bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1322: Folate receptor-targeted lipid coated albumin nanoparticles (F-LCAN) for therapeutic delivery of RX-0201 (Archexin®), an antisense oligonucleotide against Akt-1
Authors: Li Hong , Cheng Xinwei , Liu Yang , Lee Young Bok , Kim Deog Joong , Ahn Chang-ho , Lee Robert J. 
Published: July 2016

Abstract
Akt-1 is a protein kinase that contributes to cancer progression by promoting proliferation and inhibiting apoptosis of tumor cells. RX-0201 (Archexin®), a 20-mer phosphorothioate antisense oligonucleotide that inhibits the expression of Akt-1, is currently in a Phase IIa clinical trial for metastatic renal cancer. To further improve the efficacy of RX-0201, folate receptor-targeted lipid coated albumin nanoparticles containing RX-0201 (F-LCAN-RX-0201) were synthesized and evaluated for Akt-1 inhibition and antitumor activity. These nanoparticles are composed of DOTAP/soyPC/TPGS/folate-PEG-DSPE (25:70:4:1), a cationic human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate, and RX-0201. F-LCAN-RX-0201 had a particle size of 108.6±5.8 nm, zeta potential of 10.5±3.2 mV and 71.5% antisense loading efficiency. F-LCAN-RX-0201 in folate receptor-expressing KB cells inhibited cell growth at IC50 of 11.9 ± 4.0 μM while free RX-0201 did not show significant cytotoxicity at concentration up to 250 μM. Cellular uptake and Akt-1 inhibition of F-LCAN-RX-0201 was greater than the non-targeted LCAN-RX-0201 and was partially blocked by excess free folate. Pharmacokinetic studies showed that F-LCAN-RX-0201 had a longer half-life than that of free RX-0201 (30 ± 4 min vs 10 ± 2 min). In a KB xenograft tumor model, F-LCAN-RX-0201 exhibited higher tumor suppressive activity compared to the non-targeted LCAN-RX-0201 at 16 mg/kg (as a RX-0201 amount) without body weight changes. Moreover, the antitumor activity of F-LCAN-RX-0201 at a dose of 16mg/kg (as a RX-0201 amount) was similar to free RX-0201 at a dose of 90mg/kg. In conclusion, LCAN is a highly effective formulation for therapeutic delivery of antisense agents and F-LCAN-RX-0201 could be a potential therapeutic agent for tumors with increased folate-receptor expression.
Citation Format: Hong Li, Xinwei Cheng, Yang Liu, Young Bok Lee, Deog Joong Kim, Chang-ho Ahn, Robert J. Lee. Folate receptor-targeted lipid coated albumin nanoparticles (F-LCAN) for therapeutic delivery of RX-0201 (Archexin®), an antisense oligonucleotide against Akt-1. [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 1322.
Abstract 1333: Bigelovin inhibits colorectal cancer by suppressing the growth and inducing apoptosis both in vitro and in vivo
Authors: Li Ming-Yue , Yue Grace Gar-Lee , Tsui Stephen Kwok-Wing , Fung Kwok-Pui , Tan Ning-Hua , Lau Clara Bik-San 
Published: July 2016

