of a variety of physiological functions. In addition, SIRT2 has been studied in the context of pathological conditions including neurodegenerative diseases, metabolic syndrome, and cancer. The effect of SIRT2 on cancer cell growth depends on cancer tissue type. To investigate the role of SIRT2 in colon cancer, we treated HCT116 human colon cancer cells with the SIRT2-specific inhibitor AK-1, a cell-permeable benzylsulfonamide. AK-1 treatment induced proteasomal degradation of the Snail transcription factor through inactivation of the NF-κB/CSN2 pathway. Reduction in the level of Snail resulted in upregulation of p21, a cyclin-dependent kinase inhibitor, leading to G1 arrest, slow proliferation, and slow wound-healing activity. The regulation of Snail-p21 axis by AK-1 also occurs in HT-29 colon cancer cells. Therefore, inhibition of SIRT2 using AK-1 would be a beneficial intervention in the treatment of colon cancer.
Citation Format: MIN GYEONG CHEON, Ja-Eun Kim. AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5373. doi:10.1158/1538-7445.AM2015-5373
Abstract 5390: The TRK inhibitor RXDX-101 enhances the efficacy of temozolomide and irinotecan in a xenograft model of neuroblastoma
Authors: Iyer Radhika , Golden Rebecca L. , Naraparaju Koumudi , Croucher Jamie L. , Guan Peng , Li Gang , Hornby Zachary , Brodeur Garrett M. 
Published: August 2015

Abstract
Purpose: Neuroblastoma (NB) is one of the most common and deadly solid tumors of childhood. The Trk family of neurotrophin receptors plays an important role in clinical behavior of NBs. Overexpression of TrkB and its ligand, BDNF, is associated with poor prognosis. We wanted to determine if RXDX-101, an oral pan-TRK, ROS1 and ALK inhibitor, would be effective in our NB xenograft model, either alone or in combination with conventional chemotherapy.
Experimental Design: We tested the in vitro effects of RXDX-101 as a single agent, or in combination with the chemotherapeutic agents irinotecan and temozolomide (Irino-TMZ), using a subclone of the SH-SY5Y NB cell line transfected with TrkB. We also examined in vivo growth inhibition of TrkB-expressing NB xenografts with RXDX-101 alone or in combination with Irino-TMZ.
Results: RXDX-101 significantly inhibited growth of TrkB-expressing NB cells in vitro. Enhanced in vitro inhibition was observed when RXDX-101 was used in combination with Irino-TMZ. Single agent therapy with RXDX-101 resulted in significant tumor growth inhibition compared to control animals [p&lt;0.0001 for event-free survival (EFS)]. The addition of RXDX-101 to Irino-TMZ also significantly improved the EFS of animals compared to vehicle or Irino-TMZ treated animals (p&lt;0.0001 for combination vs. control, p = 0.0012 for combination vs. Irino-TMZ).
Conclusions: We show that RXDX-101 inhibits growth of TrkB expressing NB cells in vitro and in vivo. Furthermore, RXDX-101 cotreatment enhanced the efficacy of conventional chemotherapy in our NB xenograft model. Our data suggest that RXDX-101 has potential for incorporation in clinical trials for NB and other Trk expressing tumors.
Citation Format: Radhika Iyer, Rebecca L. Golden, Koumudi Naraparaju, Jamie L. Croucher, Peng Guan, Gang Li, Zachary Hornby, Garrett M. Brodeur. The TRK inhibitor RXDX-101 enhances the efficacy of temozolomide and irinotecan in a xenograft model of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2015-5390
Abstract 5393: Evaluation of compounds developed against the TAM family kinases
Authors: Zhang Hong , Zhang Zaihui , Shi Xiaoqing , Lee Erica , Li Rick , Hu Yuxiang , Yan Jun , Sanghera Jasbinder 
Published: August 2015

