bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3365: Population pharmacokinetics of oxaliplatin: An analysis across human development in infants, children and adults.
Authors: Nikanjam Mina , Stewart Clinton F. , Takimoto Chris H. , Synold Timothy W. , Capparelli Edmund V. 
Published: August 2014

Abstract
Introduction: Oxaliplatin has been studied in both adult and pediatric clinical trials as therapy for a variety of solid and hematologic malignancies, but no comprehensive pharmacokinetic analysis has been conducted to define the impact of age on oxaliplatin disposition. We combined platinum ultrafiltrate concentration data from 4 separate studies to characterize oxaliplatin pharmacokinetics across a wide range of ages and renal function.
Methods: Oxaliplatin pharmacokinetic data from Phase I and II clinical trials included 2 pediatric studies (median age 11.2 yr, range 1.3 - 22.7) and 2 adult NCI organ dysfunction studies (median age 63 yr, range 28 - 86). Oxaliplatin was given as a 2 hour infusion; the majority of subjects received 130 mg/m2 (range 60 - 160 mg/m2). Plasma samples were obtained 2- 504 hours after dosing with the pharmacokinetic analysis performed using platinum ultrafiltrate concentrations (LLOQ 1-10 ng/mL). In total 161 subjects (1416 samples) were analyzed using nonlinear mixed effects modeling (NONMEM v. VI).
Results: Oxaliplatin concentration data required a four compartment model to characterize later samples. Serum creatinine (SCR) and age were independent predictors of clearance (CL) in the univariate screen, but age was not significant in the multivariate screen. CL increased with allometric weight, but decreased with SCR. Typical values were: 24.6 L/kg (volume of distribution) and 0.526 x (SCR/0.9)0.926 L/h/kg0.75 (CL, variability 63.8%). The final model was used to simulate a dose of 130 mg/m2 in 1000 subjects with the median (IQR) exposure (AUC), CL, and SCR as follows:
SCR (mg/dL) CL (L/hr/m2) AUC (mcg*hr/mL) Age 1 yr 0.7 (0.6–0.8) 7.4 (4.6–11.6) 17.5 (11.2–28.3) Age 5 yr 0.7 (0.6–0.8) 7.9 (4.9–11.7) 16.4 (11.1–26.3) Age 50 yr 1.0 (0.9–1.2) 6.4 (4.3–10.3) 20.3 (12.6–30.4) Age 50 yr (renal dysfunction) 2.2 (1.8–2.6) 3.2 (2.0–4.9) 40.5 (26.3–65.9)
Conclusions: This combined analysis suggests that earlier models limited to 2 or 3 compartments may not characterize the true terminal phase of oxaliplatin. Differences in age were entirely accounted for by weight and renal function. Standard BSA based dosing results in similar AUC and CL values between pediatric and adult patients with adequate renal function.
Citation Format: Mina Nikanjam, Clinton F. Stewart, Chris H. Takimoto, Timothy W. Synold, Edmund V. Capparelli. Population pharmacokinetics of oxaliplatin: An analysis across human development in infants, children and adults. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3365. doi:10.1158/1538-7445.AM2013-3365
Abstract 3368: Pre-clinical PK/PD/efficacy characterization of AZD1480, a JAK1/2 kinase inhibitor.
Authors: Schroeder Patricia 
Published: August 2014

Abstract
Constitutive activation of the transcription factor STAT3, manifest as Y-705 phosphorylation, is a feature of many hematologically-derived and solid tumor malignancies. Accumulating evidence indicates that JAK kinases are the key mediators of STAT activation in solid tumor models. AZD1480, an inhibitor of Janus kinases 1 and 2 (JAK1/2), is a bioavailable small molecule whose inhibition of the JAK-STAT signalling pathway may provide clinical benefit by suppression of the pleiotropic tumorigenic effects of constitutive STAT3 activation (tumor cell proliferation, motility and survival, tumor angiogenesis, tumor immune suppression).
