bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4405: Tumor-targeted nanotherapeutics
Authors: Garbuzenko Olga B. , Kuzmov Andriy , Sapiezynski Justin E. , Taratula Oleh , Shah Vatsal , Zhang Min , Savla Ronak , John Shali , Rodriguez-Rodriguez Lorna , Minko Tamara 
Published: August 2015

Abstract
Directing anticancer agents specifically to tumors and/or cancer cells by targeting specific extracellular receptors fulfills the following three most important tasks: (1) preventing or at least substantially limiting adverse side effects on healthy tissues, (2) enhancing drug internalization by cancer cells, and (3) overcoming (at least in part) resistance mechanisms that are based on the active efflux of exogenous drugs from cancer cells.
We developed several tumor-targeted nanoscale-based formulations: various nanocarriers (liposomes, lipid nanoparticles, dendrimers, polymers, quantum dots, mesoporous silica and supermagnetic iron oxide nanoparticles); different anticancer drugs (doxorubicin, paclitaxel, camptothecin, and cisplatin); suppressors of cellular drug resistance and tumor grows (antisense oligonucleotides or siRNA targeted to BCL2, MDR1, MRP1, HIF1A, CD44 mRNA); and tumor-targeting agent - luteinizing hormone-releasing hormone (LHRH).
The proposed nanotherapeutics were tested in vitro and in vivo using established lung and ovarian cancer cell lines and highly metastatic cancer cells isolated from malignant intraperitoneal ascites from patients with advanced ovarian carcinoma. These cells were used to initiate orthotopic models of lung and ovarian cancers in nude mice that were often accompanied by the development of metastases. Tumor-targeted nanoscale-based drug formulations were delivered intravenously and intraperitoneally (for ovarian cancer) or intravenously and by inhalation (for lung cancer). Treatment with the developed therapeutics led to the suppression of targeted proteins, efficient induction of cell death, effective tumor shrinkage, prevention the development of metastases and limitation of adverse side effects.
Acknowledgements: The work was supported by R01CA100098, R01CA111766, and R01CA138533 grants from NIH.
Note: This abstract was not presented at the meeting.
Citation Format: Olga B. Garbuzenko, Andriy Kuzmov, Justin E. Sapiezynski, Oleh Taratula, Vatsal Shah, Min Zhang, Ronak Savla, Shali John, Lorna Rodriguez-Rodriguez, Tamara Minko. Tumor-targeted nanotherapeutics. [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 4405. doi:10.1158/1538-7445.AM2015-4405
Abstract 441: IL-17 and IL-17-producing cells associated with advanced stage or poor prognosis in oral cancers, through enhancing tumor progression
Authors: Lee Meng Hua 
Published: August 2015

Abstract
Introduction: Interleukin 17 (IL-17) majorly produced by Th17 and Tc17 cells, contributes greatly in inflammatory associated diseases. However, its presence was reported to suppress tumor growth by enhancing cytotoxic T cell responses. On the contrary, through inducing angiogenesis, IL-17 appeared to promote tumor progression. Here we demonstrated IL-17 and their producing cells directly correlating with advanced stage or poor prognosis of oral cancer patients.
Methods: Peripheral blood samples were obtained from the oral patients in Chang Gung Memorial Hospital, and the multi-color flow cytometric analysis and enzyme conjugated immunoassays were utilized to identify the IL-17 producing T cell subsets and to quantify the production of inflammation-associated cytokines. The effects of IL-17 on the growth and invasion of oral cancer cells were determined with the supplement with recombinant IL-17 (γhIL-17) and cell culture supernatant.
Results: The significantly increased prevalence of IL-17-producing T cells was correlated with clinical stage and the patients’ peripheral blood mononuclear cells secreted higher amount of IL-17 and other related factors. Such responses also appeared to be associated with poor prognosis. Moreover, the stimulation of γhIL-17 apparently induced cell proliferation, migration and invasion in oral cancer cells, indicating that IL-17 directly contribute to tumor progression.
Conclusion: These findings suggest IL-17 and its related factors are crucial to tumor development, and such responses may therefore lead to the clinical impact of advanced stage or poor prognosis in oral cancer.
Citation Format: Meng Hua Lee. IL-17 and IL-17-producing cells associated with advanced stage or poor prognosis in oral cancers, through enhancing tumor progression. [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 441. doi:10.1158/1538-7445.AM2015-441
Abstract 4411: Oral drug formulations containing microspheres
Authors: Do Duc P. , Kar Alexander 
Published: August 2015