Abstract
The TAM family receptor tyrosine kinases, consisting of Tyro3, Axl and Mer, are implicated in a diverse range of cellular processes such as cell survival, proliferation, migration, angiogenesis, and inflammatory response. Despite the debates over their role as a driver in carcinogenesis owing to some recent findings, their link to human cancer is strongly supported by direct correlation of the level of expression/activity with tumor grade and prognosis. In particular, Axl was found to underlie metastasis as an essential regulator of the epithelial-mesenchymal transition (EMT) process and also to confer acquired resistance to the TKI-mediated targeted therapies by up-regulation of associated kinases. Currently, none of FDA-approved kinase drugs were developed for the TAM family kinases. In our effort to develop such small-molecule inhibitors targeting the TAM kinases for oncology indications, we uncovered a series of novel potent compounds with low nM potency against Axl and Tyro3. Effect of these compounds in human cancer cell lines of different tissue origins was mediated mainly through the Axl-dependent signaling pathways. Detailed analysis of signaling proteins downstream of Axl revealed different mechanisms of action for these compounds. In addition to suppression of cell proliferation, these compounds inhibited anchorage-independent colony formation, cell migration and invasion. Four compounds were selected to be evaluated in pharmacokinetic studies in mice and the results indicated that these compounds possess reasonable PK properties with high exposure, reasonably long half-life, and good bioavailability. The results of the efficacy studies in suppressing tumor growth in a xenograft and an orthotropic mouse models will be discussed.
Citation Format: Hong Zhang, Zaihui Zhang, Xiaoqing Shi, Erica Lee, Rick Li, Yuxiang Hu, Jun Yan, Jasbinder Sanghera. Evaluation of compounds developed against the TAM family kinases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5393. doi:10.1158/1538-7445.AM2015-5393
Abstract 5410: Aspirin attenuates tumor initiating cell growth and induces reprogramming factors of mesenchymal to epithelial transition in breast cancer cell
Authors: Maity Gargi , De Archana , Banerjee Snigdha , Das Amlan , Sarkar Sandipto , Banerjee Sushanta K. 
Published: August 2015

Abstract
Acetyl Salicylic Acid (ASA) also known as aspirin, a classic, non-steroidal, anti-inflammatory drug (NSAIDs) is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemo-preventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention. Our studies, using in vitro and in vivo tumor xenograft model, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, it also significantly reduces the growth of tumor initiating cells (TICs)/ cancer stem cells (CSCs) and delayed the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory as well as reprogramming roles of ASA could be mediated through inhibition of TGF-β-signaling pathway, which is associated with growth, motility, invasion and metastasis in advanced breast cancers. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-β- SMAD4 signaling in breast carcinogenesis.
[This work is funded by VA Merit Awarded Grant (SB and SKB)]
Note: This abstract was not presented at the meeting.
Citation Format: Gargi Maity, Archana De, Snigdha Banerjee, Amlan Das, Sandipto Sarkar, Sushanta K. Banerjee. Aspirin attenuates tumor initiating cell growth and induces reprogramming factors of mesenchymal to epithelial transition in breast cancer cell. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5410. doi:10.1158/1538-7445.AM2015-5410
Abstract 5421: HER3 inhibition has little efficacy on hepatocellular carcinoma cell lines
Authors: Li Yong-Shi , Shao Yu-Yun , Wang Han-Yu , Cheng Ann-Lii , Hsu Chih-Hung 
Published: August 2015

