bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1212: Studying cancer drug resistance in patient derived xenograft tumor models
Authors: Yu Tengfei , Yan Ying , Du Wei , Yang Yuefei , Tan Tingting , Yang Xuqin , Gu Jiali , Hua Liang , Ye Xin K. , Gu Zhenyu 
Published: May 2015

Abstract
Anti-cancer drugs, either targeted therapies or cytotoxic chemotherapies, have proven to be effective in treating certain cancer patients. However, in most cases, tumors recur and become resistant to the treatment after a period of time. There are urgent needs to understand the underlying drug resistance mechanisms, to discover drug resistance targets and drug resistance biomarkers and to develop new therapies or combination therapies to tackle this widely occurring clinical problem. Currently the main approaches to study cancer drug resistance include analyzing clinical samples and developing drug resistance models in vitro. Numerous potential resistance mechanisms have been revealed. However, validation of these findings in a clinical-like setting and to test therapies in preclinical studies requires in vivo tumor models of drug resistance.
At GenenDesign, we have developed cancer drug resistance PDX tumor models through short term drug testing or long term treatment of xenograft tumor mice. Cancer drugs investigated in our studies include major classes of targeted therapeutic modalities such as Her2 inhibitors, EGFR inhibitors, FGFR inhibitors and cMet/ALK inhibitors, as well as several standard of care (SoC) chemotherapies. From these studies, we have identified de novo resistance models, acquired resistance models and reversible resistance models in multiple cancer types including lung cancer and gastric cancer.
In analyzing more than a dozen of Her2 positive but Herceptin resistance PDX models, we have uncovered molecular abnormalities such as Pten deletion, PI3K mutation, amplification of EGFR, cMet and cyclin E, which have been reported previously to be associated with Herceptin resistance in early studies. Studies are on-going to test whether combination therapies will be effective in overcoming Herceptin resistance.
In drug response profiling of our PDX models, we also found wide spread phenotypical and functional heterogeneity in individual tumors. The heterogeneity within each tumor, in some cases, contributed to evolving of drug resistance from initially responsive tumors.
Citation Format: Tengfei Yu, Ying Yan, Wei Du, Yuefei Yang, Tingting Tan, Xuqin Yang, Jiali Gu, Liang Hua, Xin K. Ye, Zhenyu Gu. Studying cancer drug resistance in patient derived xenograft tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1212. doi:10.1158/1538-7445.AM2014-1212
Abstract 1214: Preclinical models of prostate cancer: New patient-derived xenografts for preclinical studies and evaluation of prostate cancer biology
Authors: Nguyen Holly M. , Morrissey Colm , Nelson Peter S. , Zhang Xiaotun , Lange Paul H. , Vessella Robert L. , Corey Eva 
Published: May 2015

Abstract
Prostate cancer (PCa) is a heterogeneous disease and in order to increase our understanding of PCa biology and evaluate efficacy of novel pipeline agents, clinically relevant models are needed. It is well known that PCa xenografts are difficult to establish and propagate with approximate take rates of only 20%. During past the 20 years we have established and characterized a large series of LuCaP prostate cancer patient-derived xenografts (PDXs). Herein, we present a summary of the biological and molecular characterization of these PDX LuCaP models.
LuCaP PCa PDX models were derived from primary PCa and various sites of metastases. The histology of the LuCaP PDXs is similar to the originating clinical specimen, and the unsupervised gene expression array clustering analyses revealed an association between the xenograft and the originating specimen. Twenty four of the lines are adenocarcinoma and four exhibit a neuroendocrine phenotype. Characterization of the LuCaP PDX tumors includes expression arrays, RNASeq, exome sequencing, and IHC for multiple markers. Some of the models show Rb deletion, TMPRSS2/ERG translocation, PTEN deletion, PI3K activation and other critical characteristics detected in clinical specimens and associated with PCa progression. In vivo characterizations show responses to androgen suppression spanning the range of responses to this therapy seen in patients; differential levels of serum PSA, tumor-doubling time, and responses to docetaxel. Furthermore, seven of our models elicit an osteoblastic reaction when implanted in the bone.