Abstract
Oral anticancer drug formulations are considerably favorable not only for patient adherence, but also for ease of administration. The main objective of the present research was to develop extended-release capsule formulations containing doxorubicin hydrochloride-encapsulated albumin microspheres. Albumin-based polymeric microspheres were evaluated as a potential platform technology for providing extended-release of oral dosage formulations. Bovine serum albumin microspheres were prepared by spray drying and characterized for their physicochemical properties. Scanning electron microscopy (SEM) was used to analyze the size, surface morphology, and size distribution of the drug-loaded microspheres. Zeta potential measurements were carried out to assess the surface properties and stability of the microsphere formulations. Dissolution studies were conducted to analyze the release profiles of the microspheres and capsule-containing microsphere drug formulations. SEM analysis indicated that microspheres were less than 2-μm in size, which is considered to be optimal for uptake by the enterocytes. The average Zeta potential measurements were approximately -30 mV. Additionally, the data showed that microspheres, which contained 1% BSA and 0.1% glutaraldehyde, provided a drug release profile that is desirable for cancer therapy. Both microsphere and capsule-encapsulating microsphere formulations were shown to provide extended-release of the drug over 36 hours. Thus, capsules containing biodegradable microspheres show potential for effective delivery of oral drug formulations.
Citation Format: Duc P. Do, Alexander Kar. Oral drug formulations containing microspheres. [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 4411. doi:10.1158/1538-7445.AM2015-4411
Abstract 4417: Vatalanib targets ABCG2-overexpressing multidrug resistant colon cancer cells under hypoxia
Authors: To Kenneth K. , Poon Daniel C. , Wei Yuming , Wang Fang , Lin Ge , Fu Li-wu 
Published: August 2015

Abstract
Cancer microenvironment is characterized by significantly lower oxygen concentration. This hypoxic condition is known to reduce drug responsiveness to cancer chemotherapy via multiple mechanisms, among which the upregulation of an efflux transporter ABCG2 confers resistance to a wide variety of structurally unrelated anticancer drugs. Vatalanib (PTK787) is a multitargeted tyrosine kinase inhibitor for VEGFR2, Flt and c-Kit, which exhibit potent anticancer activity in vitro and in vivo. We investigated the potentiation effect of vatalanib on the anticancer activity of conventional cytotoxic drugs in colon cancer cell lines under both normoxic and hypoxic growth conditions. More significant synergistic anticancer activity was observed under hypoxic condition. Mechanistically, vatalanib was found to inhibit ABCG2 and P-gp efflux activity, probably by acting as an uncompetitive inhibitor and interfering with their ATPase activity. Under hypoxic growth condition, ABCG2-overexpressing cells sorted out by FACS technique as side population cells (SP) were found to be significantly more responsive to irinotecan (an ABCG2 substrate anticancer drug) in the presence of vatalanib. The colony formation capactiy of these SP cells was remarkably reduced upon treatment with a combination of irinotecan and vatalanib, compared to irinotecan alone. However, vatalanib, at concentrations that produced the circumvention of ABCG2-mediated resistance, did not appreciably alter ABCG2 mRNA or protein expression levels or the phosphorylation of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2). Vatalanib was also evaluated for potential interference with the cytochrome P450 metabolic enzymes by a rapid N-in-one in vitro interaction screening assay. The result indicates that vatalanib is only a mild inhibitor of both CYP34A and CYP2D, two major drug-metabolizing P450 enzymes, which presumably may avoid the undesirable drug-drug interactions in combination therapy. Our study thus advocates the further investigation of vatalanib for use in combination chemotherapy to circumvent hypoxia-mediated drug resistance.
Citation Format: Kenneth K. To, Daniel C. Poon, Yuming Wei, Fang Wang, Ge Lin, Li-wu Fu. Vatalanib targets ABCG2-overexpressing multidrug resistant colon cancer cells under hypoxia. [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 4417. doi:10.1158/1538-7445.AM2015-4417
Abstract 4423: Chemoresistance regulation by COL11A1 in ovarian cancer
Authors: Wu Yi-Hui 
Published: August 2015

