bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5122: Utilizing zebrafish to study the effect strigolactone on breast cancer cells
Authors: Lin Kira , Grivas Christopher , Boru Elema , Dayani Yaron , Berens Eric , Riegel Anna T. , Glasgow Eric , Yarden Ronit I. 
Published: July 2017

Abstract
Strigolactones (SLs) are a novel class of phytohormones that regulates shoot branching patterns and above-ground plant architecture by inhibiting the outgrowth of axillary lateral buds or meristems. The SL analogues (SLAs) inhibit the growth and survival of a wide array of cancer-derived cell lines including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while minimally affecting normal cultured cells. Interestingly, cancer cells with high metastatic potential are more sensitive to the inhibitory effect of SLAs than less aggressive cells. Treatment of cancer cells with SLAs leads to the activation of stress-related signaling including p38MAPKs and JNK1/2, and disrupt the microtubule network. Furthermore, a reduction in acetylated-alpha-tubulin was observed in SLA-treated MDA-MB-231 cells. Microtubules dynamics has been proposed as one of the mechanisms that regulate cell migration by acting on lamellipodia formation. The ECIS invasion assay data suggests that even at low concentration of SLA and as soon as 6 hours, SLAs suppress MDA-MB-231 cells’ ability to invade the HUVEC monolayer. To further examine the effect of SLAs on the invasive and metastatic behaviors of cancer cells in vivo, fluorescently labeled MDA-MB-231 cells were used as xenograft models in zebrafish. Embryos injected with MDA-MB-231 cells showed 66.6% metastasis in vehicle treated control fishes, as compared to 22.85% in SLAs treated fishes. This suggests that SLAs are potent inhibitors of cancer dissemination and metastasis.
Note: This abstract was not presented at the meeting.
Citation Format: Kira Lin, Christopher Grivas, Elema Boru, Yaron Dayani, Eric Berens, Anna T. Riegel, Eric Glasgow, Ronit I. Yarden. Utilizing zebrafish to study the effect strigolactone on breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5122. doi:10.1158/1538-7445.AM2017-5122
Abstract 5123: Targeted thieno[2,3-d]pyrimidines with fluorinated phenyl side chains as antitumor agents
Authors: Tong Nian , Gangjee Aleem , Povrik Adrianne Wallace , O’Connor Carrie , Dekhneb Aamod Aamod , Hou Zhanjun , Matherly Larry H. 
Published: July 2017

Abstract
The reduced folate carrier (RFC) is ubiquitously expressed in tissues and tumors and is the major tissue transporter for folate cofactors. Folate receptor (FR) α and β, as well as the proton-coupled folate transporter (PCFT), exhibit narrower patterns of tissue expression and are likely to serve more specialized physiologic roles. FRs are expressed in a subset of cancer cells (e.g., ovarian and non-small cell lung cancer for FRα, acute myelogenous leukemia for FRβ), whereas PCFT is expressed in a wide range of human solid tumors but not leukemias. Earlier generations of glycinamide ribonucleotide formyltransferase (GARFTase) and de novo purine nucleotide biosynthesis (e.g., Lometrexol) have shown promise as antitumor drugs. However, these compounds are excellent substrates for RFC and thus are non-selective for tumors, leading to dose-limiting toxicities. We previously reported a novel class of 6-substituted thieno[2,3-d] pyrimidines with a phenyl side chain and 3- and 4-carbon bridge lengths (AGF17 and AGF23, respectively) which selectively targeted FRs but not RFC or PCFT. To increase antitumor efficacy, we synthesized fluorinated analogs of AGF17 and AGF23, designated as AGF309 and AGF304, respectively. AGF309 and AGF304 potently inhibited proliferation of Chinese hamster ovary (CHO) cell lines engineered to individually express human FRα (IC50s of 1.08 and 2.27 nM, respectively) or FRβ (IC50s 0.48 and 1.14 nM, respectively). AGF304 and AGF309 showed nominal activity toward RFC- and PCFT-expressing CHO cells. Both AGF309 and AGF304 were also potently inhibitory toward FRα-expressing human KB human tumor cells (IC50s of 7.19 and 5.27nM, respectively). By analogy with previous iterations of 6-substituted thieno [2,3-d] pyrimidine compounds, growth inhibitory activity by AGF309 and AGF304 likely involves inhibition of de novo purine biosynthesis at GARFTase and potentially a secondary intracellular target. Collectively, our in vitro findings of the potent and selective antitumor activity and FR selectivity suggest that further preclinical evaluation of AGF309 and AGF304 as potential antitumor agents is warranted.
Citation Format: Nian Tong, Aleem Gangjee, Adrianne Wallace Povrik, Carrie O’Connor, Aamod Aamod Dekhneb, Zhanjun Hou, Larry H. Matherly. Targeted thieno[2,3-d]pyrimidines with fluorinated phenyl side chains as antitumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5123. doi:10.1158/1538-7445.AM2017-5123
Abstract 5126: Novel indolizino[8,7-b]indole hybrids with potent activity against small cell lung cancer
Authors: Chang Sue-Ming , Wu Ming-Hsi , Pidugu Hima Bindu , Su Tsann-Long , Lee Te-Chang 
Published: July 2017