Here we present a pre-clinical population-based effect-compartment pharmacokinetic / pharmacodynamic (PK/PD) model to describe the onset, intensity, and duration of pSTAT3 inhibition as a function of unbound concentration and time in the MDAH-2774 ovarian xenograft mouse model. A mathematical tumor growth inhibition model capturing the relationship between systemic exposure to AZD1480 and tumor growth inhibition was built to provide a pharmacokinetic rationale for tumor growth inhibition. Furthermore, the pSTAT3 inhibition PK/PD relationship for AZD1480 was quantitatively integrated into a tumor growth inhibition model providing a mechanistic pharmacodynamic rationale for tumor growth inhibition pre-clinically. Taken together, these pre-clinical data recommend that increasing inhibition of pSTAT3 correlates with greater tumor growth inhibition and provide a PK/PD/Efficacy platform of evidence for clinical hypothesis testing.
Citation Format: Patricia Schroeder. Pre-clinical PK/PD/efficacy characterization of AZD1480, a JAK1/2 kinase inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3368. doi:10.1158/1538-7445.AM2013-3368
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3376: Mirk/Dyrk1B modulates the development of chemoresistance in human ovarian cancer.
Authors: Gao Jingchun , Li Ji , Gao Heli , Tian Jianxin , Lv Yunyi , Yang Zhihai , Zhang Qiuping , Kong Fandou , Pang Jian , Guan Hongwei , Shi Hong 
Published: August 2014

Abstract
Ovarian cancer is one of the leading causes of cancer death in women and chemoresistance is a major obstacle that need to be overcome in the treatment of ovarian cancer patients. Our previous study along with others have found that the serine/threonine kinase Mirk/Dyrk1B is overexpressed in a wide spectrum of cell lines and clinical specimens of ovarian cancer. It has been known that Mirk/Dyrk1B regulates cell survival and sensitivity to conventional chemotherapeutics, and it also contributes to G0 arrest by destabilization of cyclin D1 and stabilization of p27kip1in ovarian cancer cells. We therefore hypothesize that Mirk/Dyrk1B may be associated with cancer ‘stem cell-like’ sustaining cells and chemoresistance formation. In this study, the mRNA and protein expressions of Mirk/Dyrk1B and the side population (SP) cells in the human ovarian cancer SKOV3, OVCAR5, and A2780S cells were measured during cisplatin resistance development. In addition, the protein expressions of ALDH1, Nanog, Ki-67, and Mirk/Dyrk1B were examined in the clinical specimens obtained from the patients with high-grade serous ovarian cancer before and after neoadjuvant chemotherapy, respectively. It was found that drug resistance formation was accompanied by a significant increase in the mRNA and protein expressions of Mirk/Dyrk1B as well as proportion of SP cells in all ovarian cancer cell strains, which was annulled after knockdown of Mirk/Dyrk1B by shRNA. Moreover, the protein expressions of ALDH1, Nanog, and Mirk/Dyrk1B were up-regulated and ki-67 was down-regulated in the specimens after neodajuvant chemotherapy. Our result confirms the important contribution of Mirk/Dyrk1B-dependent mechanisms into the development of chemoresistance of human ovarian cancer.
Citation Format: Jingchun Gao, Ji Li, Heli Gao, Jianxin Tian, Yunyi Lv, Zhihai Yang, Qiuping Zhang, Fandou Kong, Jian Pang, Hongwei Guan, Hong Shi. Mirk/Dyrk1B modulates the development of chemoresistance in human ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3376. doi:10.1158/1538-7445.AM2013-3376
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 338: Regulation of mutant p53 retarded cell growth established from mouse lung cancer.
Authors: Suh Young-Ah , Jung Chae Lim , Park Ji-Ho , Jang Se Jin 
Published: August 2014

Abstract
The genetic defects in lung cancer patient are the most important factor for malignancies, and it has been reported that approximately 50% of non-small cell lung cancer (NSCLC) patients have mutations in certain tumor-related genes. Therefore, exhaustive efforts have been devoted to uncovering the genetic alterations of lung cancer, although its driving genes and genetic determinants that attribute to the development of lung cancer so far remain elusive.
