bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 73: Targeting KDR mutations in lung adenocarcinoma
Authors: Mockus Susan M. , Potter Christopher S. , Stafford Grace A. , Ananda Guruprasad , Hinerfeld Douglas , Tsongalis Gregory J. 
Published: August 2015

Abstract
KDR, also known as VEGFR2, is a target of several VEGFR inhibitors, however, only bevacizumab, which targets the VEGF ligand, is FDA approved for lung cancer. Since an activating mutation in KDR was identified in 70% of lung adenocarcinoma patients we sought to identify the number of available clinical trials targeting KDR in lung adenocarcinomas and/or solid tumors, thereby increasing therapeutic options and treatment accessibility for these patients.
DNA from thirteen lung cancer FFPE samples was sequenced on Illumina HiSeq 2500 or MiSeq sequencers using a CLIA-certified 358-gene targeted sequencing assay. FASTQ files generated from Illumina's CASAVA software were submitted to a Clinical Genome Analytics (CGA) data analysis pipeline to perform automated read quality assessment, alignment, and variant calling. Clinical reports were written for each sample through extensive literature and clinicaltrials.gov searches.
Thirteen lung biopsies were obtained and subdivided based on pathology reports, into 10 lung adenocarcinomas, 1 mixed NSCLC/SCLC, 1 small cell carcinoma, and 1 squamous carcinoma. KDR Q472H was identified in 7/10 lung adenocarcinomas and 1/1 mixed NSCLC/SCLC, but not in the small or squamous cell carcinomas. KDR encodes Vegfr-2, a receptor tyrosine kinase overexpressed in a variety of solid tumors. KDR Q472H is an activating missense mutation, which increases phosphorylation and activation of Vegfr-2, thereby promoting increased microvessel density in lung tumor tissues. At the time of clinical report writing, there were a total of 47 actively recruiting clinical trials targeting KDR and 4 trials requiring the patient to have a molecular alteration of KDR. Further breakdown of these trials identified the use of 33 off-label VEGFR inhibitors, 5 investigational pan-VEGFR inhibitors, and 5 investigational specific KDR (VEGFR2) inhibitors.
Next-generation sequencing of 358 genes from lung cancer biopsies identified a common KDR activating mutation, Q472H, in 70% of lung adenocarcinomas. Searching clincialtrials.gov by pan-VEGFR and specific KDR inhibitors identified 47 actively recruiting trials, thus increasing the accessible repertoire of treatment options for lung adenocarcinoma patients.
Citation Format: Susan M. Mockus, Christopher S. Potter, Grace A. Stafford, Guruprasad Ananda, Douglas Hinerfeld, Gregory J. Tsongalis. Targeting KDR mutations in lung adenocarcinoma. [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 73. doi:10.1158/1538-7445.AM2015-73
Abstract 735: Honokiol enhances the anticancer effects of doxorubicin by regulating Mucin 1 and Multidrug resistance-associated protein 1 (MRP1) in mammary carcinoma MDA-MB-231 cells
Authors: Thulasiraman Padmamalini , Alshareedah Saad 
Published: August 2015

Abstract
Although great progress has been made in the treatment of breast cancer, resistance to chemotherapeutic drugs is a problem facing current cancer research, promoting the need to understand the molecular mechanisms involved in breast cancer and identify future targeted therapy. One of the mechanisms by which chemoresistance is attained in cancer cells is mediated through the expression of MDR-related proteins (MRPs). These transmembrane proteins efflux drugs across the plasma membrane, conferring resistance of cancer cells to anticancer drugs. Acquiring drug resistance has been correlated to the emergence of metastasis, accounting for two factors that may be related to progression of the disease. One of the diagnostic markers of metastatic progression is Mucin 1 (MUC1), an oncoprotein which has been implicated in reduced survival rate. Interaction of MUC1 with MRP-1 promotes resistance to conventional chemotherapeutic drugs. While several inhibitors have been identified and characterized to overcome drug resistance, thus far none of these have led to effectively managing acquired drug resistance. Along with existing drug treatments for breast cancer, the focus of clinicians and researchers have shifted towards exploring natural products to treat alone or in combination with chemotherapeutic agents to enhance the efficacy of these drugs in cancer. One such compound is honokiol, a natural phenolic compound extracted from Magnolia grandiflora that suppresses breast carcinogenesis in vitro and in vivo. The purpose of the current study is to determine whether honokiol regulates MUC1 and MRP1 in mammary carcinoma cells, MDA-MB-231, and the role of honokiol to enhance the efficacy of chemotherapeutic agent, doxorubicin. We investigated the effects of honokiol on the expression of MUC1 and MRP1 in MDA-MB-231 cells by RT-PCR and Immunoblotting. Cell proliferation assays (MTT-(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) were used to study the effect of honokiol on doxorubicin-mediated growth suppression. Honokiol suppressed mRNA and protein expression levels of MUC1 and MRP1 in MDA-MB-231 cells. In addition, honokiol suppressed the growth of mammary carcinoma MDA-MB-231 cells, and enhanced the efficacy of doxorubicin-mediated mammary carcinoma growth suppression. Taken together, suppressing the expression level of MUC1 and MRP1 by honokiol enhances the effect of conventional chemotherapeutic drugs.