Abstract
Small cell lung cancer (SCLC) is an aggressive type of lung cancer and accounts for 10% to 15% of all lung cancer cases. The malignancy has a greater tendency to be widely disseminated by the time of diagnosis as well as to develop early resistance to conventional treatments, a cure is difficult to achieve. The current standard therapy for SCLC treatment, either with monotherapy (platinum based drugs) or combination therapy (e.g., cisplatin with irinotecan or topotecan), was shown to cause serious side effects and inevitably evoke drug resistance in a short time period. We have recently synthesized a series of novel bis(hydroxymethyl)indolizino[8,7-b]indole hybrids by fusing β-carboline and bis(hydroxymethyl)pyrrole moieties for antitumor evaluation. These hybrid molecules displayed diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Our results also showed that they significantly inhibited the cell growth of various human tumor cell lines. Of the tested tumor cell lines, the SCLC cells (H526 and H211) were the most susceptible to compounds BO-2239 and BO-2329. These hybrids induced cell cycle arrest at the G2/M phase and triggered tumor cell apoptotic death. Intriguingly, the substituent at N11 (H or Me) played a critical role in modulating Topo II inhibition and DNA cross-linking. Compared to the compounds with N11-Me group, derivatives having N11-H group profoundly increased Topo II inhibition activity but reduced DNA cross-linking activity. Among these hybrids, BO-2239 (with N11-H) was as potent as irinotecan, but more effective than cisplatin, in nude mice bearing SCLC H526 xenografts. Accordingly, hybrid BO-2239 may be further developed as a potential agent for the treatment of SCLC.
Citation Format: Sue-Ming Chang, Ming-Hsi Wu, Hima Bindu Pidugu, Tsann-Long Su, Te-Chang Lee. Novel indolizino[8,7-b]indole hybrids with potent activity against small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5126. doi:10.1158/1538-7445.AM2017-5126
Abstract 513: The link between polyploidy and replication stress in melanoma
Authors: Vilgelm Anna E. , Johnson C. Andrew , Malikayil Kiran , Raman Dayanidhi , Flaherty David , Higgins Brian , Richmond Ann 
Published: July 2017

Abstract
Genomic instability is a hallmark of cancer implicated in tumor evolution and resistance to therapy. However, the molecular mechanisms that underlie genomic instability are still poorly understood. One common feature of cancer cells is an elevated genomic content (polyploidy) which is also associated with the acquisition of therapy resistance. Here we demonstrate a link between genomic instability and polyploidization in melanoma cells. We show that polyploidy induced by treatment with small molecule inhibitors of various mitotic kinases, such as AURKA, AURKB and PLK1, leads to DNA damage in cells with elevated (&gt;4n) DNA content. This DNA damage results from replication stress exacerbated by limited activation of p53 in malignant melanocytes. Pharmacological induction of p53 in polyploid cells using an MDM2 antagonist reduced DNA damage by blocking re-replication of the polyploid genome as a result of p53-mediated p21 activation and transactivation of DNA repair genes. Notably we found that p21 blockade using siRNA knockdown or genetic knockout shifted polypoid cell response to p53 activation from cytostatic to cytotoxic. As a result, p21-deficient cells exhibited enhanced sensitivity to mitotic blockade combined with p53 induction. Furthermore, TCGA dataset analysis showed poor progression free survival in melanoma patients with high p21 protein expression. These data argue for administering mitotic inhibitors and MDM2 antagonists, which are currently in clinical development, in conjunction with agents that target p21. In summary, our data here reveal that polyploidization can be a mechanism for induction of DNA damage and genomic instability associated with drug resistance in cancer and suggest a novel strategy for targeting these pathways to improve melanoma therapy.
Citation Format: Anna E. Vilgelm, C. Andrew Johnson, Kiran Malikayil, Dayanidhi Raman, David Flaherty, Brian Higgins, Ann Richmond. The link between polyploidy and replication stress in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 513. doi:10.1158/1538-7445.AM2017-513
Abstract 5131: Efficient delivery of siRNA targeted CCDC88A mRNA to pancreatic cancer tumor inhibits the invasiveness and metastasis
Authors: Taniuchi Keisuke , Yawata Toshio , Ueba Tetsuya , Saibara Toshiji 
Published: July 2017

Abstract
Introduction: We identified CCDC88A messenger RNA (mRNA) that accumulates in lamellipodia by binding to an RNA-binding protein IGF2BP3 with a next generation sequencer. The objectives of this study are as follows: (1) To identify CCDC88A specific small interfering RNAs (siRNAs) as RNA interference agents that have an inhibitory effect on the invasion and metastasis of pancreatic cancer cells in a mouse model of the invasion and metastasis of pancreatic cancer; and (2) To develop a nucleic-acid delivery system to efficiently transport the siRNAs to PDAC tissue.
Methods: After intravenous injection of CCDC88A-specific siRNAs supplemented with folic acids that can bind to the folic acid receptor—which are highly expressed on pancreatic cancer cells—and polyethylene glycol-chitosan oligosaccharide nanoparticles to a mouse model of invasion and metastasis in which a human pancreatic cell line was transplanted to induce tumor formation in the mouse pancreas, accumulation of the siRNAs in the pancreatic cancer tissue was determined by using an in vivo imaging system. After CCDC88A-specific siRNA accumulation in the pancreatic cancer tissue was identified, invasion to the retroperitoneum as well as metastasis to the lung or liver from the human primary pancreatic tumor was compared between the mice in which CCDC88A-specific siRNA accumulation was identified and those receiving a scrambled control siRNA.
Results: CCDC88A-specific siRNAs could be delivered to the pancreatic cancer cells of cancer-bearing nude mice by supplementation with folic acids and chitosan oligosaccharide nanoparticles. Supplementation with folic acids and chitosan oligosaccharide nanoparticles caused no hemolysis and had no effect on liver, kidney, or pancreatic function. Invasion to the retroperitoneum and metastasis to the lung or liver from the primary pancreatic cancer were suppressed in cancer-bearing nude mice by administration of those siRNAs, which target CCDC88A mRNA accumulated in lamellipodia of pancreatic cancer cells.
Conclusions: This study suggests the potential to develop a siRNA drug to inhibit the invasion and metastasis of pancreatic cancer.
Citation Format: Keisuke Taniuchi, Toshio Yawata, Tetsuya Ueba, Toshiji Saibara. Efficient delivery of siRNA targeted CCDC88A mRNA to pancreatic cancer tumor inhibits the invasiveness and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5131. doi:10.1158/1538-7445.AM2017-5131
Abstract 5134: Novel trifunctional immunoliposome delivery system to minimize resistance and side effects for anticancer therapy
Authors: Vaidya Tanaya R. , Ait-Oudhia Sihem 
Published: July 2017

Abstract
Background: Breast cancer (BC) is the second leading cause of cancer death in women worldwide. About 25% of BCs have overexpression of the HER2 receptor. Although HER2 targeted therapies have shown considerable improvement in HER2-positive BC patients’ outcome, treatment resistance remains a clinical challenge. Here, we sought to develop and evaluate a novel tri-functional immune-liposome (TFIL) that overcomes HER2 treatment resistance and associated cardiotoxicity by dually targeting HER2 on BC cells and CD3 receptors on cytotoxic T-lymphocytes (CTLs).
Material and methods: Anti-HER2 (Trastuzumab) and anti-CD3 (OKT-3) antibodies, were conjugated to lipid nanoparticles by the micelle-transfer method, and the resulting formulation was purified by dextran gradient ultra-centrifugation. Targeted lipid nanoparticles were formulated with a fluorescent lipophilic dye, DiD, for studying receptor binding and internalization. Studies were conducted with HER2-positive BT474 cells and CD3-positive Jurkat cells using flow cytometry analyses. Doxorubicin (DXR) was encapsulated in the nanoparticles by the remote-loading technique for cell-kill experiments. In vitro cell-kill studies were conducted by co-culturing BT474 as the target cells, and peripheral blood mononuclear cells as the effector cells, at varying ratios.
Results: Purified formulations were successfully characterized for conjugation by determining the protein to lipid ratio. Flow cytometry analyses demonstrated successful cell binding and/or internalization of the TFIL with both the HER2 and CD3-positive cell lines. Moreover, these dual-targeted nanoparticles were able to retarget T cells to kill HER2 positive BC cells, and showed improved efficacy compared to non-targeted and plain HER2-targeted formulations in vitro.
Conclusion: A novel drug delivery system, TFIL, that targets HER2 receptors on tumor cells, CD3 on CTLs, and is able to slowly release DXR was successfully developed and evaluated in vitro on HER2 overexpressing BC cells. Our findings show great promise at overcoming resistance and associated cardiotoxicity to present HER2 targeted BC therapies, and may translate into improved anti-tumor activity clinically compared to other treatment options.
Citation Format: Tanaya R. Vaidya, Sihem Ait-Oudhia. Novel trifunctional immunoliposome delivery system to minimize resistance and side effects for anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5134. doi:10.1158/1538-7445.AM2017-5134
Abstract 5138: Development of a gold nanoparticle platform capable of selective homing to tumor tissues for intravenous antitumor therapy
Authors: Han Zhen 
Published: July 2017

Abstract
Intratumoral administration of high mobility group nucleosome-binding protein 1 (HMGN1) and R848/resiquimod together with a checkpoint inhibitor can eradicate large established tumors. However, the intratumoral route of administration is difficult to use on cancers of internal organs. To improve potential clinical use of HMGN1 and R848, it is necessary to deliver HMGN1 and R848 systemically to the tumor tissue. Gold nanoparticles (AuNP) have been extensively studied as a vehicle for various types of drugs, including anticancer compounds. In this study, we established a means of generating PEGylated Au-HMGN1-R848 (Au-PEG-HMGN1-R848) complexes, which, upon intravenous IV administration, preferentially target ectopic hepatoma or colon tumor tissue and avoids uptake of the particles by liver and spleen of tumor-bearing mice. Additionally, Au-PEG-HMGN1-R848 complexes were stable and preserved the capacity of HMGN1 and R848 to stimulate the maturation of dendritic cells. IV administration of Au-PEG-HMGN1-R848 complexes plus a checkpoint inhibitor had effective antitumor activity in curing 80% of C57BL/6 mice bearing large (1 cm in diameter) Hepa1-6 hepatoma and Balb/c mice bearing CT26 colon tumors. Therefore, an Au nanoparticle platform capable of selectively delivering HMGN1 and R848 systemically to tumor tissues can be used to effectively to cure ectopic Hepa1-6 hepatoma and CT26 colon carcinoma.
Note: This abstract was not presented at the meeting.
Citation Format: Zhen Han. Development of a gold nanoparticle platform capable of selective homing to tumor tissues for intravenous antitumor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5138. doi:10.1158/1538-7445.AM2017-5138
Abstract 514: Genetic load in cancer cell populations
Authors: Zhang Yuezheng , Shen Xu , Li Yawei , Zhu Tianqi , Tao Yong , Li Tao , Wang Di , Li Xueying , Ma Qin , Lu Xuemei , Wang Hurng-Yi , Wu Chung-I 
Published: July 2017

Abstract
Populations accumulate deleterious mutations that have yet to be removed by natural selection. This mutated portion of the population that does not contribute to its fitness is called the genetic load and is proportional to the deleterious mutation rate. