bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 366: A novel transcript variant of androgen receptor identified in circulating tumor cells from castration-resistant prostate cancer patients as a potentially prognostic biomarker
Authors: Kang Zhigang , Shah Avani , Yu Yunkai , Zhu Yuelin , Bhagat Ali Asgar , Zhao Kyra , Wu Andrew , Gao James , Madan Ravi , Gulley James , Dahut William , Meltzer Paul , Cao Liang 
Published: August 2015

Abstract
Circulating tumor cells (CTCs) are rare cancer cells in the bloodstream thought to have a key role in cancer metastasis. There are enormous interests in their analysis for castration-resistant prostate cancer (CRPC) due to their tendency to metastasize to bone. In this study, we applied a surface marker-independent microfluidic device for CTCs capture and retrieval that is based on cell size and deformability. Our device was able to capture 90% and recover 30% of tumor cells in spike experiments. We also developed and validated assays capable of detecting the transcript levels of selected molecular markers in single cells prepared with C1TM Single-Cell AutoPrep System. Blood samples drawn from 34 CRPC patients and 10 primary prostate cancer patients (PPC) were preceded for CTC isolation and molecular characterization. We found that 73% CRPC patients and 10% PPC patients were positive for EpCAM, and only about half of the EpCAM-positive CRPC cases were PSA or AR positive. It is interesting that while there is a strong association between AR and PSA expression in CTC samples, there is no correlation between AR or PSA transcripts in CTCs and serum PSA protein levels in CRPC patients. The positive detection of AR or PSA, but not EpCAM is statistically associated with poor prognosis of the CRPC patients. Very intriguingly, we identified a novel androgen receptor (AR) transcript variant -ARv from four CRPC patients’ CTCs. This ARv lacks a 554bp sequence region in the ligand binding domain (LBD), resulting in a loss of the entire LBD. Clinical data analysis revealed that the ARv is significantly associated with worse survival of CRPC patients (p&lt;0.0001). In vitro functional studies showed this novel ARv is constitutively active in the absence of testosterone. Our findings suggest that this AR variant might contribute to the late stage progression of the diseases and could be used as a potential indicator for alternative therapies. In summary, our new fluidic device is capable of isolating CTC to enable molecular marker analysis, providing value in prognosis and guidance to therapy.
Citation Format: Zhigang Kang, Avani Shah, Yunkai Yu, Yuelin Zhu, Ali Asgar Bhagat, Kyra Zhao, Andrew Wu, James Gao, Ravi Madan, James Gulley, William Dahut, Paul Meltzer, Liang Cao. A novel transcript variant of androgen receptor identified in circulating tumor cells from castration-resistant prostate cancer patients as a potentially prognostic biomarker. [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 366. doi:10.1158/1538-7445.AM2015-366
Abstract 3661: Development of novel small-molecule inhibitors of ETS oncoproteins as anti-prostate cancer agents
Authors: Tian Xiaohong 
Published: August 2015