Abstract
Epithelial ovarian carcinoma remains the most lethal gynecologic malignancy. While initial response to first-line therapy (consisting of surgical cytoreduction and combination platinum/taxane therapy) is usually effective, the majority of patients will ultimately recur with chemotherapy-resistant cancer and succumb to disease. Biomarkers that predict patient's responsiveness to chemotherapy might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the molecular mechanisms of collagen type XI alpha 1 (COL11A1) in chemo-resistance of ovarian cancer. We analyzed the expression profiles of 60 epithelial ovarian cancer tissue samples obtained at first cytoreductive surgery to identify genes linked with chemotherapy response. Among the 47 selected genes, collagen type XI alpha 1 (COL11A1) was the most highly elevated in chemo-resistance tumors. Small interfering RNA-mediated specific reduction of COL11A1 protein levels increased the sensitivity of ovarian chemoresistant cells to cisplatin and paclitaxel. A combination of experimental approaches, including real-time RT-PCR, western blotting, luciferase assay and chromatin immunoprecipitation (ChIP) assays, showed that the c/EBPβ binding site on the COL11A1 promoter was identified as the major determinant of cisplatin and paclitaxel-dependent COL11A1 activation. Furthermore, COL11A1 silencing suppressed phosphorylated Akt expression, which was in concert with increased PDK1 degradation in chemoresistant cells. Analysis of 104 EOC patients showed that high COL11A1 mRNA levels are significantly associated with poor chemoresponse and poor clinical outcome. In conclusion, activation of COL11A1 by anticancer drugs confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization.
Note: This abstract was not presented at the meeting.
Citation Format: Yi-Hui Wu. Chemoresistance regulation by COL11A1 in ovarian 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 4423. doi:10.1158/1538-7445.AM2015-4423
Abstract 4425: Multiple -omic analyses of a pair of primary HCC tumor cell lines with different drug response revealed the mechanisms of drug resistance
Authors: Hu Gang , Du Alicia , Huang Yong , Liu Kunyan , Xie Fubo , Tang Xuzhen , Yang Xueyan , Gu Qi , Zhang Yixin , Tao Weikang , Zhang Yingjia , Tang Wei , Zhou He 
Published: August 2015

Abstract
Previously we reported the establishment of a pair of primary HCC cell lines from LIX-004, a patient-derived HCC xenograft model. LIXC004-NA was developed from an untreated PDX tumor; LIXC004-SR was generated from a PDX tumor progressed despite long term in vivo treatment with sorafenib. The two cell lines displayed similar response to sorafenib treatment in vitro. However, LIXC004-NA is sensitive and LIXC004-SR is resistant to sorafenib treatment in vivo. IHC and in vitro functional studies revealed activation of alternative angiogenic pathways as one of the potential reasons for the sorafenib resistance of LIXC004-SR. To fully explore different mechanisms/pathways, we performed a) micro-array analyses; b) whole exome sequencing; c) RNA-seq analyses of the two cell lines; d) metabolomic analyses of the cell lines in vitro culture in the presence and absence of different therapeutics; e) RNAseq analyses of the tumors derived from these two cell lines. The combination of different types of -omic analyses is our systematic approach to address the potential mechanisms of drug resistance without bias. The two cell lines shared a lot of the genetic mutation and expression profile for most genes. Differentially mutated or expressed genes were also identified at basal level. More changes were observed with the treatment of different therapeutics as well as analyses of the xenograft derived from the cell lines. Pathway analyses are performed to explore the underlying mechanisms for the development of drug resistance.
Citation Format: Gang Hu, Alicia Du, Yong Huang, Kunyan Liu, Fubo Xie, Xuzhen Tang, Xueyan Yang, Qi Gu, Yixin Zhang, Weikang Tao, Yingjia Zhang, Wei Tang, He Zhou. Multiple -omic analyses of a pair of primary HCC tumor cell lines with different drug response revealed the mechanisms of drug resistance. [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 4425. doi:10.1158/1538-7445.AM2015-4425
Abstract 4427: Apoptosis, autophagy and ATP: The dynamic interaction of cellular ATP and drug resistance in MET amplified gastric cancer
Authors: Dunbar Schroeder Rebecca , Hong David , McConkey David J. 
Published: August 2015

