bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 179: Atypical protein kinase C inhibition in prostate cancer cells: a study of ICA-1 and ACPD
Authors: Apostolatos Andre H. 
Published: July 2016

Abstract
Aggressive and metastatic prostate cancers are highly lethal tumors and are one of the leading causes of death among men. Certain prostate cancers are highly lethal tumors due to the emergence of therapy-resistant cancer cells. There is a gap in knowledge relating to which intracellular chemicals confer the emergence of therapy-resistant prostate cancer cells, which intracellular chemicals are responsible for prostate cancer survival and which chemicals regulate intracellular signaling pathways in prostate cancer. To address this critical problem, we investigated two drugs that act as inhibitors of atypical Protein Kinase C Iota. The objective of this study was to test the effectiveness of ACPD as an atypical PKC inhibitor and ICA-1 as an inhibitor of PKC iota. [The Inter. J. Biochem. & Cell Biol. 43:784-794(2011)] DU-145 and PC-3 prostate carcinoma cells and non-malignant prostate RWPE-1 cells were each cultivated in separate flasks. They were treated with drugs of interest for three consecutive days. The cells were counted before and after the treatments and a statistical analysis was performed. The cells were lysed and levels of PKC iota and PKC zeta were measured by Western blotting and immunoprecipitation. Our preliminary results show that treatment of DU-145 and PC-3 showed a statistically significant decrease in cells that was proportional to the concentration in both drugs. Treatment of the RWPE-1 cells showed no statistically significant change in population. The Western blotting showed both drugs decreased PKC iota. In conclusion ACPD and ICA1 are effective inhibitors of PKC iota and PKC zeta and consequently significantly reduced the neogenesis of the prostate DU-145 and PC-3 carcinoma cells while having negligible effect on the non-malignant prostate RWPE-1 cells.
Citation Format: Andre H. Apostolatos. Atypical protein kinase C inhibition in prostate cancer cells: a study of ICA-1 and ACPD. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 179.
Abstract 1796: Metformin may function as an anti-cancer agent of pancreatic cancer via targeting RET signaling pathway
Authors: Tan Xiang-Lin , Yue Wen , Wang Tao , Carpizo Darren , Lin Yong , Zheng Xi , Yang Chung S. , Zhang Lanjing , Xu Qing , DiPaola Robert S. 
Published: July 2016

Abstract
Pancreatic cancer (PaCA) is one of the most lethal human cancers and is the fourth leading cause of cancer-related deaths in the United States. However, there are currently no established recommendations for prevention of PaCA using pharmacological agents. Metformin has recently gained attention as an anti-cancer drug and/or a chemoprevention agent because of its effects on inhibiting mTOR, lowering hyperinsulinemia, modulating inflammatory responses, and selectively killing cancer stem cells. However, the key underlying molecular mechanisms for the inhibitory effects of metformin on PaCA progression remain largely unknown. Using RNA sequencing followed by the confirmation of RT-PCR and Western blotting, we found that metformin significantly decreased the mRNA and protein levels of RET (REarranged during Transfection), a single-pass transmembrane receptor tyrosine kinase (RTK). RET and its ligand, glial cell-derived neurotrophic factor (GDNF), were strongly expressed in PaCA and correlated to invasion and worse survival after surgical resection. GDNF, as a chemoattractant for PaCA cells, can activate RET to induce tumor progression, migration and invasion in vitro and in vivo. We further observed that metformin significantly inhibited GDNF-induced migration and invasion of PANC-1 cells. These data indicate that targeting RET with metformin or the combination of metformin and RET inhibitors may be an attractive and novel strategy for the prevention and treatment of PaCA progression and metastasis. To elucidate the molecular mechanisms for the inhibitory effects of metformin on the growth and spread of PaCA in humans, further in vitro and in vivo studies are warranted to investigate how metformin modulates RET signaling to inhibit the progression and metastasis of PaCA. Such studies have potential clinical significance using metformin as adjuvant preventive and therapeutic options for PaCA prevention and treatment. [This work was supported by grants from the National Cancer Institute at the National Institutes of Health (K07CA190541 and P30CA072720) and the National Natural Science Foundation of China (Grant No.: 81470132)]
Citation Format: Xiang-Lin Tan, Wen Yue, Tao Wang, Darren Carpizo, Yong Lin, Xi Zheng, Chung S. Yang, Lanjing Zhang, Qing Xu, Robert S. DiPaola. Metformin may function as an anti-cancer agent of pancreatic cancer via targeting RET signaling pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1796.
Abstract 1805: CYP3A4 regulation of androgen receptor signaling in ER+ breast cancer
Authors: Gorjala Priyatham , Goodman Jr Oscar , Mitra Ranjana 
Published: July 2016

Abstract
Purpose: Eighty percent of breast cancers that are estrogen receptor-positive (ER+) express AR. According to American Cancer Society, every two out of three women are ER+ and initially respond to estrogen-receptor targeted therapies but later almost 50% of breast cancers, despite the presence of ER, fail to respond. Acquired resistance to these therapies is common and portends a poor prognosis, frequently requiring the use of cytotoxic therapies. Our preliminary results indicate that endocrine-resistant tumors express higher levels of AR and may depend on AR for their growth. Hence AR targeted therapies may be appropriate for these resistant tumors. As we have recently demonstrated that CYP3A regulates androgen receptor signaling, we wish to ascertain the role of CYP3A in regulating AR in endocrine-resistant breast cancer.
Methods: The ER+ cell lines MCF7 and T47D were used to study the role of AR in breast cancer. To study endocrine resistance in breast cancer, tamoxifen resistant MCF7 and T47D lines were generated with recurrent treatment of IC90 dosage of tamoxifen over 6 months’ time period. Cell fractionation, western blotting and q-RTPCR techniques were used to study the role of AR. siRNA inhibition of CYP3A4, the isoform expressed in breast, was used to study its role in regulating AR in breast cancer.
Results: Our results indicate that both MCF7 and T47D express active AR, inducible by DHT and R1881. Similar to prostate cancer we also observe that AR in these lines is regulated by CYP3A4. Cell fractionation studies indicate that inhibition of CYP3A4 by siRNA results in reduced AR migration to the nucleus inhibiting its role as a transcription factor. Our results also indicate that tamoxifen resistant cell lines express increased levels of AR. Tamoxifen resistant cell lines respond to bicalutamide/enzalutamide with a lower IC50 value than the native cell lines, reflecting their AR dependence. The resistant cell lines also show increased AR nuclear migration with R1881 induction as compared to native breast cell lines.
Conclusions: Endocrine-resistant breast cancer is sensitive to antiandrogen therapy. CYP3A4 may play an important role in endocrine-resistant breast cancer by negatively regulating AR activity.
Citation Format: Priyatham Gorjala, Oscar Goodman Jr, Ranjana Mitra. CYP3A4 regulation of androgen receptor signaling in ER+ breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1805.
Abstract 181: Constitutive IRAK1/4 kinase activation contributes to NF-kB activity and chemoresistance in pancreatic cancer
Authors: Zhang Daoxiang , Li Lin , Jiang Hongmei , Yu Jinsheng , Knolhoff Brett , Head Richard , Lockhart Albert C. , DeNardo David G. , Wang-Gillam Andrea , Ruzinova Marianna B. , Lim Kian-Huat 
Published: July 2016