Citation Format: Padmamalini Thulasiraman, Saad Alshareedah. Honokiol enhances the anticancer effects of doxorubicin by regulating Mucin 1 and Multidrug resistance-associated protein 1 (MRP1) in mammary carcinoma MDA-MB-231 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 735. doi:10.1158/1538-7445.AM2015-735
Abstract 736: Combining PD1- and CTLA4-inhibiting antibodies with cisplatin or PARP inhibition in an attempt to eradicate BRCA1-deficient mouse mammary tumors
Authors: Blatter Sohvi , Guyader Charlotte , Küçükosmanoğlu Aslı , Freriks Stephan , de Visser Karin , Borst Piet , Rottenberg Sven 
Published: August 2015

Abstract
Solid tumors are usually not eradicated by conventional chemotherapy resulting in disease relapse and mortality. An intriguing example is BRCA-associated breast cancer. A genetically engineered mouse model for BRCA1-associated breast cancer (K14Cre;Brca1F/F;p53F/F), which highly resembles disease in human patients, can be used to study therapy escape and residual disease in BRCA-deficient tumors. Due to the BRCA inactivation, the tumors that arise in this model lack homologous recombination-directed DNA repair, an Achilles heel that has provided a therapeutic opportunity to eradicate tumors with DNA damage-inducing agents. Despite repeated sensitivity some residual cancer cells escape the deadly effect of anticancer therapy and lead to disease relapse. A special histopathological feature of BRCA1-mutated tumors in both humans and mice is the presence of infiltrating lymphocytes. This may be explained by the high frequency of genomic alterations of BRCA1-mutated tumors resulting in the generation of many neo-antigens. Our hypothesis is that blocking inhibitory T-cell signaling, using antibodies directed against CTLA4 and PD1, may increase the activity of the T-cell compartment towards a diverse pool of antigens, and successfully eliminate residual tumor cells in combination with DNA damage-inducing drugs. In particular, we will present data of combining CTLA4- and PD1- targeting antibodies with PARP inhibition or cisplatin to eliminate residual tumor cells in this mouse model for BRCA1-mutated breast cancer.
Citation Format: Sohvi Blatter, Charlotte Guyader, Aslı Küçükosmanoğlu, Stephan Freriks, Karin de Visser, Piet Borst, Sven Rottenberg. Combining PD1- and CTLA4-inhibiting antibodies with cisplatin or PARP inhibition in an attempt to eradicate BRCA1-deficient mouse mammary tumors. [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 736. doi:10.1158/1538-7445.AM2015-736
Abstract 756: Inhibition of ABCB1 overcomes cancer stem cell-like properties and acquired resistance to MET inhibitor in non-small cell lung cancer
Authors: Sugano Teppei , Seike Masahiro , Noro Rintaro , Soeno Chie , Nakamichi Shinji , Nishijima Nobuhiko , Matsumoto Masaru , Takeuchi Susumu , Miyanaga Akihiko , Kubota Kaoru , Gemma Akihiko 
Published: August 2015

Abstract
Non-small cell lung cancer (NSCLC) patients with EGFR mutations have shown a dramatic response to EGFR inhibitors (EGFR-TKI). EGFR T790M mutation and MET amplification have been recognized as mechanisms of acquired resistance to EGFR-TKI. Recently, MET inhibitors have been used in NSCLC patients for clinical trials. In this study, we tried to identify the mechanisms of acquired resistant to MET inhibitor. We analyzed the antitumor effects of two MET inhibitors; PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC1 cells with MET amplification were only sensitive cells to both of MET inhibitors. We have established PHA-665752 resistant cells; namely EBC1-R cells. EBC1-R cells showed high expression levels of ATP-binding Cassette Sub-family B Member 1 (ABCB1) as wells as phosphorylation MET (p-MET). EBC1-R cells grew as cell sphere that exhibited cancer stem cell-like (CSC) properties and epithelial mesenchymal transition (EMT) feature. Two miRNAs, miR-374a and miR-138 which targeted ABCB1, were decreased in EBC1-R cells. ABCB1 inhibitor elacridar could suppress sphere numbers and EMT phenomenon and restore to the resistance to PHA-665752 in EBC1-R cells. Our study demonstrated that ABCB1 overexpression associated with CSC properties and EMT may be critical for acquire resistance for MET inhibitor. ABCB1 inhibition might be a novel therapeutic strategy for resistance to MET inhibitor in NSCLC cells.