Abstract
Currently advanced prostate cancer is treated by suppressing androgen receptor (AR) signaling. Since AR could be activated via multiple mechanisms, inhibition of one or two of these mechanisms could be initially effective, but drug resistance can rapidly develop due to kick-in of other AR-activating mechanisms, resulting in lethal castration-resistant prostate cancer (CRPC). The therapeutic effects of all of the currently available AR-targeting agents are short-lived. To achieve long lasting therapeutic effect for prostate cancer, it appears we need to get out of the box of AR. Here, we propose to develop chemical inhibitors of oncogenic protein ERG, which is an ETS transcriptional factor. The rationale for inhibiting ERG as a possible treatment for prostate cancer has two folds: i) ERG plays a critical role in prostate cancer initiation and progression, and ii) Half of all prostate cancer patients are TMPRSS2-ERG fusion positive, which result in high level of ERG oncoprotein. ERG is a transcriptional factor that directly regulates EZH2, oncogene c-Myc and tumor suppressor Nkx3.1 and many other targets in prostate cancer. ERG cooperates with PI3K/AKT and AR in tumor initiation. ERG knockdown inhibits tumor growth in xenograft of VCaP cells. To date, accumulated studies in patients and experimental models have indicated that ERG overexpression as a result of TMPRSS2-ERG fusion plays a critical role in prostate cancer initiation and progression.
However, ERG protein has no obvious functional sites or enzymatic activity to be inhibited and is considered ‘undruggable’. In contrast to such view, our laboratory has recently discovered a novel chemical inhibitor of ERG by combining virtual screening and reporter assay. We have built a structural model of ERG DBD and identified a putative binding-site for virtual screening study. We discovered a novel compound, which substantially inhibits ERG-dependent reporter activity in HEK293 cells and inhibits expression of ERG-regulated genes, such as EZH2 and c-Myc, in VCaP cells. We further showed that our compound inhibits proliferation of VCaP cells, and disrupts association of ERG with its essential coactivator PARP1 by co-IP assay. Surface Plasmon Resonance (SPR) analysis has confirmed that our compound has direct binding with recombinant ERG protein. As recent studies indicated that advanced prostate cancer with TMPRSS2-ERG fusion have substantial higher tendency to metastasize to lymph nodes, ERG inhibitors could be an effective therapeutics to prevent this progression. Importantly, ERG inhibitors could be effective therapeutics for advanced prostate cancer.
Citation Format: Xiaohong Tian. Development of novel small-molecule inhibitors of ETS oncoproteins as anti-prostate cancer agents. [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 3661. doi:10.1158/1538-7445.AM2015-3661
Abstract 3662: Design and development of a novel series of HDAC6-selective inhibitors for the treatment of hematological and solid tumors
Authors: Shuttleworth Stephen J. 
Published: August 2015

Abstract
Inhibition of the zinc-dependent histone deacetylase (HDAC) family of enzymes has been pursued as a clinical strategy in cancer for many years. HDACs regulate the expression and activity of numerous proteins involved in both cancer initiation and cancer progression; by removal of acetyl groups from histones, HDACs create a non-permissive chromatin conformation that prevents the transcription of genes that encode proteins involved in tumorigenesis. The current landscape of HDAC-targeting therapeutics has, however, been dominated by pan-inhibitors that regulate the activity of most, if not all, of the HDAC family members which, through dysregulation of expression of a myriad of genes, has led to agents with undesirable toxicities and narrow therapeutic margins. Recently, however, attention has begun to turn to the role of specific HDAC isoforms in tumorigenesis and, in turn, the development of more selective therapeutics. HDAC6 has emerged as a particularly interesting target as it plays an essential role in aggresomal protein degradation: specifically, HDAC6 binds polyubiquitinated misfolded proteins and recruits misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 fail to clear these misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins, which leads to activation of apoptosis. Further, recent evidence has emerged of HDAC modulating immune-related pathways in solid tumors, notably regulating PDL-1 expressions through STAT3 modulation. This presentation will outline the design and development of a new class of highly-potent, selective and orally-active HDAC6 inhibitors with the potential in the treatment of multiple tumor types. Uniquely, this series of compounds has been designed such that selectivity levels for HDAC6 over other isoforms can be finely regulated, enabling the investigation of preferred levels of HDAC6 specificity for therapy, and opening possibilities for broader combination modalities in a clinical setting.
Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of HDAC6-selective inhibitors for the treatment of hematological and solid tumors. [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 3662. doi:10.1158/1538-7445.AM2015-3662
Abstract 3666: Synthesis and evaluation of itraconazole analogues for hedgehog pathway inhibition
Authors: Pace Jennifer , Hadden M. Kyle 
Published: August 2015