Abstract
Constitutive activation of the NF-κb transcription factor is a major molecular mechanism that contributes to the aggressive behavior and treatment resistance of pancreatic cancer. Understanding the molecular mechanisms that activate NF-κB will provide novel therapeutic opportunities to improve the dismal outcome of pancreatic cancer patients. In the present study, we showed that the Interleukin-1 Receptor-Associated Kinases 1 and 4 (IRAK1 and IRAK4) are constitutively activated in a majority of pancreatic cancer cell lines and patients samples, and are major drivers of NF-κB activity. Notably, we found that constitutive phosphorylation of IRAK4 is associated with poor patient prognosis. Suppression of IRAK1 and IRAK4 with small molecule inhibitor or RNA-interference in pancreatic cancer cells significantly reduces NF-κB activity, three-dimensional growth, invasiveness, production of inflammatory, and augment their sensitivity to chemotherapeutic agents in vitro. Notably, we showed that the NF-κB activity of pancreatic cancer cell with IRAK4 ablated using CRISPR technology can be restored with wild-type, but not kinase-dead IRAK4 mutant, supporting development of IRAK4 inhibitor as a novel therapeutic agent in pancreatic cancer. Silencing of IRAK1 or IRAK4, and more potently both, significantly abrogated the tumorigenic potential of human and murine pancreatic cancer cells as xenograft in mice. Lastly, we showed that IRAK1/4 inhibitor augments the therapeutic effect of gemcitabine in tumor-bearing mice by suppressing proliferation and increasing apoptosis of neoplastic cells, and reducing stromal fibrosis. Together, our data established IRAK4 kinase inhibitors as a promising novel class of targeted agent in pancreatic cancer.
Citation Format: Daoxiang Zhang, Lin Li, Hongmei Jiang, Jinsheng Yu, Brett Knolhoff, Richard Head, Albert C. Lockhart, David G. DeNardo, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Constitutive IRAK1/4 kinase activation contributes to NF-kB activity and chemoresistance in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 181.
Abstract 1810: Heterogeneous activation of PP-1 and Akt determines AR-v7 protein expression in prostate cancer cells under AR inhibition
Authors: Li Yinan , Xie Ning , Gleave Martin E. , Rennie Paul , Dong Xuesen 
Published: July 2016

Abstract
Background: Blocking the androgen receptor (AR) signaling is the first- and second-line treatment for metastatic prostate cancers. Although the newly developed AR pathway inhibitor (ARPI) improves patient survival, tumors invariably recurs and are most often driven by reactivation of the AR signaling. Enhanced expression of the AR splice variant, AR-v7, had been demonstrated to be one of the key mechanisms that confer prostate tumors with therapy resistance. However, molecular mechanisms by which control AR-v7 protein expression remain unclear.
Experimental Design: Multiple prostate cancer lines were challenged with androgen depletion and/or Enzalutamide treatment. Protein phosphatase-1 (PP-1) and Akt kinase activation were measured. AR and AR-v7 serine phosphorylation, ubiquitination, protein degradation as well as subcellular localization were determined.
Results: Enzalutamide induces differential activation of protein phosphatase-1 (PP-1) and Akt kinase depending on the genetic background of prostate cancer cell lines. PP-1 activation prevents AR-v7 from serine213 phosphorylation, Mdm2-mediated ubiquitination modification, cytoplasmic localization and proteasomal protein degradation. By contrast, Akt activation functions in the opposite to PP-1 and stimulates AR-v7 degradation. Therefore, the balance of PP-1 and Akt activations under ARPI treatment determines AR-v7 protein expression in prostate cancer cells.
Conclusion: Our studies highlight the decisive roles of PP-1 and Akt for AR-v7 protein expression and activities when AR is functionally blocked. It also provides an explanation on heterogeneous AR-v7 protein expression in prostate tumor biopsies.
Citation Format: Yinan Li, Ning Xie, Martin E. Gleave, Paul Rennie, Xuesen Dong. Heterogeneous activation of PP-1 and Akt determines AR-v7 protein expression in prostate cancer cells under AR inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1810.
Abstract 1825: ONC201 induces cell death in androgen receptor positive prostate cancer cells and shows synergistic effect with anti-prostate cancer drugs
Authors: Lev Avital , Lulla Amriti R. , Dicker David T. , El-Deiry Wafik S. 
Published: July 2016

