bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4887: Mitochondrial SOD2 is the mainstay to protect the stemness-featured glioblastoma cells against drug-induced reactive oxygen stress
Authors: Chang Kwang-Yu , Chien Chia-Hung , Chu Jui-Mei , Chung Pei-Hsuan , Liu Ming-Sheng , Chuang Jian-Ying 
Published: August 2018

Abstract
Glioblastoma (GBM) is a highly aggressive primary brain tumor with presence of stemness-featured cells that are prone to survive from cancer treatment. We reported Sp1-induced SOD2 was associated with the process to acquire temozolomide (TMZ) resistance that the significance remained to be elucidated. Resistant models were established through long-term coincubation with TMZ in GBM cell lines, which expressed significantly higher stemness properties in extreme limiting dilution analysis (ELDA) and serial transplantation. These cells also showed increased expression of SOD2. Enrichment of stemness-featured cells by spheroid culturing or by CD133-positive cells selection resulted in increased SOD2, suggesting their associations. The impact of the protein to glioma stem cells (GSCs) was then studied through SOD2 RNA interference (RNAi), displaying downregulated stemness features in the knockdown models. Functional studies of the resistant cells showed superior scavenging ability in TMZ- or H2O2-induced ROS that would be dysfunctioned in pretreatment with SOD2 RNAi. In addition, co-treatment with the reagents over the knockdown cells resulted in enhancement of apoptosis as well as inhibition in tumor spheroid culture and cell clonogenic formation, suggesting re-sensitization to the drug. By establishing in vivo model from patient derived xenograft implantation that was obtained from clinical resistant disease, the mouse receiving combination treatment with TMZ and SOD inhibitor had lower tumor proliferation comparing to those receiving TMZ alone. These data indicate that there was an association between SOD2 and the stemness features, suggesting the protein to play important roles in regulation of GSCs behavior. Down-regulation of SOD2 levels may thus be a potential therapeutic strategy for modulating stemness properties of GSCs, making these cells more susceptive to the chemo-therapeutic agent.
Citation Format: Kwang-Yu Chang, Chia-Hung Chien, Jui-Mei Chu, Pei-Hsuan Chung, Ming-Sheng Liu, Jian-Ying Chuang. Mitochondrial SOD2 is the mainstay to protect the stemness-featured glioblastoma cells against drug-induced reactive oxygen stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4887.
Abstract 4890: Understanding the crosstalk between glycosylation and drug resistance
Authors: Thulasiraman Padmamalini , Kerr Kelbie 
Published: August 2018

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 glycoproteins (MRPs). These transmembrane proteins efflux drugs across the plasma membrane, conferring resistance of cancer cells to anticancer drugs. Elevated expression of Multidrug Resistance Protein 1 (MRP1) has been associated with poor prognosis and survival rate among breast cancer patients. Acquiring drug resistance has been correlated to the emergence of metastasis, accounting for the progression of the disease. Altered cell-surface glycosylation is a common feature of cancer initiation and progression. During glycosylation, the MRP1 undergoes N-linked glycosylation but it is unclear how glycosylation impacts the drug transport activity. To examine the crosstalk between MRP1 and Neuraminidase 1 (Neu1), the enzyme that catalyzes the removal of sialic acid residues from glycoproteins, we initiated our studies using plant derived natural product honokiol to examine the effect of honokiol on Neu1. In this study, we demonstrated that honokiol suppressed Neu1 in two breast cancer cell lines using Western Blot Analysis. To determine whether there is a link between Neu1 and MRP1 in improving the efficacy of doxorubicin-facilitated growth suppression, we treated the breast cancer cells with Neu1 inhibitor, Oseltamivir Phosphate (OP) and demonstrated that at 600 ug/ml and 800 ug/ml, OP suppressed breast cancer cell growth. OP in combination with doxorubicin reduced growth of breast cancer cells and enhanced the efficacy of doxorubicin-mediated growth inhibition. Future studies are underway to examine the effect of OP and honokiol on the glycosylation of MRP1. We propose that these studies will lead to the understanding on how glycosylation of MRP1 contributes to the transport of chemotherapeutic agents and eventually to the spread of the disease.
Citation Format: Padmamalini Thulasiraman, Kelbie Kerr. Understanding the crosstalk between glycosylation and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4890.
Abstract 4892: Del-1 promotes the proliferation and migration of tamoxifen-resistant breast cancer
Authors: Chae Yee Soo , Kim Jong Gwang , Jeong Jae-Hwan , Lee Soo Jung , Lee Jeeyeon , Jung Jin Hyang , Park Ho Yong , Baek Moon-Chang , J Senten Richard , Park Ji Young 
Published: August 2018