Abstract
Colorectal cancer (CRC) is one of the most common cancers with high incidence and mortality worldwide. In 2014, CRC was the second commonest cancer and second leading cause of cancer deaths in Hong Kong. National Cancer Institute estimates that 132,700 people will be diagnosed with CRC and 49,700 people will die from the disease in 2015 worldwide. Despite effectiveness of the chemotherapeutics, severe side effects often affect patients’ normal life. Traditional Chinese medicines can be a good source of anti-tumor agent with better safety profile. Here, we reported a sesquiterpene lactone (bigelovin) isolated from Inula helianthus- aquatica, which was shown to induce anti-angiogenesis1 and apoptosis2 in vitro. Although previous studies reported its apoptotic effects on various cell lines, there were no detailed mechanistic or animal studies on its effect on colon cancer cells. To further explore its effect on CRC, we used both in vitro and in vivo assays. The effects of bigelovin in vitro were determined by Annexin V/PI double staining, cell cycle assay and western blotting. Bigelovin was shown to have better selectivity in colon cancer cells than primary normal colon cells. Besides, CRC cells treated with bigelovin resulted in decrease in cell proliferation and increase in apoptosis in both time- and dose-dependent manner. Western blot results also showed caspase activation and protein changes of key molecules (p-H2A.X-DNA damage marker, Cyclin B1-cell cycle, etc). Furthermore, bigelovin (20 mg/kg) significantly reduced the growth of CRC cells-driven tumors in vivo without severe side effects comparing to FOLFOX (containing folinic acid, 5-fluorouracil and oxaliplatin) treatment. Taken together, these results suggested that bigelovin can be a promising therapeutic candidate for colorectal cancer.
References:
1. Yue, G.G.L., et al. Anti-angiogenesis and immunomodulatory activities of an anti-tumor sesquiterpene bigelovin isolated from Inula helianthus-aquatica. Eur J Med Chem, 2013, 59: 243-52.
2. Zhang, H.H., et al. Bigelovin inhibits STAT3 signaling by inactivating JAK2 and induces apoptosis in human cancer cells. Acta Pharmacol Sin, 2015, 36(4): 507-16.
Citation Format: Ming-Yue Li, Grace Gar-Lee Yue, Stephen Kwok-Wing Tsui, Kwok-Pui Fung, Ning-Hua Tan, Clara Bik-San Lau. Bigelovin inhibits colorectal cancer by suppressing the growth and inducing apoptosis both in vitro and in vivo. [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 1333.
Abstract 1347: NTRK1/TRKA as a therapeutic target in castration resistant prostate cancer
Authors: Korkola James E. , Liu Moqing , Smith Rebecca , Liby Tiera , Gray Joe W. 
Published: July 2016

Abstract
Treatment options remain limited for men with castration resistant prostate cancer, with current chemotherapy offering mainly palliative benefits. Thus, there is an urgent need to identify new targets for therapeutic intervention in men who have progressed on anti-androgen therapy. We have compiled a panel of 20 prostate cancer cell lines that has been extensively characterized at the molecular level that enables us to perform high throughput drug and siRNA screens to identify novel therapeutic targets. We performed an siRNA screen targeting kinases using eight representative lines, both in the presence and absence of the anti-androgen MDV3100. Knockdown of NTRK1 (TRKA) significantly inhibited growth in 4/8 of the cell lines tested. To confirm this, we screened the entire panel of cell lines with the inhibitor CEP-701, which targets FLT3, JAK2, and TRK-A/B/C. CEP-701 showed GI50 values (dose required to inhibit growth by 50%) less than 400 nM in 8/20 cell lines. Since this drug had already been tested in clinical trials for prostate cancer and the trials were discontinued due to lack of PSA decline, we looked for other drugs that also inhibit TRKA. Both BIBF-1120 and GSK-1363089 are also known to inhibit TRKA, but neither have been tested in prostate cancer expressing TRKA. We tested GSK-136089 in a subset of 9 prostate cell lines, and found that 4/9 lines reached GI50 at 1 uM or less, including AR mutant or null lines such as 22rv1 and PC3 that are non-responsive to MDV3100. Additional tests with BIBF-1120 and GSK-1363089 are underway. These data suggest that NTRK1 may be a potential target for patients with castration resistant prostate cancer.
Citation Format: James E. Korkola, Moqing Liu, Rebecca Smith, Tiera Liby, Joe W. Gray. NTRK1/TRKA as a therapeutic target in castration resistant 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 1347.
Abstract 1350: New NCI experimental therapeutics program (NExT) small molecule libraries for academic investigator hts projects
Authors: Misra Raj N. , Eckert Michael , Laggner Christian 
Published: July 2016