Abstract
Prostate cancer is the most common cancer and the second leading cause of cancer related death among men in the United States. Current therapy for advanced prostate cancer is mainly based on androgen deprivation, though in many cases tumors become androgen-independent and resistant to available treatments. Thus, accessing novel therapies for prostate cancer and resistant tumors remains an important goal in the field. ONC201 is a first-in-class small molecule anti-cancer drug, shown to selectively induce cell death in most cancer cells tested in contrast to matched normal cells. In this study we investigated the single-agent and combination efficacy of ONC201 on a panel of prostate cancer cell lines with varied androgen receptor (AR) and receptor tyrosine kinases (RTKs) expression status. Our preliminary data suggests that the pro-apoptotic effects of ONC201 correlate with expression of androgen receptor and other receptor tyrosine kinases (RTKs). Specifically, high AR and low RTK (c-MET, EGFR, HER2 and IGFR) expression demonstrated higher sensitivity to ONC201 as compared to low AR and high RTK expression as evaluated by cell viability using the Cell-Titer Glo assay. We further modeled these findings in ONC201-sensitive 22Rv1 and ONC201-resistant DU145 cell lines. ONC201 induced robust apoptosis (cleaved PARP) in ONC201-sensitive 22Rv1 cells as compared to ONC201-resistant DU145 cells In addition, ONC201-sensitive 22RV1 cells showed abrogation of total AR expression 72 hours following treatment with ONC201. Thus, AR and RTK status seem to be emerging efficacy markers for response of ONC201 in prostate cancer cells. We are further investigating the involvement of ONC201 in the signal transduction pathway of AR and other RTKs in prostate cancer. Lastly, our initial screening for treatment of cells with a combination of ONC201 and FDA-approved therapies for prostate cancer showed synergistic potential of ONC201 with everolimus and docetaxel in both AR-dependent and independent cells. As expected, synergism of anti-androgen MDV3100 (enzalutamide) with ONC201 was restricted to AR positive prostate cancer cell lines. Our results indicate that ONC201 has therapeutic potential both as a single agent and in combination therapy for prostate cancer. Our long-term goal is to integrate our pre-clinical studies and translate the findings to single agent/combination trials of ONC201 for prostate cancer patients.
Citation Format: Avital Lev, Amriti R. Lulla, David T. Dicker, Wafik S. El-Deiry. ONC201 induces cell death in androgen receptor positive prostate cancer cells and shows synergistic effect with anti-prostate cancer drugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1825.
Abstract 1826: IMI's CANCER-ID: Status of liquid biopsy standardization
Authors: Pantel Klaus , Terstappen Leon WMM , Baggiani Barbara , Krahn Thomas , Schlange Thomas 
Published: July 2016

Abstract
The CANCER-ID (www.cancer-id.eu) consortium was established in early 2015 with more than 30 partners as part of the Innovative Medicines Initiative (IMI), Europe's largest public-private partnership funded in equal parts by the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The goal is to develop standard operating procedures (SOPs) and qualify respective mature technologies for pre-analytical sample handling, enrichment, isolation and analysis of Circulating Tumor Cells (CTCs), circulating free tumor DNA (ctDNA) and microRNAs (miRNAs) as novel blood-based biomarkers in cancer liquid biopsy, with a particular focus on Non-Small Cell Lung Cancer (NSCLC) and HER2-treatment refractory breast cancer. Over the 5-year period of the project, CANCER-ID will evaluate different technologies in the field, testing their clinical utility in multicenter clinical studies in support of regulatory approval of these devices. During the first year of the project, a number of different technology platforms have been implemented at several partner sites to establish SOPs with standardized blood samples spiked with selected cancer cell lines as standards. An important outcome of these studies are pre-analytical sample handling procedures, e.g. using different fixatives and tube systems as well as biobanking protocols that allow shipment and standardized long-term storage of liquid biopsy material. Most importantly, the knowledge generated within IMI's CANCER-ID will be used to establish and validate SOPs for the analysis of patient blood samples using different technologies, which represents a promising diagnostic tool holding the potential for optimized treatment decisions and therapeutic monitoring of cancer patients. The international exchange of human patient samples for research purposes poses a number of regulatory challenges linked to the different legal and ethical environments. The diverse national regulations for clinical samples and data require coordinated monitoring of interactions and guidance of the different partner organizations. As close collaboration with regulatory authorities is crucial for CANCER-ID to achieve its objectives, the consortium has established a contact with CDER/FDA via a Critical Path Innovation Meeting (CPIM). We will discuss the CANCER-ID approach to meet these many requirements and will present a matrix for coordinating such international efforts with stakeholders from different organizations.
Citation Format: Klaus Pantel, Leon WMM Terstappen, Barbara Baggiani, Thomas Krahn, Thomas Schlange. IMI's CANCER-ID: Status of liquid biopsy standardization. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1826.
Abstract 1838: Differential CXCL13 and CXCR5 expression mediated by down-regulation of select miRNAs in prostate cancer
Authors: Hinton Denise E. , Lillard James 
Published: July 2016