In summary the diversity of phenotypes and responses of the LuCaP PDXs to therapy are representative of responses seen in the clinical setting. Therefore, the LuCaP PCa PDXs are highly clinically relevant models to study PCa biology and evaluate new treatment modalities. These models are available to researchers worldwide for studies aiming to improve survival of PCa patients and quality of life of men suffering from this disease.
Citation Format: Holly M. Nguyen, Colm Morrissey, Peter S. Nelson, Xiaotun Zhang, Paul H. Lange, Robert L. Vessella, Eva Corey. Preclinical models of prostate cancer: New patient-derived xenografts for preclinical studies and evaluation of prostate cancer biology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1214. doi:10.1158/1538-7445.AM2014-1214
Abstract 1216: Effects of phenformin in LKB1/KRAS mutated non-small cell lung cancer patient derived xenograft
Authors: Moro Massimo , Roz Luca , Caserini Roberto , Pastorino Ugo , Sozzi Gabriella 
Published: May 2015

Abstract
Metformin is an oral antidiabetic drug of the biguanide class. Several epidemiological and case-control studies reported that diabetics using metformin may have lower cancer risk in comparison to those using other antidiabetic medications. Recent studies in experimental models suggest that another biguanide, phenformin, has higher anticancer activity compared with metformin. The aim of this study was to evaluate the effects of metformin and phenformin in Non-Small Cell Lung Cancer (NSCLC) models. In particular, the effects of these compounds in LKB1 or LKB1/KRAS mutated compared to wild type models have been investigated. NSCLC cell lines (A549, H460, H1299, LT73) have been treated with either metformin or phenformin to evaluate in vitro dose/response depending on the different mutational status of KRAS and LKB1 genes. The effects of the two biguanide have been investigated also in vivo models, exploiting the panel of Patient Derived Xenografts (PDXs) directly generated from NSCLC patients in our Institute. In vitro experiments indicated that cell lines with already impaired metabolism (LKB1 and/or KRAS mutated) were more sensitive to phenformin treatment. Interestingly, treatments of these cell lines with r phenformin resulted in a 50% decrease in the amount of CD133+ Tumor Initiating Cells (TIC). Moreover, high doses of phenformin (LD75) did not result in the increase of TIC previously observed after Cisplatin treatment. In vivo, early treatments (Tumor Volume = 50-100mm3) of an LKB1 mutated PDX model resulted in a significant reduction of tumor volume (300 ± 50 mm3 in phenformin treated vs 750 ± 100 mm3 in vehicle treated tumors) already after three weeks of treatment (100mg/Kg/day). Importantly, no regrowth was observed in responding tumors even after the end of treatments. No effects were observed in LKB1 wild type PDX treated with phenformin. Taken together, these preliminary data indicate a selective action of phenformin on LKB1 mutated lung adenocarcinoma models in vitro and in vivo. Interestingly, this compound seems to be more active in TIC than normal chemotherapeutic drugs (i.e. cisplatin). Effects of biguanide on TIC could be the cause of the lack of tumor regrowth after treatment, thus making these compounds potentially useful in counteracting disease recurrence and/or metastasis formation. Further investigations are needed to elucidate the different effects of metformin and phenformin in double mutated (LKB1 and KRAS) PDXs models.