Abstract
Background: We previously demonstrated a prognostic role of exosomal Del-1 with breast cancer patients. However, the mechanisms of Del-1 expression are barely understood. Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Accordingly, we investigated the function of Del-1 in tamoxifen-resistant (TAMR) breast cancer cell line and tumor specimens.
Materials and Methods: Del-1 expression in MCF7 and TAMR MCF7 cells was performed by quantitative RT-PCR, western blot, and ELISA. The effects of Del-1 with RNA interference on proliferation, migration and invasion of TAMR MCF7 cells were observed by MTT, wound healing and Matrigel transwell assay. Meanwhile, the tumoral expression of Del-1 was determined immunohistochemistry (IHC) from 10 tamoxifen resistant-breast cancer patients. Tumor tissue before (tamoxifen sensitive) and after tamoxifen resistance were assessed.
Results: Del-1 was highly expressed in TAMR MCF7 cells compared to MCF7 cells (p&lt;0.001). And the expression of secretory del-1 was also increased in the culture media of TAMR MCF7 cells. Moreover, down-regulation of Del-1 significantly inhibited the proliferation and migration of TAMR MCF7 cells. There was no difference in the invasion of TAMR MCF7 cells. Increased Del-1 expression was preferentially observed in in TAMR tumor tissues when compared to tamoxifen sensitive or normal breast tissue.
Conclusion: Prominent expression of Del-1 in TAMR MCF7 cells was associated with the proliferation and migration of TAMR MCF7 cells. And the tumoral expression of Del-1 was also significantly associated with tamoxifen resistance. These results suggest that the expression of Del-1 promote tamoxifen resistance in breast cancer cells and could be a novel target for anti-breast cancer treatment.
Citation Format: Yee Soo Chae, Jong Gwang Kim, Jae-Hwan Jeong, Soo Jung Lee, Jeeyeon Lee, Jin Hyang Jung, Ho Yong Park, Moon-Chang Baek, Senten Richard J, Ji Young Park. Del-1 promotes the proliferation and migration of tamoxifen-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4892.
Abstract 4895: Human ATP-binding cassette proteins ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines
Authors: Hsiao Sung-Han , Vahedi Shahrooz , Ambudkar Suresh V. , Wu Chung-Pu 
Published: August 2018

Abstract
Histone deacetylase 6 (HDAC6), localized primarily in the cytoplasm, is responsible for the deacetylation of non-histone substrates such as α-tubulin and heat shock protein 90 (Hsp90). HDAC6 has recently emerged as an important epigenetic therapeutic target for cancer, and much effort has been invested into developing novel inhibitors of HDAC6. Ricolinostat (ACY-1215) is the first safe and well tolerated inhibitor of HDAC6 that has progressed into human clinical trials, both as a single agent and in combination therapy. Ricolinostat is currently under evaluation in phase I and II clinical trials in patients with multiple myeloma, relapsed or refractory lymphoid malignancies, relapsed chronic lymphocytic leukemia, unresectable or metastatic breast cancer and for the treatment of gynecological cancer. The overexpression of ATP-binding cassette (ABC) drug transporters ABCB1 and ABCG2 in cancer cells is often associated with the development of multidrug resistance (MDR) phenotype and poor clinical outcome in patients with metastatic breast cancer, chronic lymphocytic leukemia or relapsed multiple myeloma. In this study, we report that ABCB1 and ABCG2 are capable of actively transporting and conferring resistance to ricolinostat. Moreover, we demonstrated that the efficacy of ricolinostat on the activity of HDAC6 and drug-induced apoptosis was significantly reduced in ABCB1- and ABCG2-overexpressing cancer cells, which can be fully restored by an competitive inhibitor of ABCB1 or ABCG2.Our finding is supported by biochemical data and a docking analysis of ricolinostat in the drug-binding pocket of ABCB1 and ABCG2. Taken together, our study indicate that the overexpression ABCB1 or ABCG2 in cancer cells may potentially play a significant role in the development of resistance to ricolinostat in cancer cells.
Citation Format: Sung-Han Hsiao, Shahrooz Vahedi, Suresh V. Ambudkar, Chung-Pu Wu. Human ATP-binding cassette proteins ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4895.
Abstract 4896: The role of SLC7A5 (LAT1) in endocrine therapy-resistant breast cancer
Authors: Sevigny Catherine M. , Sengupta Surojeet , Luo Zhexun , Jin Lu , Pearce Dominic , Clarke Robert 
Published: August 2018