Abstract
Background: MET amplification occurs in 20% of gastric tumors, MET protein overexpression is present in approximately 50% of advanced gastric cancers and activating MET mutations are exceedingly rare in gastric cancer. Several ongoing trials have reported responses in gastric and esophageal patients with MET amplification .Methods: To investigate the effects, of MET inhibition on proliferation and cell death in gastric cancer I used two complementary approaches 1) siRNA mediated knockdown of MET; 2) incubation with crizotinib, a clinically approved small molecule inhibitor of MET. Both resulted in decreased proliferation and increased cell death only in the MET amplified gastric cancer cell lines. Results: The effects on growth arrest were stronger than the effects on cell death. To look for possible resistance mechanisms we performed whole genome mRNA expression profiling. Molecular changes related to autophagy were among the top alterations observed. Consistent with these findings, autophagy levels increased in a concentration dependent manner when exposed to crizotinib. In order to investigate the role of autophagy on cell death, I inhibited autophagy using two approaches 1) siRNA mediated knockdown of ATG5 and ATG7; 2) exposure to chloroquine, a clinically approved agent that inhibits autophagy by raising lysosomal pH. I then measured apoptosis levels with the autophagy inhibitor alone or in combination with MET knockdown or crizotinib. Autophagy inhibition caused a dramatic decrease in apoptosis in one of the MET amplified cell lines (MKN45) but not in the other (SNU-5). Because autophagy provides energy for cells, we explored the effects of MET or autophagy inhibition on cellular ATP levels using the Cell Titer-glo assay. The MKN45 cells had the lowest basal levels of ATP and these levels were further diminished in combination with autophagy inhibition. Conclusions: Overall, our data reveal a novel relationship between low ATP levels and resistance to MET inhibitor-induced cell death. Clinically this is significant because it may discourage the use of combination therapies with autophagy inhibitors in gastric cancer patients whose tumors contain MET amplification.
Citation Format: Rebecca Dunbar Schroeder, David Hong, David J. McConkey. Apoptosis, autophagy and ATP: The dynamic interaction of cellular ATP and drug resistance in MET amplified gastric 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 4427. doi:10.1158/1538-7445.AM2015-4427
Abstract 4429: EGR1-MIR152 pathway overcomes acquired cisplatin resistance in ovarian cancer cells by inhibiting cyto-protective autophagy via ATG14
Authors: He Jun , Yu Jing-Jie , Jiang Bing-Hua 
Published: August 2015

Abstract
The cytotoxic-based platinum compound cisplatin has been commonly used in ovarian cancer treatment for almost three decades. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for overall survival. A growing body of evidence indicates a role of autophagy as a prosurvival and resistance mechanism against chemotherapy. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatin-resistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in human ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatin resistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin resistance by preventing cyto-protective autophagy in ovarian cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Jun He, Jing-Jie Yu, Bing-Hua Jiang. EGR1-MIR152 pathway overcomes acquired cisplatin resistance in ovarian cancer cells by inhibiting cyto-protective autophagy via ATG14. [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 4429. doi:10.1158/1538-7445.AM2015-4429
Abstract 4455: Relapsed/refractory AML responds robustly to IACS-10759, a novel OXPHOS inhibitor
Authors: Protopopova Marina , Bandi Madhavi , Bardenhagen Jennifer , Bristow Christophor , Carroll Christopher , Chang Edward , Feng Ningping , Gay Jason , Geck Do Mary , Greer Jennifer , Konopleva Marina , Matre Polina , Kang Zhijun , Liu Gang , Muller Florian , Lofton Timothy , McAfoos Timothy , Theroff Jay , Sun Yuting , Wu Yuanqiang , Smith Melinda , Chin Lynda , Draetta Giulio , Jones Philip , Toniatti Carlo , Di Francesco M. Emilia , Marszalek Joseph R. 
Published: August 2015

Abstract
Acute myeloid leukemia (AML) is a highly aggressive disease that is made up of several genetically and clinically diverse hematological malignancies that are characterized by clonal expansion of malignant stem/progenitor cells with limited ability to differentiate into mature blood cells. Standard of care for AML has progressed minimally in the past 30 years for relapse/refractory AML, with survival rates of &lt;12% for those aged &gt;65 years. Therefore, novel, highly effective therapeutics are needed for this population. Growing evidence suggests that in AML, metabolism is altered and that the tumor cells become highly dependent of mitochondria oxidative phosphorylation (OXPHOS) for their survival. We developed IACS-10759 as a novel small molecule inhibitor of complex I that potently inhibits oxygen consumption, eliminates hypoxia, and strongly inhibits the proliferation of cells grown in galactose medium with EC50 values between 1-10 nM. When AML cell lines as well as primary AML cells from relapsed/refractory patients were treated ex vivo with IACS-10759, apoptosis was robustly induced with EC50 values also ranging between 1-10 nM. It is noteworthy, that while apoptosis was induced in primary AML cells, normal patient-derived bone marrow cells were not sensitive. In AML orthotopic xenografts, daily oral dosing with 15 mg/kg IACS-10759 extended median survival to 70 days from 18 days in control animals. Taken together, the robust response in AML cell lines, primary AML samples ex vivo, and efficacy in orthotopic xenografts, IACS-10759 has entered IND enabling studies with first-in-human studies targeted for third quarter of 2015.
Citation Format: Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christophor Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Jay Theroff, Yuting Sun, Yuanqiang Wu, Melinda Smith, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. Relapsed/refractory AML responds robustly to IACS-10759, a novel OXPHOS inhibitor. [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 4455. doi:10.1158/1538-7445.AM2015-4455