Abstract
The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in embryonic development. While the pathway is generally quiescent during adult life, dysregulation of the Hh pathway can lead to cell proliferation and tumor growth. This abnormal Hh signaling is typically responsible for tumors associated with basal cell carcinoma (BCC) and medulloblastoma (MB) and inhibiting the Hh pathway is a valid target to develop novel chemotherapeutic agents. Most Hh inhibitors identified to date target the protein smoothened (SMO), a crucial component of the Hh pathway. Vismodegib is a SMO inhibitor that was recently approved by the FDA for the treatment of advanced BCC. However, there has been an emergence of resistance to Vismodegib; this resistance is a result of a point mutation in SMO. This occurrence of Vismodegib-resistant SMO mutations highlights the therapeutic need for new Hh pathway inhibitors. Itraconazole (ITZ), a well-known antifungal agent, was recently determined to be a potent inhibitor of the Hh pathway in vitro and in vivo; ITZ was also found to be a potent inhibitor of wild type SMO and Vismodegib-resistant SMO. ITZ is well-characterized and there is a good understanding of its potential side effects. This well-known safety profile makes ITZ a desirable drug candidate. Our ongoing studies on the ITZ scaffold are focused on exploring the regions of ITZ that are required for potent Hh pathway inhibition. The design, synthesis, and preliminary in vitro evaluation of these ITZ analogues will be reported herein.
Citation Format: Jennifer Pace, M. Kyle Hadden. Synthesis and evaluation of itraconazole analogues for hedgehog pathway inhibition. [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 3666. doi:10.1158/1538-7445.AM2015-3666
Abstract 3667: Synthesis and biological evaluation of vitamin D3 analogues as selective Hedgehog pathway inhibitors
Authors: Maschinot Chad A. , Hadden Kyle 
Published: August 2015

Abstract
Constitutive signaling of the Hedgehog (Hh) pathway has been linked to the development of a variety of cancers, specifically basal cell carcinoma (BCC) and medulloblastoma (MB). In recent years, vitamin D3 (VD3) was identified as an inhibitor of the Hh pathway. However, studies indicated that it is non-selective and activates canonical vitamin D signaling through the Vitamin D Receptor (VDR). One of the focuses of our lab is the development of VD3 analogues that will result in increased potency and selectivity for the Hh pathway. Previous studies indicated that the northern region of VD3 maintained approximately 95% of the inhibitory activity associated with intact VD3 with minimal activation of canonical vitamin D signaling. In initial SAR studies of the A-ring motif, the incorporation of a phenolic A-ring motif with an ester linkage to Grundmann's alcohol proved to be a potent, selective inhibitor. Utilizing a phenolic A-ring motif, SAR studies have continued with the development of the next generation of VD3-based analogues. Progress towards the next generation of analogues as well as results of biological studies will be described herein.
Citation Format: Chad A. Maschinot, Kyle Hadden. Synthesis and biological evaluation of vitamin D3 analogues as selective Hedgehog pathway inhibitors. [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 3667. doi:10.1158/1538-7445.AM2015-3667
Abstract 3673: High-density lipoprotein-like nanoparticles target SR-B1 and inhibit the cellular uptake of melanoma-cell derived exosomes
Authors: Plebanek Michael P. , Matov Alexandre , Mautharasan Kannan , Gatlin Jesse , Thaxton C. Shad 
Published: August 2015