The K-ras activation due to the mutant is notorious in many kinds of cancer types, including pancreatic cancer and lung adenocarcinoma, as is generally accepted as driving mutation for lung malignancy of lung adenocarcinoma. Another predominantly alternated gene in lung cancer is the EGFR that hits the similar signaling with K-ras activation, to which small molecules and antibodies target to halt the tumor progression. The tumor suppressor p53 is also often altered in almost all kinds of cancers and lung cancer. In this reason, K-ras activated mouse is utilized as lung cancer mouse model. K-ras activated mouse eventually develops lung adenocarcinoma, which can be accelerated with mutated p53.
Due to the gain-of-function, mutant p53 protein contributes to tumor metastasis and shortening of the latency of tumor progression. Thereby activated K-ras/mutant p53 mouse is preferentially used as lung adenocarcinoma preclinical model. Here, we have regulated mutant p53 protein expression in mouse embryo fibroblast (MEF) or tumor cells derived from activated K-ras/mutant p53 mouse with small molecules to inhibit tumor growth. The cell growth was inhibited when the mutant p53 was destabilized. We assessed the mechanism that is responsible for the regulation of gain-of-function metastatic phenotype observed in the p53 mutant mouse
Citation Format: Young-Ah Suh, Chae Lim Jung, Ji-Ho Park, Se Jin Jang. Regulation of mutant p53 retarded cell growth established from mouse lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 338. doi:10.1158/1538-7445.AM2013-338
Abstract 3380: Overcoming platinum resistance in ovarian cancer using the novel compound MLN4924.
Authors: Jazaeri Amir A. , Shibata Etsuko , Park Jonghoon , Bryant Jennifer , Conaway Mark R. , Modesitt Susan C. , Smith Peter G. , Milhollen Michael , Berger Allison J. , Dutta Anindya 
Published: August 2014

Abstract
Purpose: The objective of this investigation was to evaluate the preclinical activity of MLN4924, an investigational inhibitor of the NEDD8-activating enzyme, against chemoresistant and chemosensitive ovarian cancer cells.
ExperimentalDesign: Efficacy of MLN4924 both alone and in combination with cisplatin was assessed using short-term tetrazolium based and longer term focus formation assays. Mechanistic studies included cell cycle analysis, evaluation of DNA-platinum adduct formation (using an ELISA), and evaluation of DNA damage repair pathways. In addition, we employed an siRNA screen to assess the contribution of each member of the Cullin RING-Ligase (CRL) family of E3 ubiquitin ligases, the best characterized downstream mediators of MLN4924’s biological effects.
Results: Single agent MLN4924 exhibited moderate activity in ovarian cancer cell lines. The combination of MLN4924 with cisplatin or carboplatin resulted in significant platinum sensitization in SKOV3 and ES2 cells, as well as, in several primary ovarian cancer cell lines established from high grade serous, clear cell, and serous borderline ovarian tumors. Furthermore, the platinum sensitizing effect of MLN4924 was also observed in several in vitro models of platinum resistant ovarian cancer (using both established and primary chemoresistant ovarian cancer cells). Mechanistically, we show that depletion of CUL3 and CUL5 augment, while knockdown of CUL1 and CUL4A antagonize cisplatin-induced cytotoxicity in ovarian cancer cells. The combination of cisplatin and MLN4924 was not associated with DNA re-replication, altered platinum-DNA adduct formation, or abrogation of FANCD2 monoubiquitination.
Conclusions: Our investigation reveals a novel mechanism for overcoming platinum resistance in vitro, and provides a strong rationale for clinical investigations of platinum and MLN4924 combinations in ovarian cancer. This work also highlights that different CRL ubiquitination pathways can have distinct and opposing effects on platinum sensitivity and resistance in ovarian cancer cells.
Citation Format: Amir A. Jazaeri, Etsuko Shibata, Jonghoon Park, Jennifer Bryant, Mark R. Conaway, Susan C. Modesitt, Peter G. Smith, Michael Milhollen, Allison J. Berger, Anindya Dutta. Overcoming platinum resistance in ovarian cancer using the novel compound MLN4924. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3380. doi:10.1158/1538-7445.AM2013-3380
Abstract 3389: Nuclear accumulation of c-Rel transcription factor is correlated with the proteasome inhibitor resistance in mantle cell lymphoma.