Citation Format: Teppei Sugano, Masahiro Seike, Rintaro Noro, Chie Soeno, Shinji Nakamichi, Nobuhiko Nishijima, Masaru Matsumoto, Susumu Takeuchi, Akihiko Miyanaga, Kaoru Kubota, Akihiko Gemma. Inhibition of ABCB1 overcomes cancer stem cell-like properties and acquired resistance to MET inhibitor in non-small cell lung cancer. [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 756. doi:10.1158/1538-7445.AM2015-756
Abstract 783: Ponatinib demonstrates antitumor activity in RET- and FGFR-driven patient-derived xenografts
Authors: Gozgit Joseph M. , Song Youngchul , Rivera Victor M. 
Published: August 2015

Abstract
Background: Ponatinib is a potent pan-BCR-ABL tyrosine kinase inhibitor (TKI) approved for patients (pts) with refractory or T315I+ chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia. We have previously shown that ponatinib also inhibits oncogenic variants of KIT, RET, and FGFR in vitro. Moreover, ponatinib induced complete regression of KIT-mutant tumors in a gastrointestinal stromal tumor (GIST) patient-derived xenograft (PDX), a finding consistent with the preliminary evidence of efficacy observed in pts with refractory GIST (NCT01874665). In this study, we evaluated ponatinib in a panel of PDXs harboring oncogenic variants of RET and FGFR.
Methods: The efficacy of ponatinib (20 mg/kg once-daily oral dosing) was compared to that of vehicle in 10 PDXs derived from a variety of tumor types containing oncogenic RET or FGFR fusions, high-level FGFR amplification (amp), or no known oncogenic drivers (WT; Table 1). Chemotherapeutic comparators (cisplatin or 5-fluorouracil) were included in 6 models. To confirm target modulation, levels of RET or FGFR phosphorylation in tumors were analyzed 6 hrs post dosing.
Results: Ponatinib induced tumor regression or ∼80% tumor growth inhibition (TGI) in the 4 RET fusion PDXs, and 62-98% TGI in the 3 FGFR PDXs (Table 1). Complete abrogation of target phosphorylation due to ponatinib treatment was verified in the 3 models examined. The efficacy of ponatinib exceeded that of the chemotherapy comparator in RET-driven but not WT PDXs, further suggesting this efficacy was driven primarily through inhibition of the driver oncogene.
Conclusion: Ponatinib demonstrates marked efficacy across several PDX models with either RET fusion-, FGFR2/3 fusion-, or FGFR2 amp-driven cancers, in a target dependent manner. These results provide additional support for evaluating ponatinib in pts with cancers positive for these aberrations; such trials are planned or ongoing (NCT01813734, NCT02265341, NCT01935336, and NCT02272998).