Abstract
The NCI Experimental Therapeutics Program (NExT) is making available two new smaller (3.5K) screening libraries suitable for academic investigator HTS drug discovery programs. The NExT program is a partnership between NCI's Division of Cancer Treatment and Diagnosis (DCTD) and the Center for Cancer Research (CCR). NExT consolidates NCI's anticancer drug discovery and development resources with the goal of maintaining a robust and balanced therapeutics pipeline. It encompasses tasks from new target validation through Phase III clinical trial evaluation. The Program is designed to streamline development and testing of promising new anticancer drugs and to expedite their delivery to the bedside. As part of the Program to support HTS drug discovery, NCI has previously offered academic oncology investigators access to our full 83K NExT Diversity Library in single-use, 384-well plate format. The set was designed to identify lead small molecules for drug discovery programs. We are now making available 2 smaller pre-plated subsets of this library, the NExT Diversity 3500 and NExT Diversity 3500 SAR, for when screening the full set is not appropriate. Each library contains 3,500 compounds: NExT Diversity 3500 is a diverse sampling across the entire 83K library while the NExT Diversity 3500 SAR is designed to facilitate rapid SAR follow-up by sampling only those compounds that have at least 5 close neighbors in the 83K library. The new libraries were designed by initially filtering the full NExT Diversity Library for undesirable compounds such as PAINS. Both atom-pair based 2D pharmacophore fingerprints and ECFP6 topological fingerprints from ChemAxon were then employed to generate the two non-overlapping subset libraries. The NExT screening libraries are provided as a resource to academic oncology investigators through the NExT Program (see NExT Resources: http://next.cancer.gov/). The design details and physiochemical characteristics of the two new sets, NExT Diversity 3500 and NExT 3500 SAR, and procedures and criteria for accessing this resource are presented along with several other screening sets available through the Developmental Therapeutics Program (DTP).
Citation Format: Raj N. Misra, Michael Eckert, Christian Laggner. New NCI experimental therapeutics program (NExT) small molecule libraries for academic investigator hts projects. [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 1350.
Abstract 1361: Progress in light activatable prodrug for the combinational treatment of PDT and site-specific chemotherapy: paclitaxel prodrugs
Authors: Thapa Pritam , Li Mengjie , Bio Moses , Rajaputra Pallavi , Sun Yajing , Woo Sukyung , You Youngjae 
Published: July 2016

Abstract
We developed the photoactivatable prodrug of Paclitaxel (PTX) for the combinational treatment of chemo and photodynamic therapy (PDT). PTX causes dose-limiting side effects as other anticancer drugs when administered systemically. On the other hand, PDT suffers from incomplete ablation and subsequent reoccurrence in part due to the short half-life and poor diffusion rate of singlet oxygen. We prepared a conjugate of PTX with phthalocyanine via a singlet oxygen cleavable linker, as a unique prodrug of PTX, to overcome the problems of PDT and systemic chemotherapy. The PTX prodrug was evaluated for tubulin polymerization, the release rate of PTX from prodrug upon illumination at 690 nm, stability in complete media, and the combination effect in killing ovarian cancer cells in vitro (SKOV-3). The PTX prodrug did not enhance the tubulin polymerization unlike PTX. While it was stable in the media under dark, it rapidly released PTX upon illumination with far-red light: &gt; 90% release in 30 min. The prodrug showed much lower dark toxicity compared to PTX. When illuminated with 690 nm at 5.6 mW/cm2, the prodrug showed very potent phototoxicity: IC50 = 3.9 nM, through the combinational effect of PDT and PTX. In conclusion, we found that the PTX prodrug have desired properties as light-activatable prodrug expressing the combinational effect of PDT and local PTX chemotherapy. Animal study is underway to evaluate the antitumor effect of the PTX prodrug.
Citation Format: Pritam Thapa, Mengjie Li, Moses Bio, Pallavi Rajaputra, Yajing Sun, Sukyung Woo, Youngjae You. Progress in light activatable prodrug for the combinational treatment of PDT and site-specific chemotherapy: paclitaxel prodrugs. [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 1361.
Abstract 1362: Novel proton coupled folate transporter (PCFT) and reduced folate carrier (RFC) pharmacophore models for development of transporter-selective antifolates
Authors: Raghavan Sudhir , Gangjee Aleem , Matherly Larry H. 
Published: July 2016