Abstract
Breast cancer is the leading cancer diagnosis for women in the United States. Endocrine therapies, such as tamoxifen and aromatase inhibitors, are used to treat the estrogen receptor-positive (ER+) breast cancers that comprise 70% of all new cases. Unfortunately, emergence of resistance to these therapies presents a major clinical challenge. Cancer cells can adapt to dysregulate the bioenergetics of cellular metabolism and evade cell death. Solute carrier family 7 member 5 (SLC7A5 or LAT1) is expressed across the cell membrane and is a transporter of large, neutral amino acids (such as leucine or tyrosine) supporting cell proliferation. Using LCC9 breast cancer cells that are resistant to tamoxifen and fulvestrant, we studied the role of LAT1 in endocrine therapy-resistant cells as compared to sensitive MCF7 breast cancer cells. SLC7A5 expression was upregulated by estrogen in MCF7 cells that was blocked in the presence of fulvestrant treatment. A significant 2.75-fold upregulation of SLC7A5 protein and 71-fold upregulation of SLC7A5 mRNA was found in LCC9 cells (as compared with MCF7 cells) without any estrogen regulation. Fulvestrant treatment did not significantly alter SLC7A5 mRNA or protein expression. These data suggest that higher levels of SLC7A5 in resistant cells may help in transporting key amino acids from their microenvironment to support cell growth. Inhibiting the functions of SLC7A5 using a pharmacologic inhibitor, JPH203, or depleting its expression by using siRNA led to significant growth suppression of LCC9 cells. Cell cycle analysis revealed that SLC7A5 depletion increased G1 phase of cell cycle and reduced S phase cells. In five publicly available data sets, of estrogen receptor-positive and tamoxifen-treated breast cancer patients, high expression of SLC7A5 was associated with worse prognosis. Endocrine therapy resistance is partly driven by autophagy in breast cancer cells. We depleted SLC7A5 expression in LCC9s to better understand the role of this transporter in autophagy. This study uncovers a novel adaptive mechanism in endocrine therapy-resistant breast cancer cells that is facilitated by increased SLC7A5 mediated transport of large neutral amino acids enabling them to supplement their increased metabolic needs and promoting cell growth. Therefore, blocking the functions of SLC7A5, perhaps in conjunction with inhibition of autophagy, may offer an avenue of potential therapeutic intervention in endocrine therapy-resistant breast cancers.
Citation Format: Catherine M. Sevigny, Surojeet Sengupta, Zhexun Luo, Lu Jin, Dominic Pearce, Robert Clarke. The role of SLC7A5 (LAT1) in endocrine therapy-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4896.
Abstract 4898: Reduction of TGFBR2 in osteoblasts by enzalutamide causes drug resistance in prostate cancer bone metastasis
Authors: Ark Alexandra Vander , Woodford Erica , Meng Xiangqi , Ganguly Sourik , Zhang Xiaotun , Madaj Zachary , Li Xiaohong 
Published: August 2018