Authors: Blonska Marzenna , Pan Deng , Ou Zhishuo , Zhang Liang , Lin Xin , Wang Michael 
Published: August 2014

Abstract
Purpose: Nuclear factor kB (NF-kB) plays essential roles in survival and drug resistance of multiple malignancies including mantle cell lymphoma (MCL) and multiple myeloma (MM). Proteasome inhibitors have been shown to block constitutively active NF-kB and clinical data indicates a high overall response of MCL and MM patients to this treatment. The 2nd generation proteasome inhibitor, carfilzomib (CFZ), has a therapeutic effect on relapsed or refractory disease and low toxicity to normal lymphocytes. However, there are increasing numbers of proteasome inhibitor-resistant cases. Thus, this study was designed to identify the molecular mechanism that leads to CFZ-resistance.
Experimental design: In this study we have determined the cytotoxic effect of CFZ in a panel of MM and MCL cell lines, as well as primary tumor cells. The cell growth inhibition was assessed by the thymidine intake and MTT assay. NF-kB activity was examined by electrophoretic mobility shift assay (EMSA) using nuclear extracts from CFZ-treated and control cells. Nuclear pattern of NF-kB family members, such as RelA/p50, cRel/p50 and RelB/p52 complexes, was analyzed by supershift and western blot.
Results: CFZ-induced NF-kB inhibition was not observed in two (out of eight) examined cell lines, even with the highest doses (100 nM). Consistently, cell growth was suppressed only in cells with a CFZ-sensitive NF-kB activity (IC50&lt;20 nM), as shown by EMSA and MTT assay. In contrast, the treatment with proteasome inhibitor increased the nuclear accumulation and DNA binding of NF-kB in CFZ-resistant cells. Furthermore, we have found that only these cells had upregulated c-Rel/p50 member of NF-kB family. Supershift analysis revealed that all examined cell lines and primary cells had constitutively active classical (RelA/p50 dimer) and/or non-classical (RelB/p52 dimer) NF-kB, excluding CFZ-resistant cells with prominent nuclear accumulation of c-Rel. This data suggests that activated c-Rel may trigger resistance to CFZ. Enhanced nuclear accumulation of c-Rel is also an unwanted molecular consequence of exposure to CFZ.
Conclusion: Our work indicates the need for new treatment strategies in c-Rel-positive cases. A strategic combination targeting different signaling mediators, especially upstream of c-Rel, would enhance the ultimate anticancer effect.
Citation Format: Marzenna Blonska, Deng Pan, Zhishuo Ou, Liang Zhang, Xin Lin, Michael Wang. Nuclear accumulation of c-Rel transcription factor is correlated with the proteasome inhibitor resistance in mantle cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3389. doi:10.1158/1538-7445.AM2013-3389
Abstract 3391: Overexpression of Nek2 promotes bortezomib resistance in multiple myeloma cells.
Authors: Flory Jessica , Brog Rachel , Meng Ling Yao , Call Lee , Vankayalapati Hariprasad , Tricot Guido , Zhan Fenghuang , Bearss David J. 
Published: August 2014

Abstract
Drug resistance is a major complication in cancer therapy but the molecular mechanisms driving both innate and acquired drug resistance still remain largely unknown for many anti-cancer agents. Microarray analyses on paired primary multiple myeloma samples at baseline and after therapy or at relapse showed that the mitotic kinase NEK2 was one of the most up-regulated genes in myeloma cells after high-dose chemotherapy or at relapse. Nek2 is a Serine/Threonine kinase that is activated during mitosis and is associated centrosome function and structure at the G2/M transition. A role for Nek2 has been suggested in the separation of centrosomes as well as promoting cell cycle from G2 phase to M phase but no role for Nek2 in mediating drug resistance has been described. By analyzing the published (&gt; 2,500) microarrays and clinical datasets, we found that NEK2 expression is increased in many malignancies, and that high expression of NEK2 was associated with a shorter event-free and overall survival. Moreover, NEK2 expression was typically increased in tumors with aggressive subtype and advanced stage. Our studies in myeloma cells indicate that over-expressing NEK2 results in enhanced cell proliferation and drug resistance, whereas knockdown of NEK2 induced significant cancer cell death and growth inhibition. Nek2 transfected myeloma cell lines ARP1, H929 and KMS28PE were used to investigate Nek2’s function relative to bortezomib resistance. We found that Nek2 over-expression significantly elevated the proteasome activity of transfected cells leading to decreased activity of Bortezomib in these cells. Using novel small molecule Nek2 inhibitors developed in our lab, we demonstrated efficient inhibition of proteasome activity in Nek2 over-expressing cancer cell lines. The treatment of cell with our lead compounds significantly inhibited the degradation of some proteasome targeted cell cycle regulators. Further, the combinations of these Nek2 inhibitors and bortezomib, greatly elevated the efficiency of bortezomib in decreasing the proteasome activity in vitro. The treatment with these novel Nek2 inhibitors successfully rescued the drug resistance in Nek2 over-expressed cells, indicating a potential therapy for bortezomib resistant myeloma patients. We conclude that NEK2 represents a predictor for drug resistance and poor prognosis in cancers and could be a potential target for cancer therapy.