Abstract
RFC is a ubiquitously expressed folate transporter that is present in normal tissues and tumors. RFC is utilized by reduced folates and by all the clinically used classical antifolates. In contrast, PCFT shows more limited expression in normal tissues and is highly effective in folate transport under low pH conditions associated with hypoxic solid tumors. Antifolates that are selectively transported by PCFT over RFC offer significant promise for development of targeted therapies of tumors (over)expressing PCFT. We previously reported 6-substituted pyrrolo[2,3-d]pyrimidines and thieno[2,3-d]pyrimidines as part of a continued effort to elucidate the SAR for substrate binding and cellular uptake for RFC, PCFT as well as folate receptors (FRs). While the X-ray crystal structure of FRs bound to antifolates has been resolved, the absence of X-ray crystal structures of PCFT and RFC has hindered structure-based medicinal chemistry efforts for development of antifolates selectively transported by PCFT. To address this, pharmacophore models were developed for the first time using Discovery Studio for PCFT and RFC using a series of thirty six 6-substituted bicyclic pyrrolo[2,3-d]pyrimidines and/or thieno[2,3-d]pyrimidines that included highly potent and selective compounds such as AGF94 (PCFT = 0.3 nM; RFC = 101 nM) previously reported by us. Compounds used for model development displayed a 3-log range inhibition of cancer cells overexpressing PCFT or RFC. The best models display a 4-point pharmacophore with excellent regression values (r2 PCFT = 0.96; RFC = 0.92). The models were internally validated by leave-one-out analysis (q2 PCFT = 0.752; RFC = 0.59) and externally validated using a test set of 6-substituted bicyclic analogs not used in model development. Comparison of the pharmacophore models indicates different conformational and structural requirements for compounds for binding to PCFT or RFC. We have used these models to explain the potent PCFT inhibitory activity and selectivity of compounds such as AGF94. These models are being used in the development of selectively transported targeted antifolates that would result in decreased toxicity compared to standard antifolates such as methotrexate (MTX) or pemetrexed (PMX) which utilize all three folate transport systems.
Citation Format: Sudhir Raghavan, Aleem Gangjee, Larry H. Matherly. Novel proton coupled folate transporter (PCFT) and reduced folate carrier (RFC) pharmacophore models for development of transporter-selective antifolates. [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 1362.
Abstract 1385: Patient-derived xenografts as validation material for NGS assays: Analysis of genetic homogeneity
Authors: Konigshofer Yves , Anekella Bharathi , Garlick Russell 
Published: July 2016

Abstract
Full process controls and validation materials for next generation sequencing (NGS)-based molecular diagnostics in Oncology that mimic a biopsy sample and are renewable and scalable have been elusive. Patient-derived Xenografts (PDXs), which are similar in morphology and somatic mutations to original tumors, may present a solution to this pressing need.
In order to evaluate the abilities of PDXs to serve as full process controls and validation materials, we had PDXs that contained established driver mutations KRAS G12C analyzed by clinical laboratories using a variety of different NGS-based assays. The resulting data was analyzed for genetic homogeneity as well as for the presence of mouse-derived variants.
PDXs were found to be generally compatible with NGS-based assays and similar variant frequencies of driver mutations were reported. High concordance was also observed in variant frequencies of PDXs at passage 5 that were derived from the same tumor but grown in different mice. For example, the observed differences in over 90% of variants and all driver mutations were not statistically significant.
In amplicon-based assays, which represent the majority of current assays that look at mutational hotspots, mouse-derived variants were rare. Typically, variant data was usable without any further processing. In hybrid/capture-based assays, mouse-derived variants were common because of the lower binding stringency used by these assays. Without further processing, this manifested in slightly lowered variant frequencies for driver mutations - where wild-type “reference” sequences are often conserved between species and thus inflate the number of reference sequences - and greatly elevated numbers of total variants. However, by processing the data at the FASTQ stage using in-house developed software, it was possible to effectively remove mouse-derived variants in a manner that would be compatible with patient testing as well.
In conclusion, we show that PDXs are compatible with NGS-based assays and can be used to control the full process from the point where the Pathologist first fixes the tissue. Those containing driver mutations that have been previously characterized in cancer also enable laboratories to control and validate their assays by showing that they can consistently detect these mutations.
Citation Format: Yves Konigshofer, Bharathi Anekella, Russell Garlick. Patient-derived xenografts as validation material for NGS assays: Analysis of genetic homogeneity. [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 1385.
Abstract 1387: Application of target enrichment combined with unique molecular identifiers to determine allelic frequencies of human cancers
Authors: Kraushaar Daniel C. , Bowman Sarah K. , Davis Theodore B. , Emerman Amy B. , Henig Noa , Patel Kruti M. , Russello Salvatore , Hendrickson Cynthia L. 
Published: July 2016