Abstract
Background: HER3 is a member of the ErbB family of receptor tyrosine kinases that are involved in the pathogenesis of many malignancies, including hepatocellular carcinoma (HCC) (Hsieh et al: Hepatology 2011). When bound with neuregulins (NRGs) or in the presence of HER2 amplification, HER3 dimerizes with HER2 and activates the signaling transduction cascade. We planned this study to evaluate the efficacy of HER3 inhibition by an anti-HER3 monoclonal antibody, LJM716 (Novartis®), in HCC.
Methods: Human HCC cell lines Huh7, HepG2, PLC5, Hep3B, and SK-Hep1 were used in the experiments. We used the quantitative RT-PCR to evaluate the mRNA expression levels of HER2, HER3 and NRGs in HCC cell lines. We used the MTT assay to evaluate the growth inhibitory efficacy of LJM716 alone or in combination with sorafenib, and used the Western blotting to study the expression phospho-HER3 downregulated by LJM716 in these cells.
Results: None of the HCC cell lines have HER2 amplification. Huh7 and HepG2 had higher HER2 expression, SK-Hep1 had lower HER3 expression, SK-Hep1 and Hep3B had higher NRG1 and NRG2 expression, and PLC5 had higher NRG2 but not NRG1 expression compared with other HCC cells. In HCC cells cultured with ordinary serum-containing medium, we found LJM716 up to 20 μg/ml showed little suppressive effect in the proliferation of HCC cells; in HCC cells cultured in the presence of NRG1, LJM716 could induce a 20 to 30% growth-suppressive effect at best. LJM716 inhibited NRG1-induced phosphorylation of HER3 in HCC cells dose-dependently. The treatment of sorafenib slightly increased RNA expression levels of NRG1 and HER2 in PLC5, Huh-7, and HepG2 cells. We combined LJM716 and sorafenib to evaluate their combination effect in HCC cells, but found that LJM716 failed to show any synergistic effect to sorafenib.
Conclusions: Despite inhibitory effect on HER3 phosphorylation, LJM716 showed minimal therapeutic efficacy on HCC cell lines, either alone or in combination with sorafenib.
Citation Format: Yong-Shi Li, Yu-Yun Shao, Han-Yu Wang, Ann-Lii Cheng, Chih-Hung Hsu. HER3 inhibition has little efficacy on hepatocellular carcinoma cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5421. doi:10.1158/1538-7445.AM2015-5421
Abstract 5427: Small molecule inhibitors of Musashi family of RNA-binding proteins
Authors: Lan Lan , Appelman Carl , Smith Amber , Yu Jia , Larsen Sarah , Marquez Rebecca , Wu Xiaoqing , Liu Hao , Roy Anuradha , Anbanandam Asokan , Gowthaman Ragul , Karanicolas John , Rogers Steven , Aubé Jeffrey , De Guzman Roberto , Neufeld Kristi , Xu Liang 
Published: August 2015

Abstract
Musashi family of RNA-binding proteins are key regulators of several stem cell populations and are also involved in tumor proliferation and maintenance. There are two Musashi proteins in humans, Msi1 and Msi2, both of which regulate target mRNAs translation. We aim to identify small molecule inhibitors of Msi activity thus blocking the growth of a broad range of cancer cells. Known mRNA targets of Msi1 include Numb, APC and p21WAF-1, key regulators of Notch, Wnt signaling and cell cycle progression, respectively. Numb is also an mRNA target of Msi2. We confirmed the binding between numb and Msi1/Msi2 by RNA-IP. Using a fluorescence polarization assay, we screened small molecules from several chemical libraries for those that disrupt the binding of Msi1 to its consensus RNA binding site. Hits were validated by surface plasmon resonance, amplified luminescent proximity homogeneous assays and nuclear magnetic resonance. Among the small molecules that we screened, we found several hit compounds that disrupt the Msi1-numb RNA binding potently. Our study supports the hypothesis that Msi1 inhibition is a viable and effective anti-cancer strategy and we identified (-)-gossypol as the first small molecule inhibitor of Msi1 that inhibits tumor xenograft growth in vivo.
Citation Format: Lan Lan, Carl Appelman, Amber Smith, Jia Yu, Sarah Larsen, Rebecca Marquez, Xiaoqing Wu, Hao Liu, Anuradha Roy, Asokan Anbanandam, Ragul Gowthaman, John Karanicolas, Steven Rogers, Jeffrey Aubé, Roberto De Guzman, Kristi Neufeld, Liang Xu. Small molecule inhibitors of Musashi family of RNA-binding proteins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5427. doi:10.1158/1538-7445.AM2015-5427
Abstract 5447: Association of the hedgehog signal pathway to Gefitinib sensitivity in a 3D cancer cell lines screening
Authors: Castillo Gonzalo , Jiang Xiuyun 
Published: August 2015