Citation Format: Massimo Moro, Luca Roz, Roberto Caserini, Ugo Pastorino, Gabriella Sozzi. Effects of phenformin in LKB1/KRAS mutated non-small cell lung cancer patient derived xenograft. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1216. doi:10.1158/1538-7445.AM2014-1216
Abstract 1225: Generation and characterization of a sorafenib-resistant hepatocellular carcinoma model from patient-derived tumor xenografts
Authors: Hu Gang , Fang Houshan , Tang Xuzhen , Ouyang Kedong , Yang Xueyan , Xie Fubo , Wang Ke , Zhang Yixin , Jiang Zhenzhou , Zhang Luyong , Zhou He , Tao Weikang 
Published: May 2015

Abstract
Hepatocellular carcinoma (HCC) is a common malignancy worldwide and sorafenib is a standard of care therapeutics for unresectable HCC. Although sorafenib, a multikinase inhibitor, can suppress both angiogenesis and cell proliferation, its efficacy is hampered by the emergency of drug resistance during the treatment. Thus, it is useful to understand the mechanism underlying sorafenib resistance in an animal model with resemblance of human HCC. Here, we report the generation and characterization of a sorafenib-resistant HCC xenograft model derived from patient tumors. A patient-derived xenograft (PDX) mouse model (LIX004) was treated with sorafenib. While sorafenib inhibited tumor growth at the initial stage of treatment, a few tumors regrew after prolonged sorafenib treatment. A cancer cell line (LIXC-004SR) was generated from a resistant tumor and the xenograft derived from this cell line maintained sorafenib resistance in vivo. On contrary, another cell line (LIXC-004NA) established from the treatment-naïve LIX004 PDX model remained sensitive to sorafenib. We compared the gene expression profiles between these two cell lines using both cDNA microarray and qPCR and found that a class of genes involved in angiogenesis were significantly upregulated in LIXC-004SR cells vs. LIXC-004NA cells, which include those encoding secreted angiogenesis stimulators such as MMP1, FGF-5 and VEGFA. Consistently, increased angiogenesis was detected in sorafenib-resistant LIXC-004SR tumor compared to sorafenib-sensitive LIXC-004NA tumor. Furthermore, the conditional medium from LIXC-004SR cell culture could stimulate HUVEC proliferation as well as MEK,ERK and Akt phosphorylation. These results suggest that sorafenib resistance may arise by bypassing the inhibition of angiogenesis via upgregulation of pro-agiogenesis genes. The generation and molecular characterization of sorafenib-resistant tumor models could shed light on the mechanism of sorafenib resistance which may aid in the development of strategies to overcome drug resistance.
Citation Format: Gang Hu, Houshan Fang, Xuzhen Tang, Kedong Ouyang, Xueyan Yang, Fubo Xie, Ke Wang, Yixin Zhang, Zhenzhou Jiang, Luyong Zhang, He Zhou, Weikang Tao. Generation and characterization of a sorafenib-resistant hepatocellular carcinoma model from patient-derived tumor xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1225. doi:10.1158/1538-7445.AM2014-1225
Abstract 1233: Inhibition of STAT-3 by piperlongumine induces anoikis, prevents tumor formation in pancreatic cancer in vitro and in vivo
Authors: Fofaria Neel Manoj , Srivastava Sanjay K. 
Published: May 2015

Abstract
Metastasis of pancreatic cancer is a major challenge leading to the failure of its therapy. Hence, novel strategies to prevent metastasis are of prime importance. Anoikis is an anchorage independent cell death. Resistance to anoikis is one of the key features of a metastatic cell. In the current study, we show induction of anoikis by piperlongumine, a component of black pepper, through inhibition of STAT-3. Treatment of various pancreatic cancer cell lines under low attachment conditions with piperlongumine reduced the anoikis resistance in a concentration-dependent manner. The decrease in anoikis resistance was associated with decrease in the expression of STAT-3 and its phosphorylation at Y705. Significant down-regulation of Bcl-2 and Mcl-1, which are under the transcriptional regulation of STAT-3, were also observed by piperlongumine treatment indicating the role of STAT-3 in anoikis. Concentration-dependent cleavage of poly (ADP-ribose) polymerase (PARP) was observed by piperlongumine treatment in these cells. IL-6 treatment not only increased the phophorylation of STAT-3 at Y05 but also abrogated the anoikis induced by piperlongumine in Panc-1 and HPAC cells. Silencing STAT-3 by shSTAT-3 sensitized BxPc-3 and Panc-1 cells to piperlongumine treatment. On the other hand, over-expression of STAT-3 in Panc-1 cells conferred resistance to anoikis induced by piperlongumine. STAT-3 -/- BxPc-3 cells were highly sensitive to anoikis upon piperlongumine treatment. Finally, our in vivo studies established that pancreatic cancer cells treated with piperlongumine in suspension condition lost their potential to form tumors in xenograft model. On the other hand, untreated cells in suspension conditions formed aggressive tumors. Moreover, cells treated with PL in suspension conditions completely failed to metastasize when injected intravenously in mice whereas the untreated cells extensively metastasized in lungs and liver. The presence of metastatic tumors was detected by bioluminescence imaging as well as immunohistochemistry. Taken together, our study suggests that the decrease in anoikis resistance induced by piperlongumine was mediated by STAT-3 inhibition which resulted in reduced tumorigenic as well as metastatic potential of pancreatic cancer cells. Notably, STAT-3 has been shown to be constitutively upregulated in pancreatic cancer rendering it resistant to chemotherapy and potential to metastasize. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Neel Manoj Fofaria, Sanjay K. Srivastava. Inhibition of STAT-3 by piperlongumine induces anoikis, prevents tumor formation in pancreatic cancer in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1233. doi:10.1158/1538-7445.AM2014-1233
Abstract 1234: Tamoxifen synergizes cytotoxic activity of 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD), a novel resveratrol analogue against breast cancer cells
Authors: Ronghe Amruta Mukund , Chatterjee Anwesha , Abdalla Fatma , Bhat Hari K. 
Published: May 2015

Abstract
Tamoxifen is currently the first line of therapy against estrogen receptor (ER)-positive breast cancers. Prolonged treatment with tamoxifen has been associated with the development of resistant tumor phenotypes. Moreover, this treatment strategy is ineffective against ER-negative breast cancers. In this study, we have investigated the role of 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD), a novel analog of resveratrol, either alone or in combination with tamoxifen on the growth inhibition of breast cancer cells. Breast cancer cell lines MCF-7, T47D, MDA-MB-231 and MDA-MB-468 as well as non-neoplastic breast epithelial cell lines MCF-10A, MCF-10F and HMEC were treated with different doses of HPIMBD or a combination of tamoxifen (2µM) and HPIMBD (at its IC50 dose). Cell proliferation was determined by MTT assays. No effect on cell proliferation was observed upon treatment of non-neoplastic breast cells with HPIMBD. A dose dependent growth inhibition was demonstrated upon treatment of breast cancer cells with HPIMBD. IC50 values of HPIMBD were determined. Tamoxifen at a dose of 2µM showed no effect on the growth of breast cancer or non-neoplastic breast epithelial cell lines. However, a significant increase in inhibition of cellular proliferation of breast cancer cells was demonstrated when tamoxifen (2µM) was used in combination with HPIMBD at its IC50 dose. To investigate the mechanism of inhibition, autophagy markers, beclin-1 and LC3B were quantified by Western blot analyses. The combination treatment significantly increased the expression of autophagy marker beclin-1 and the cleavage of LC3BI to LC3BII. Cell cycle analysis showed an arrest in the S-phase by HPIMBD and G0/G1-phase by tamoxifen. Our studies suggest that a combination of tamoxifen and HPIMBD synergistically inhibit the proliferation of breast cancer cells. Autophagy and cell cycle arrest appear to be the primary mechanisms of inhibition by the combination treatment.