Abstract
In the United States, over 80% of prostate cancer patients die with bone metastases. Second-line hormonal therapies, such as enzalutamide, only improve overall patient survival by a few months in about 50% of patients, and almost all patients develop drug resistance. Thus, there is an urgent need to determine the mechanisms of drug resistance in order to provide better treatments for prostate cancer bone metastasis. Enzalutamide is a small-molecule inhibitor of the androgen receptor. Our study showed that although enzalutamide inhibited the tumor growth of castration-resistant prostate cancer C4-2B cells when xenografted subcutaneously, it had no effect on the growth of C4-2B tumors in the bone or on the development of bone lesions. These data suggested a crucial role of the microenvironment in enzalutamide resistance in prostate cancer bone metastasis. To dissect the role of enzalutamide on the bone microenvironment, we treated bone cells, both osteoblasts and osteoclasts, with enzalutamide. We found that enzalutamide significantly and specifically reduced the TGF-β type II receptor (TGFBR2) protein in osteoblasts. This observation was also confirmed in prostate cancer bone metastatic tissue microarray, in which we performed immunohistochemistry and found a significant decrease of TGFBR2 expression specifically in cancer-associated osteoblasts from patients who had undergone treatment with second-line hormonal therapies, either enzalutamide or abiraterone. Statistical analysis showed that the decrease of TGFBR2 in cancer-associated osteoblasts was a causative effect from the hormonal therapies. To determine the role of TGFBR2 in the osteoblasts during bone metastasis, we used a mouse model (Tgfbr2Col1CreERT KO) with inducible Tgfbr2 knockout specifically in the osteoblasts. We found that loss of TGFBR2 in osteoblasts significantly promoted prostate cancer bone metastasis. Together, our data showed for the first time that reduction of TGFBR2 in osteoblasts by enzalutamide causes resistance to the drug in prostate cancer bone metastasis.
Citation Format: Alexandra Vander Ark, Erica Woodford, Xiangqi Meng, Sourik Ganguly, Xiaotun Zhang, Zachary Madaj, Xiaohong Li. Reduction of TGFBR2 in osteoblasts by enzalutamide causes drug resistance in prostate cancer bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4898.
Abstract 4905: Utility of human FcRn transgenic mice for preclinical screening of immunotherapeutics
Authors: Christianson Gregory J. , Lowell Emily , Lutz Cat 
Published: August 2018

Abstract
Preclinical assessment is required for the growing number of immunotherapeutics in development. Clinically relevant pharmacokinetic analysis can be achieved by using transgenic mice that uniquely express the human Fc receptor neonatal (hFcRn). To demonstrate the utility of the human FcRn Tg mouse model platform, three immunotherapeutics (pembrolizumab, ipilimumab, and belatacept) were administered IV to Tg32, Tg276, FcRn null, and B6 wild type mice. The mice were blood sampled (25 µL) at 1, 3, 5, 7, 9, 12, 16, 19, 22, 26, and 30 days. Immunotherapeutic plasma concentations, assessed by human IgG ELISA, were pharmacokinetically analyzed. Tg32 mice yielded half-life values for these immunotherapeutics with ranges that mimicked patient data. Though reduced in scale, Tg276 mice also produced half-life data that correlated with the established human half-life data for pembrolizumab, ipilimumab, and belatacept. These results confirm that the human FcRn Tg model platform can be broadly applied to preclinical pharmacokinetic screening of mAb and Fc-fusion based immunotherapeutics.
Citation Format: Gregory J. Christianson, Emily Lowell, Cat Lutz. Utility of human FcRn transgenic mice for preclinical screening of immunotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4905.
Abstract 4906: Effect of gender on the rodent pharmacokinetics of ON 123300, a dual inhibitor of ARK5 and CDK4/6, for the treatment of cancer
Authors: Ren Chen , Mudunuru Jennypher , Taft David , Maniar Manoj 
Published: August 2018