Table 1: Ponatinib's efficacy in PDX tumor modelsCancer TypeTargetTumor growth inhibition (%)Tumor regression (%)CRCCCDC6-RET-78CRCNCOA4-RET79-NSCLCKIF5B-RET80-NSCLCKIF5B-RET-12NSCLCMCU-FGFR290-GliomaTACC3-FGFR362-GastricFGFR2 amp98-CRCWT (control)41-CRCWT (control)24-NSCLCWT (control)51-
Citation Format: Joseph M. Gozgit, Youngchul Song, Victor M. Rivera. Ponatinib demonstrates antitumor activity in RET- and FGFR-driven patient-derived xenografts. [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 783. doi:10.1158/1538-7445.AM2015-783
Abstract 797: Discovery of a highly selective and potent small molecule inhibitor against c-MET for cancer therapy
Authors: Bao Rudi , Pan Zhongzong , Zhao Zhiming , Yu Hongping , Xu Yaochang 
Published: August 2015

Abstract
c-MET is a receptor tyrosine kinase that is dysregulated in several types of maliganacies, including gastric, liver and lung cancers. Abnormal activation of c-MET could be caused by gene amplification, overexpression, or HGF aberrant expression. Activation of c-MET is involved in several cellular processes, including cell proliferation, cell migration, and angiogenesis. To explore c-MET targeted therapy, we discovered a small molecule that selectively inhibits c-MET activity with an IC50 of single digit nanomolar concentration across several cell lines. In xenograft tumor models from cell lines harboring cMET amplification including liver, gastric and lung cancer, tumor growth was significantly inhibited by this compound in a dose dependent manner. In addition, PD studies showed that c-MET and down-stream signaling pathways were blocked by the compound in the cMET amplified tumors. The compound also showed desirable PK and safety profiles. These data warrants further development of this compound for cancer therapy in cMET dysregulated cancers.
Citation Format: Rudi Bao, Zhongzong Pan, Zhiming Zhao, Hongping Yu, Yaochang Xu. Discovery of a highly selective and potent small molecule inhibitor against c-MET for cancer therapy. [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 797. doi:10.1158/1538-7445.AM2015-797
Abstract 814: Truncated HBx-dependent silencing of growth arrest-specific 2 promotes hepatocarcinogenesis through inhibition of p53-mediated apoptosis
Authors: Cheng Alfred S. L. , Zhu Ranxu , Mok Myth T.S. , Kang Wai , To Ka-Fai , Sung Joseph J.Y. , Chan Henry L.Y. 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV encoded X antigen (HBx) is a trans-regulatory protein involved in the virus-induced hepatocarcinogenesis. Although the carboxyl-terminus truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms have yet been fully defined. In this study, we investigated the molecular pathogenesis of a naturally-occurring HBx variant which has 35 amino acids deleted at C-terminus (HBxΔ35). By performing genome-wide scanning analysis and PCR validation, we identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and suppress its expression to promote hepatocellular proliferation and tumorigenicity. Further functional assays showed that overexpression of GAS2 inhibited tumor growth both in vitro and in vivo by inducing p53-dependent apoptosis. Conversely, siRNA-mediated knockdown of GAS2 in hepatocytes attenuated apoptotic response and reduced cell susceptibility to etoposide-induced apoptosis. Notably, GAS2 expression was significantly down-regulated in truncated HBx-expressing HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 ablates p53-driven apoptosis via direct silencing of GAS2, and thereby provides survival advantage for pre-neoplastic hepatocytes to facilitate cancer development.
Citation Format: Alfred S. L. Cheng, Ranxu Zhu, Myth T.S. Mok, Wai Kang, Ka-Fai To, Joseph J.Y. Sung, Henry L.Y. Chan. Truncated HBx-dependent silencing of growth arrest-specific 2 promotes hepatocarcinogenesis through inhibition of p53-mediated apoptosis. [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 814. doi:10.1158/1538-7445.AM2015-814
Abstract 818: Chronic oxidative stress induces conversion of estrogen-dependent non-aggressive breast cancer cells into estrogen-independent aggressive phenotype
Authors: Mahalingaiah Prathap Kumar S. , Ponnusamy Logeswari , Singh Kamaleshwar P. 