Citation Format: Amruta Mukund Ronghe, Anwesha Chatterjee, Fatma Abdalla, Hari K. Bhat. Tamoxifen synergizes cytotoxic activity of 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD), a novel resveratrol analogue against breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1234. doi:10.1158/1538-7445.AM2014-1234
Abstract 1237: Mechanisms of Vernonia amygdalina-induced apoptosis of human breast adenocarcinoma (MCF-7) cells
Authors: Yedjou Clement G. , Tchounwou Paul 
Published: May 2015

Abstract
Breast cancer (BC) is the leading cause of death of women between 40 and 55 years of age and is the second overall cause of death of women. Fortunately, the mortality rate from BC has decreased in recent years due to an increased emphasis on early detection and more effective treatments. Despite early detection and conventional methods of treatment, about 7% of women diagnosed with BC still die every year. Therefore, novel therapeutic agents are needed to improve the clinical outcome of this disease. The development of new drugs from natural products is considered important. Previous studies from our laboratory show that a novel natural product, extracts of Vernonia amygdalina (VA) leaf exerts DNA-damaging anticancer activities against BC. Therefore, the central goal of this research was to determine the therapeutic mechanisms of VA leaf extracts in breast cancer cells. To achieve this goal, cell viability, live and death cells were determined by the means of the MTT assay, trypan blue test, and propidium iodine assay, respectively. Cell apoptosis was measured by flow cytometry analysis of phosphatidylserine externalization (Annexin V assay) and caspase 3 activity, and by DNA laddering assay. Data obtained from the MTT assay indicated that VA significantly reduced the viability of MCF-7 cells a dose-dependent response. On one hand, the Trypan blue dye exclusion test demonstrated the integrity of the membrane of untreated cells in culture. On the other hand, the trypan blue dye exclusion test demonstrated a loss of viability in VA-treated cells due to membrane damage. The result of the propidium iodine demonstrated a significant (p&lt;0.05) increase of necrotic cell death in VA-treated cells, indicative of membrane rupture by VA. Flow cytometry data showed a strong dose-response relationship between VA exposure and Annexin-V positive MCF-7 cells. These results were confirmed by data of DNA laddering assay showing a clear evidence of nucleosomal DNA fragmentation in VA-treated cells. A statistically significant was recorded with regard to caspase 3 activity in MCF-7 cells. Taken together, our research demonstrated that VA represents an apoptosis-inducing agent and its apoptotic mechanisms involve phosphatidylserine externalization, activation of p53 tumor suppressor gene and caspase-3, and nucleosomal DNA fragmentation.
Citation Format: Clement G. Yedjou, Paul Tchounwou. Mechanisms of Vernonia amygdalina-induced apoptosis of human breast adenocarcinoma (MCF-7) cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1237. doi:10.1158/1538-7445.AM2014-1237
Abstract 1240: Bioactive proanthocyanidins from grape seeds inhibit cigarette smoke condensate-enhanced invasion of human non-small cell lung cancer cells by targeting NADPH oxidase and epithelial-mesenchymal transition
Authors: Vaid Mudit , Katiyar Santosh K. 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer-related deaths in the United States, and the dismal 5-year survival rate of approximately 14% has shown no improvement over the past three decades. Cigarette smoke (CS) is the cause of ∼90% of lung cancer cases, and promotes drug resistance in lung cancer patients and is even known to limit effectiveness of treatment of cancers of other organs. It is therefore important to develop more effective strategies targeting CS-induced molecular abnormalities. Cigarette smoking increases oxidative stress particularly via activation of NADPH oxidase (NOX), a key source of superoxide anion production. Here we report the inhibitory effects of bioactive phytochemicals, grape seed proanthocyanidins (GSPs), on the migration potential of human non-small cell lung cancer (NSCLC) cells (A549, H460 and H1299) and assessed whether CS-induced NOX activation is their target. Using an in vitro invasion assay, we found that treatment of NSCLC cells with CS condensate (CSC) increased the migration of NSCLC cells in a dose-dependent manner, via enhancing NOX mediated-reactive oxygen species (ROS) accumulation. Treatment of NSCLC cells with GSPs inhibited the cell migration via reduction in ROS accumulation or oxidative stress and subsequent reduction of epithelial-to-mesenchymal transition. To examine the molecular targets of GSPs, we studied the effect of GSPs on CSC-induced alterations in the levels of key NOX components, namely, p22phox and p47phox, using A549 cells. We also determined the effect of GSPs on CSC-induced interaction between p22phox and p47phox proteins, a key event in NOX activation. Our results indicate that treatment of A549 cells with GSPs not only reverse CSC-induced expression levels of p22phox and p47phox, but also inhibit CSC-induced NOX activation by decreasing the binding of p22phox and p47phox proteins. This new insight into the anti-lung cancer cell migration activity of GSPs could serve as a basis for chemoprevention or therapy of advanced stage of lung cancer in human patients.
Citation Format: Mudit Vaid, Santosh K. Katiyar. Bioactive proanthocyanidins from grape seeds inhibit cigarette smoke condensate-enhanced invasion of human non-small cell lung cancer cells by targeting NADPH oxidase and epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1240. doi:10.1158/1538-7445.AM2014-1240