Abstract
Drug profiling of cancer cell lines is a useful tool for predictive biomarker discovery, traditional done in two-dimensional cultures, a growing body of evidence suggests that results cannot always be translated into xenografts or in the clinic due to the lack of complexity of the culture conditions. 3D cultures offer the ability to carry out the same type of studies with the added benefit of incorporating the 3-dimentional cellular interactions and physiological gradients normally seen in a tumor microenvironment. In this study we used Numira's 3D cell line screening platform on Gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR). We determined IC50 of Gefitinib in a panel of 60 cell lines grown as spheroids and used this information to investigate genes associated with sensitivity. Two mutated genes were associated with sensitivity to Gefitinb, as expected, the epidermal growth factor receptor (EGFR) was one of them, since mutations on EGFR are required for clinical efficacy. The second gene was smoothened (SMO), a G protein-coupled receptor of the hedgehog signaling pathway. It has been suggested that blockade of the hedgehog signaling pathway enhances anti-proliferative effects of EGFR inhibitors, we explored this potential synergy in a combination studies of Gefitinib and SMO inhibitors, Cyclopamine and GDC0449, the results are discussed.
Citation Format: Gonzalo Castillo, Xiuyun Jiang. Association of the hedgehog signal pathway to Gefitinib sensitivity in a 3D cancer cell lines screening. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5447. doi:10.1158/1538-7445.AM2015-5447
Abstract 5453: Different mechanism of Oxaliplatin resistance in human colorectal cancer cell lines
Authors: Yamano Tomoki , Kubo Shuji , Yano Aya , Tomita Naohiro 
Published: August 2015

Abstract
Purpose: The mechanism of Oxaliplatin (OHP) resistance is partly understood and no molecular marker for prediction of the sensitivity is available in clinic. We analyzed OHP resistant clones to establish the molecular marker for OHP sensitivity in colorectal cancer.
Experimental design: We established several OHP-resistant clones from human colon cancer cell lines, DLD1 and HCT116. Then we assayed IC50 of OHP- resistant clones against OHP, 5-FU, and CPT-11. We measured gene expression profiling by microarray analysis and gene mutations by exome sequencing. Based on these results, we selected candidate genes associated with OHP sensitivity, which had gene mutations with significant change of gene expression. To validate the results, we assessed the gene expression of candidate genes in colorectal cancer patients.
Results: All OHP-resistant clones derived from HCT116 were also resistant against 5-FU and CPT-11, although all OHP-resistant clones derived from DLD1 were still sensitive against 5-FU and CPT-11. Microarray analysis and exon sequencing indicated gene mutations in SMAD7 and IRF9 with amplified gene expression were candidate molecular markers for multidrug resistance in OHP-resistant clones derived from HCT116, although the gene expression in tumors of these genes were lower than normal mucosa in most of colorectal cancer patients.
Conclusions: The mechanisms of OHP resistance were different between OHP-resistant clones derived from DLD1 and those from HCT116, but the same among the clones if the parental cells were same. SMAD7 and IRF9 were candidate molecular markers to predict multidrug resistance.
Citation Format: Tomoki Yamano, Shuji Kubo, Aya Yano, Naohiro Tomita. Different mechanism of Oxaliplatin resistance in human colorectal cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5453. doi:10.1158/1538-7445.AM2015-5453
Abstract 5459: Overcoming resistance to HER2-targeting drugs using CDK8 inhibitors
Authors: McDermott Martina , Ivers Laura , O'Donovan Norma , Crown John , Roninson Igor , Broude Eugenia V. 
Published: August 2015