Abstract
Purpose: To evaluate gender differences in the metabolism of ON 123300 in rats in vitro and in vivo. ON 123300, a novel small molecule dual inhibitor of the c-MYC activated kinases ARK5 and CDK4/6, is being developed by Onconova Therapeutics, Inc. as a novel anti-cancer drug candidate.
Methods: In vitro metabolism experiments were performed in rat liver microsomes from male and female donors. ON 123300 was incubated with microsomes, and samples were withdrawn at specified times over 60 minutes and, immediately quenched and centrifuged. The supernatant was analyzed for ON 123300 and its metabolites by HPLC. An in vivo pharmacokinetic study was performed in male and female SD rats. ON 123300 was administered as a single oral dose (100 mg/kg), and blood samples were collected over 24 hours. ON 123300 concentrations were measured by LC-MS/MS. Pharmacokinetic parameters were estimated by non-compartmental analysis.
Results: The results are provided in Table 1. ON 123300 displayed more rapid microsomal degradation in vitro (increase of Clint) in males compared to females. This translated into a significantly higher exposure of ON 123300 (3 fold increase of AUC) following oral administration to female rats. Based on these results, the higher plasma concentrations observed in females can be primarily attributed to reduced hepatic clearance compared to males.
Conclusions: Gender differences in pharmacokinetics and pharmacodynamics can potentially impact the design of safe and effective dosing regimens for treatments. This investigation demonstrated a significantly lower metabolism of ON 123300 in female rats, which resulted in dramatically high systemic exposure. Additional testing is warranted to assess the potential clinical implications of these findings.
Table 1. ON 123300 In Vitro and In Vivo Pharmacokinetic Parameters
In Vitro Metabolism (n = 2/group)In Vivo Pharmacokinetics (n = 5/group)Parameter (mean)MalesFemalesParameter (mean± SD)MalesFemalest1/2 (min)10.838.2Tmax (hr)2.3 ± 1.60.6 ± 0.2Clint (ml/min/mg)13036.7Cmax (ng/ml)321 ± 66.01253 ± 660Predicted In Vivo Cl(ml/min/kg)a239.267.5AUC0-∞ (ng-hr/ml)1803 ± 7575520 ± 2163Cl/F (ml/min/kg)1116 ± 474390 ± 269t1/2 (hr)1.9 ± 0.503.0 ± 0.5 apredicted from venous equilibration model assuming rat blood flow = 13.8 ml/min, 99% protein binding and blood:plasma ratio = 1 Citation Format: Chen Ren, Jennypher Mudunuru, David Taft, Manoj Maniar. Effect of gender on the rodent pharmacokinetics of ON 123300, a dual inhibitor of ARK5 and CDK4/6, for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4906.
Abstract 4908: Exemestane worsens everolimus-associated stomatitis in cancer patients
Authors: Lima Vladmir C. de , Lima Matheus H. de , Alves Fabio A. , Hajj Gláucia N. 
Published: August 2018

Abstract
Everolimus is an antitumor drug usually indicated for the treatment of breast, kidney and neuroendocrine malignancies that inhibits the activation of the mammalian Target of Rapamycin (mTOR). Despite the efficacy and success of the treatment, side effects are not uncommon, and stomatitis is quite prevalent. mTOR inhibitor associated stomatitis (mIAS) is described as ulcerated aphthous-like lesions associated with mTOR inhibitors use. mIAS may cause severe pain, leading to nutritional deficiency and general health decline, besides drug dose reduction or suspension. Clinical observation suggested mIAS to be more common among breast cancer patients. Thus, we hypothesized that exemestane could contribute to increase everolimus toxicity in the oral mucosa. We prospectivelly collected clinical data from patients who used everolimus, associated or not with exemestane, from March 2016 to September 2017, and correlated them with information regarding mIAS (date of onset, number of lesions in the oral cavity, grading). We also performed in vitro experiments with Dysplastic Oral Keratinocytes (DOK). Cells were treated with vehicle, everolimus, exemestane or the combination of everolimus and exemestane. Drug induced citotoxicity was evaluated by MTT assay and migration inhibition by scratch wound healing assay. All assays were done in triplicate. Frequencies were compared by Fisher's exact or McNemar test. Log-rank and Wilcoxon tests were employed to compare time to mIAS development. Multivariate ANOVA was used to compare results from in vitro experiments. SPSS and Image J were used to make all statistical analysis. One hundred and thirty patients were evaluated. Mostly were females, with mean age of 60 years, and had previously treated advanced stage (IV) breast cancer. 30.3% developed mIAS. Breast cancer patients (treated with exemestane plus everolimus) had 2.29 higher chance to develop mIAS when compared to neuroendocrine tumos patients (treated with everolimus alone). In vitro experiments showed that the association of everolimus and exemestane increased cell death and migration (wound healing) inhibition of DOK in comparison with cells treated with everolimus or exemestane alone. The clinical data suggests that exemestane increases the risk of developing mIAS, and the in vitro experiments reinforces the idea that exemestane may enhance oral mucosa toxicity mediated by everolimus.
Citation Format: Vladmir C. de Lima, Matheus H. de Lima, Fabio A. Alves, Gláucia N. Hajj. Exemestane worsens everolimus-associated stomatitis in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4908.