Abstract
Existing target enrichment and library preparation for next-generation sequencing typically utilize PCR amplification steps that introduce substantial bias and sequencing of duplicate reads, which in turn affect the quantification accuracy of somatic allele frequencies. Unique molecular identifiers (UMIs) are random molecular tags that uniquely label each molecule prior to library amplification and aid in the identification of true PCR duplicates and thereby improve the accuracy in estimating the relative molecular copy number of the original sample. Here, we applied a target enrichment method for hybridization-based capture of regions of interest, combined with unique molecule labeling and next-generation sequencing to determine allelic frequencies of select cancer targets. Target enrichment and library preparation can be performed in just under seven hours, and our UMI method is compatible with sample indexing using separate barcodes. To demonstrate the robustness and accuracy of our method, we present the detection and assessment of allelic frequencies of multiple cancer genes across multiple reference standards. The result is a fast and cost-efficient method that enables the determination of even low allelic frequencies with high confidence.
Citation Format: Daniel C. Kraushaar, Sarah K. Bowman, Theodore B. Davis, Amy B. Emerman, Noa Henig, Kruti M. Patel, Salvatore Russello, Cynthia L. Hendrickson. Application of target enrichment combined with unique molecular identifiers to determine allelic frequencies of human cancers. [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 1387.
Abstract 1391: Gene expression profiling for cancer classification in circulating tumor cells
Authors: Soifer Harris S. , Salunga Ranelle C. , Harris Tristan G. , Ramirez Jose , Gogoi Priyadarshini , Wang Yixin , Sepehri Saedeh , Handique Kalyan , Schnabel Catherine A. 
Published: July 2016

Abstract
Background: Enumeration and molecular characterization of circulating tumor cells (CTCs) offer a non-invasive method for tumor analysis, particularly in cases where the biopsy is difficult to obtain or has been exhausted by conventional diagnostic methods. The 92-gene assay (CancerTYPE ID®, bioTheranostics, Inc.) is a clinically-validated cancer classifier based on the collective expression of 87 informative genes, many of which are involved in lineage commitment and signal transduction. The objective of this study was to determine the feasibility of a blood-based application using differential gene expression.
Methods: Technical feasibility studies for cancer cell enrichment and RNA viability were conducted by purifying cancer cell lines that were spiked into donor blood using a microfluidic chip (Celsee PREP™100 system, Celsee Diagnostics) followed by immunodepletion of leukocytes. Quantitative RT-PCR and immunoflourescence were performed on cells harvested at different steps of the purification workflow. Quantitative RT-PCR on individual genes specific to each lineage compartment was used to estimate cell types and cell numbers that were co-purified by the workflow. Gene expression was evaluated by the 92-gene assay.
Results: An integrated workflow was established that allows for the molecular characterization of cancer cells purified from blood. Cell enrichment on the microfluidic chip followed by purification using immunodepletion resulted in efficient recovery (&gt; 80% of input cells) and viable RNA from cancer cells spiked into whole blood. A key result of this study was the demonstration that the level of cancer-specific gene expression in purified samples was similar to the level of expression from an equivalent number of unspiked cancer cells suggests that significant cell loss does not occur during the purification workflow. A comparison of gene expression profiles from purified and mixed cell populations allowed for the identification of subsets of genes that are differentially expressed in cancer cells compared with leukocytes.
Conclusion: A functional workflow with viable RNA and efficient recovery of cancer cells that are within the technical specifications of the 92-gene assay was established. Findings from this feasibility study are fundamental to the potential for CTC-based cancer classification.
Citation Format: Harris S. Soifer, Ranelle C. Salunga, Tristan G. Harris, Jose Ramirez, Priyadarshini Gogoi, Yixin Wang, Saedeh Sepehri, Kalyan Handique, Catherine A. Schnabel. Gene expression profiling for cancer classification in circulating tumor cells. [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 1391.