Abstract
HER2-targeting therapies transformed the treatment of patients with HER2+ breast cancer and are now being explored in other cancer types. However, nearly 70% of patients with HER2+ metastatic breast cancer have intrinsic resistance and almost all develop acquired resistance to HER2-targeting drugs. New therapeutic approaches aimed at resistance to HER2-targeting therapies are urgently needed. We have previously found that resistance to HER2-targeting drugs involves increased activity of the phosphatase PP2A. PP2A was reported to stimulate the kinase activity of CDK8, a transcription-regulating kinase that in contrast to some other members of the CDK family does not regulate cell cycle progression. Thus CDK8 may play a role in resistance to HER2-targeting therapies. CDK8 has been identified as an oncogene amplified in 50% of colon cancers. Immunohistochemical staining of breast tissue arrays and meta-analysis of breast cancer microarray data revealed that CDK8 is overexpressed in breast cancers and that higher CDK8 expression correlates with the failure of systemic therapy. Selective small-molecule inhibitors of CDK8 and its paralog CDK19 show no limiting toxicities at therapeutically effective doses. We have found that an optimized CDK8/19 inhibitor Senexin B has a synergistic growth-inhibitory effect in combinations with an anti-HER2 monoclonal antibody (a biosimilar of trastuzumab) and with the HER2/EGFR small-molecule inhibitor lapatinib. These synergistic effects were observed in all HER2+ breast and colon cancer cell lines tested so far, including those that are either sensitive to HER2-targeting drugs or non-responsive to these agents due to innate or acquired resistance. Furthermore, combining lapatinib with Senexin B inhibited the development of de novo resistance to lapatinib. Taken together these results suggest that combining anti-HER2 and anti-CDK8 therapies is a rational potential treatment for HER2+ cancers, which may overcome both innate and acquired resistance to HER2-targeting drugs.
Citation Format: Martina McDermott, Laura Ivers, Norma O'Donovan, John Crown, Igor Roninson, Eugenia V. Broude. Overcoming resistance to HER2-targeting drugs using CDK8 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5459. doi:10.1158/1538-7445.AM2015-5459
Abstract 547: Diagnosis of lung tumor types based on metabolomic profiles in lymph node aspirates
Authors: Sappington Daniel R. , Helms Scott A. , Siegel Eric , Jeffus Susanne K. , Bartter Teka , Bartter Thaddeus , Boysen Gunnar 
Published: August 2015

Abstract
Lung cancer is the leading cause of cancer-related deaths in the US and worldwide. The majority of lung cancer patients are diagnosed with an advanced stage, precluding curable surgical resection, and therapy is limited to thoracic radiation and chemotherapy. The efficacies have improved in recent years due to patient pre-selection based on the cytology of fine needle aspirates of lymph nodes, which harbor circulating tumor cells. We report herein the evaluation of lymph node aspirates for the presence of metabolite features that are suitable to distinguish patients with lung cancer from patients without malignancies and to separate patients with adenocarcinoma from patients with squamous cell carcinoma. The results provide evidence that patient groups can be separated based on their metabolite profiles. Multivariate statistical analyses (PLS and OPLS) produce a set of consensus features that can be further developed into clinical biomarkers. Two of the features were identified as kynurenine and oxidized glutathione, and their identities were confirmed in a second larger sample set. In addition, the accompanying metabolites glutamate, glutamine and tryptophan were included in the validation experiment to utilize relative metabolite ratios as indicators for corresponding enzyme activities. The validation results demonstrate significant differences in metabolites and metabolite ratios between lymph node aspirates harboring a circulating tumor cell and aspirates negative for malignancy. Subsequently, a second set of lymph node samples were analyzed for an extended panel of metabolites and of these 42 were suitable biomarker to be statistically significant to distinguish between at least one of the pair wise comparisons. Together the results demonstrate that metabolite profiles in lymph node aspirates are suitable to differentiate patients with adenocarcinoma from patients with squamous cell carcinoma.
Citation Format: Daniel R. Sappington, Scott A. Helms, Eric Siegel, Susanne K. Jeffus, Teka Bartter, Thaddeus Bartter, Gunnar Boysen. Diagnosis of lung tumor types based on metabolomic profiles in lymph node aspirates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 547. doi:10.1158/1538-7445.AM2015-547