Abstract
Chemokines and their receptors are involved in the inflammatory response by attracting immune cells to sites of infection and wound healing. Chemokines have also been implicated in the progression of prostate cancer (PCa). We have previously shown a positive correlation between the expression of CXCL13 and CXCR5 proteins with PCa progression; in particular, the CXCR5 protein is expressed to a greater extent by prostate tumors isolated from African Americans than compared to those from European Americans. In the present study, we sought: (i) to determine whether CXCL13 and CXCR5 mRNA expression patterns correlated with overall and/or disease-free survival in PCa cases and (ii) to identify the possible molecular mechanisms that govern this association. CXCL13 and CXCR5 mRNA levels and PCa survival rates were evaluated using The Cancer Genome Atlas (TCGA) data sets and the CbioPortal, respectively. CXCR5 and CXCL13 mRNA expression did not correlate with prostate tumor stage or grade and was not associated with overall PCa survival. However, CXCR5 mRNA expression was significantly associated with poor disease-free survival. Gene map analysis using the UCSC Genome Browser revealed consensus sequence binding sites for four miRNA's (miR-192/215, miR-486, and miR-494) that could bind the 3’ UTR of the cxcr5 transcript. Our results showed that miR-494 was frequently deleted or down-regulated, confirming other reports that miR-494 is down-regulated in high-grade PCa cases. Of note, miR-494 also targets cxcr4 mRNA and suppresses migration of PCa cells. Others have shown that miR-486 is associated with p53 and PI3K-Akt pathways and miR-186 has a putative binding site in the 3’ UTR region of the cxcl13 transcript. This miRNA was down-regulated in PCa patients with initial metastasis. These results confirm our previous studies demonstrating a correlation between tumor expression and PCa progression and reveal new mechanisms of post-translational regulation of this chemokine receptor.
Citation Format: Denise E. Hinton, James Lillard. Differential CXCL13 and CXCR5 expression mediated by down-regulation of select miRNAs in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1838.
Abstract 1846: Gene expression analysis of P-glycoprotein and LMWPTP in chronic myeloid leukemia cells treated with metformin and imatinib mesylate
Authors: Oliveira Ligia P. , Ferro Rafael G. , Galvão. Ana CSS 
Published: July 2016

Abstract
Chemotherapy is an effective treatment for many tumors; however, some tumors begin to exhibit a wide range of resistance after a few cycles of chemotherapy, which is known as phenotype of resistance to multiple drugs (multidrug resistance - MDR). The MDR phenotype arises through various mechanisms, but often is associated with an increased efflux of hydrophobic cytotoxic drugs. Therefore, the search for more selective and efficient antitumor compounds in the elimination of cancer cells boosts the research in oncology area. Studies of genes and pathways that are deregulated in tumors and that are essential to their growth may provide new strategies that lead to the development of therapeutic agents that target these pathways. Previous data from our research group have shown potent toxic activity of metformin, an oral hypoglycemic used for more than 30 years for the treatment of type II diabetes, on chronic myeloid leukemia cells (CML), potentiating the effects of imatinib mesylate, the standard chemotherapy used in the treatment of CML. CML cells treated with these agents showed changes in expression of proteins associated with the MDR phenotype. In this way, this project aimed to evaluate the expression of ABCB1 (Pgp) e ACP1 (LMWPTP) by Polymerase Chain Reaction in real time (qPCR) in LCM K562 cells and Lucena before and after treatment with metformin and/or imatinib mesylate, seeking to verify the effects of metformin, alone or in combination with Imatinib mesylate in the expression of these genes in Lucena in K562 cells. We found statistically significant differences in expression between treatments compared to control and between K562 and Lucena cells. It is possible to conclude that these genes may be associated with MDR phenotype.
Citation Format: Ligia P. Oliveira, Rafael G. Ferro, Ana CSS Galvão. Gene expression analysis of P-glycoprotein and LMWPTP in chronic myeloid leukemia cells treated with metformin and imatinib mesylate. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1846.