Abstract
Exosomes play a crucial role in the progression of cancer through the transport of a variety molecular cargo, including proteins, lipids, and nucleic acids, to and from cells as a means of intercellular communication. Unraveling mechanisms of exosome-cell interactions may open avenues for studying cellular communication and lead to new therapies. Cellular exosome uptake depends on cholesterol-rich membrane microdomains called lipid rafts. Non-specific depletion of lipid raft cholesterol reduces cellular exosome uptake; however, to our knowledge, no targeted mechanism of inhibiting cellular exosome uptake has been reported. Scavenger receptor type B-1 (SR-B1) localizes to lipid rafts, and is a high-affinity receptor for cholesterol-rich high-density lipoproteins (HDL). SR-B1 is an intriguing therapeutic target because it is upregulated in many different cancers due to the high need for cholesterol of rapidly dividing cancer cells. Therefore, we hypothesized that specific targeting of SR-B1 and modulation of cholesterol flux through this receptor with biomimetic HDL-like nanoparticles (HDL NPs) would disrupt cellular exosome uptake. As a model, we explored exosomes derived from melanoma cells as they have been shown to promote angiogenesis and immunosuppression both crucial events in melanoma progression. Melanoma exosomes have also been shown to actively prepare metastatic sites, creating a suitable microenvironment allowing for the development of metastasis. Because of this, targeting exosomes and intercellular signaling could be beneficial for the treatment of metastatic melanoma. Using a variety of techniques including confocal microscopy, flow cytometry and automated image analysis, data demonstrate that HDL NPs specifically target SR-B1 in lipid rafts in melanoma cells and modulate cholesterol flux through this receptor. This leads to a clustering of SR-B1 at the cell membrane and potent inhibition of the cellular uptake of melanoma cell-derived exosomes.
Citation Format: Michael P. Plebanek, Alexandre Matov, Kannan Mautharasan, Jesse Gatlin, C. Shad Thaxton. High-density lipoprotein-like nanoparticles target SR-B1 and inhibit the cellular uptake of melanoma-cell derived exosomes. [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 3673. doi:10.1158/1538-7445.AM2015-3673
Abstract 3684: Nanoparticle-encapsulated piperine and piperlongumine inhibit breast cancer cell growth and metastatic activity
Authors: Ghassemi-Rad Javad , Hoskin David W. 
Published: August 2015

Abstract
Breast cancer is the second leading cause of cancer-related deaths among women in Canada and the United States. Metastatic disease is the primary cause of death, despite recent advances in breast cancer treatment strategies and personalized medicine. Novel anti-cancer therapeutics are therefore urgently needed to increase the lifespan of breast cancer patients and prevent metastasis. Piperine (PIP) and piperlongumine (PL), two of the major alkaloids in pepper spices, show inhibitory effects on breast cancer cell growth in vivo and in vitro; however, their lipophilicity has restricted possible clinical application. The encapsulation of these phytochemicals in biodegradable nanoparticles is predicted to increase their water solubility and bioavailability. The goal of this study was first, to optimize a method for the preparation of PIP- and PL-containing polymeric nanoparticles, and second, to explore the inhibitory effects of nanoparticle-encapsulated PIP and PL on breast cancer cell growth and metastatic activity. In contrast to the single oil-in-water emulsion method, PIP- and PL-nanoparticles prepared by the thin-film hydration method were more spherical and showed a uniform size distribution. PIP- and PL- containing nanoparticles decreased the viability of MDA-MB-231 and MDA-MB-468 triple-negative breast cancer cells to the same extend as free PIP and PL. In addition, a noncytotoxic concentration of PIP- and PL-containing nanoparticles inhibited the in vitro migration and invasion of triple-negative breast cancer cells. These findings demonstrate that the encapsulation of PIP and PL within polymeric nanoparticles is possible without compromising the bioactivity of these phytochemicals. PIP- and PL-nanoparticles therefore warrant further investigation in mouse models of breast cancer to establish their utility in the treatment of breast cancer.
Citation Format: Javad Ghassemi-Rad, David W. Hoskin. Nanoparticle-encapsulated piperine and piperlongumine inhibit breast cancer cell growth and metastatic activity. [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 3684. doi:10.1158/1538-7445.AM2015-3684
Abstract 3687: A novel computational platform technology (VOLVOX™) for designing anticancer supramolecular therapeutics
Authors: Pandey Prithvi Raj , Sengupta Shiladitya , Roy Sudip 
Published: August 2015