Published: August 2015

Abstract
We have recently reported increased growth and tumorigenic potential of estrogen receptor (ER) positive breast cancer cells with chronic exposure to oxidative stress. In this study, we evaluated mechanistic basis for chronic oxidative stress-induced aggressiveness in ER positive MCF-7 breast cancer cells. Loss of estrogen dependency is known to be associated with acquisition of aggressive form in breast cancer cells. Therefore, the objective of this study was to evaluate changes in estrogen response in ER-positive breast cancer cells exposed to chronic oxidative stress. MCF-7 cells were exposed to hydrogen peroxide (H2O2)-induced oxidative stress for chronic period (6 months). Using these cells, growth response to 17-β estradiol was evaluated by MTT assay and cell cycle analysis. Surprisingly, in response to 17-β estradiol treatment, there was no significant growth stimulation in cells exposed to chronic oxidative stress. Cell cycle analysis by flow cytometry further confirmed the cell growth data. Quantitative RT-PCR analysis also revealed significant down regulation of ER-α in chronically exposed breast cancer cells. To understand the role of epigenetic mechanism, the expression of epigenetic regulatory genes were determined at both transcript and protein level. In addition, the levels of histone modifications were also evaluated by Western blot analysis. Changes in both the expression of epigenetic regulatory genes (DNMT1, DNMT3b, HDAC1, MBD4, and HAT1) and the levels of histone modifications (H3K27 tri-methylation and H3K18 acetylation) were observed in MCF-7 cells chronically exposed to H2O2. Treatment with DNA de-methylating agent (5-aza-2′-deoxycytidine) restored the ER-α expression level, estrogen-induced growth and oxidative stress induced histone modifications. To summarize, the findings of this study suggest that chronic exposure to oxidative stress can convert estrogen-dependent non-aggressive breast cancer cells into estrogen-independent aggressive form potentially by epigenetic mechanism.
Citation Format: Prathap Kumar S. Mahalingaiah, Logeswari Ponnusamy, Kamaleshwar P. Singh. Chronic oxidative stress induces conversion of estrogen-dependent non-aggressive breast cancer cells into estrogen-independent aggressive phenotype. [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 818. doi:10.1158/1538-7445.AM2015-818
Abstract 825: Molecular mechanisms of regulation of cytochrome P4501A enzymes by 3-methylcholanthrene (MC) in mice in vivo
Authors: Moorthy Bhagavatula , Weiwu Jiang , Wang Lihua , Chu Chun , Kondraganti Sudha R. , Maturu Paramahamsa 
Published: August 2015

Abstract
3-Methylcholanthrene (MC) is one of the most potent polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke, diesel exhausts, and charcoal broiled meats, etc. Cytochrome P450 (CYP)1A enzymes play key roles in the activation of PAHs to carcinogenic metabolites. We previously showed persistent induction of CYP1A enzymes by MC in vivo. In this study, we tested the hypothesis that MC elicits persistent induction of CYP1A1 in vivo by sustained transcriptional activation of the CYP1A1 promoter. Thirty two C57B6 (WT) mice were divided into two groups. Group I was treated with vehicle corn oil (CO) (8ml/kg) and group II was treated with a single dose of MC (100 μmol/kg), i.p. Four animals from each group were sacrificed at 6, 12, 24, and 48 h after MC withdrawal. The mRNA levels, protein content and enzyme activities of CYP1A1 were determined by real-time PCR, Western blotting, and fluorimetry, respectively at different time points. In addition, the binding of MC-AHR-AHR nuclear translocator (ARNT) to the AHREs on the CYP1A1 promoter region were determined by chromatin immunoprecipitation (ChIP) assay. The translocation of AHR was also analyzed by immunofluorescence. The ChIP experiments indicated that transcriptional activation of CYP1A1 was most pronounced at 6 h, followed by 12 h, but declined at later time points. On the other hand, the expression of CYP1A1 at the mRNA, protein and enzyme levels persisted for up to 48 h both in lung and liver tissues. These results suggest that transcriptional activation of CYP1A1 at 6-12 h is sufficient to result in sustained induction of CYP1A mRNA and protein expression for up to 48 h. Isolation of the immunoprecipitated promoter fragment (containing the xenobiotic response elements), which binds to the MC-AHR complex, followed by 32P-postlabeling revealed the formation of MC-DNA adducts, suggesting that DNA adducts are sequence-specific and target the CYP1A1 promoter. Our results suggest that DNA adducts might play a role in regulation of CYP1A1 by MC, a phenomenon that may be of relevance to PAH-mediated carcinogenesis.
Citation Format: Bhagavatula Moorthy, Jiang Weiwu, Lihua Wang, Chun Chu, Sudha R. Kondraganti, Paramahamsa Maturu. Molecular mechanisms of regulation of cytochrome P4501A enzymes by 3-methylcholanthrene (MC) in mice in vivo. [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 825. doi:10.1158/1538-7445.AM2015-825