Citation Format: Jessica Flory, Rachel Brog, Ling Yao Meng, Lee Call, Hariprasad Vankayalapati, Guido Tricot, Fenghuang Zhan, David J. Bearss. Overexpression of Nek2 promotes bortezomib resistance in multiple myeloma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3391. doi:10.1158/1538-7445.AM2013-3391
Abstract 3392: New findings of kinase switch in gastrointestinal stromal tumor under imatinib using phosphoproteomic analysis.
Authors: Ako Maiko , Takahashi Tsuyoshi , Serada Satoshi , Fujimoto Minoru , Miyazaki Yasuaki , Shimada Kazuki , Ikezoe Takayuki , Taguchi Takahiro , Kurokawa Yukinori , Yamasaki Makoto , Miyata Hiroshi , Nakajima Kiyokazu , Takiguchi Shuji , Mori Masaki , Doki Yuichirou , Naka Tetsuji , Nishida Toshirou 
Published: August 2014

Abstract
Despite the initial effectiveness of imatinib for gastrointestinal stromal tumors (GISTs), patients must continue lifelong imatinib therapy, and may eventually relapse owing to acquired drug resistance. Pathology reveals the persistence of viable cells during imatinib therapy, even in the disappearance region upon radiological examination. These cells are thought to cause acquired drug resistance and relapse. To uncover the mechanisms underlying these clinical issues, we used GIST-T1 cells to investigate the phosphoproteomic alterations induced by imatinib treatment. Because some tyrosine kinases might be activated after imatinib exposure, it is important to reveal the increased phosphorylation of proteins on a proteomic scale, and elucidate drug-resistant proteins. Proteins extracted from imatinib-treated or untreated GIST-T1 cells were digested with trypsin. The resulting tyrosine-phosphorylated peptides were purified using an immunoaffinity-enriched and iTRAQ-labeled reagent, and analyzed using mass spectroscopy. Using this phosphoproteomic approach, we identified 171 tyrosine phosphorylation sites spanning 134 proteins. We also detected increased tyrosine phosphorylation of Fyn (Y420) and focal adhesion kinase (FAK) (Y576). Increased phosphorylation was also confirmed by Western blot analysis, and knockdown of Fyn or FAK increased cells’ sensitivity to imatinib. Furthermore, the anti-proliferative effect of imatinib significantly enhanced imatinib-resistant GIST-T1 cells, which exhibited constitutive phosphorylation of FAK when treated with a FAK-selective kinase inhibitor. Moreover, FYN was proved to be a signal of FAK of upper reaches.
These results indicate that an iTRAQ-based quantitative phospho-tyrosine-focused phosphoproteomic approach is a powerful method for screening phosphoproteins associated with drug resistance. Fyn or FAK might be potential therapeutic targets to overcome acquired resistance to imatinib in GISTs.
Citation Format: Maiko Ako, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Yasuaki Miyazaki, Kazuki Shimada, Takayuki Ikezoe, Takahiro Taguchi, Yukinori Kurokawa, Makoto Yamasaki, Hiroshi Miyata, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichirou Doki, Tetsuji Naka, Toshirou Nishida. New findings of kinase switch in gastrointestinal stromal tumor under imatinib using phosphoproteomic analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3392. doi:10.1158/1538-7445.AM2013-3392