Abstract
Current chemotherapy approaches are limited by suboptimal pharmacology. For example, only a fraction of drug administered reaches the tumor. While drug delivery platforms, such as ADCs or nanoparticles, aim to address this limitation by aiming to enhance targeted tumor delivery, these too are limited by drug loading and stability. Here we describe the development of a computational platform technology, VOLVOX, for designing anticancer supramolecular therapeutics. Supramolecular therapeutics evolve as a result of supramolecular assembly of molecular building blocks, thereby altering the PK/PD profile of the building blocks, while increasing drug loading, stability and anti-tumor efficacy. Specifically, VOLVOX envisages interaction of drug candidates with lipid bilayers using molecular simulations, generating information on packing the right excipients in the lipid bilayer. This method is applicable in loading wide range of excipients or drugs having different chemical compositions governed by hydrophilicity and hydrophobicity, shape (geometry/symmetry) and size, and in varying concentrations. This method is applicable for particle based simulation technique at different length and time scale (e.g., all atomistic molecular dynamics (MD), Coarse Grained MD, or Mesoscale MD). As proof of this platform technology, we present development of a novel taxane and a PI3K targeting supramolecular therapeutic.
Citation Format: Prithvi Raj Pandey, Shiladitya Sengupta, Sudip Roy. A novel computational platform technology (VOLVOX™) for designing anticancer supramolecular therapeutics. [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 3687. doi:10.1158/1538-7445.AM2015-3687
Abstract 3689: Comparative oncology drug discovery for Osteosarcoma in dogs and humans
Authors: Fulbright Joy M. , Neville Kathleen , Broward Melinda , Bruns Tyce A. , Roy Anuradha , McDonald Peter , Ottomeyer Megan , Thamm Douglas H. , Iwakuma Tomoo 
Published: August 2015

Abstract
Introduction: The purpose of this study was to identify FDA approved drugs that initiate cell death or growth arrest in canine and human osteosarcoma (OS) cell lines in vitro followed by confirmation of anticancer activity in these cell lines. The ultimate objective of this comparative oncology project is to identify promising agents for the treatment of osteosarcoma in dogs and humans, a disease in which survival rates have remained low and stagnant for the last three decades.
Procedures: A library of 2,328 FDA approved drugs was screened for activity in 2 canine and 2 human OS cell lines, as well as in 1 corresponding normal cell line. Cell viability was measure using the Cell Titer-Glo™ Luminescent Cell Viability Assay (Promega). FDA approved drugs meeting pre-determined screening criteria for activity, selectivity, and potency were selected for confirmatory studies. Effects on cell proliferation were confirmed using cell counting using trypan blue exclusion performed over a 10 day period. Effects on cell cycle and apoptosis were performed using propidium iodide staining and flow cytometry.
Summary: Nine FDA approved drugs were identified based on activity and selectivity. Auranofin, a FDA approved rheumatoid arthritis agent, was selected for cell proliferation and cell cycle evaluation due to its IC50 value in control cells in comparison to OS cell lines. Auranofin displayed cytostatic effects in canine and human OS cell lines at low doses and drugs appeared to induce G2 arrest in treated cells.
Conclusions: Auranofin is an FDA approved drug that demonstrates promising, selective anticancer activity in canine and human OS cell lines. The next steps are to determine whether this agent possesses additive or synergistic activity in combination with anticancer agents that have already demonstrated clinical activity in dogs and humans with OS. In vivo preclinical proof of concept will be determined in mouse xenograft studies and dogs with spontaneous OS for promising drug combinations. Subsequently, we hope to rapidly translate preclinical proof of concept findings to human OS patients.
Citation Format: Joy M. Fulbright, Kathleen Neville, Melinda Broward, Tyce A. Bruns, Anuradha Roy, Peter McDonald, Megan Ottomeyer, Douglas H. Thamm, Tomoo Iwakuma. Comparative oncology drug discovery for Osteosarcoma in dogs and humans. [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 3689. doi:10.1158/1538-7445.AM2015-3689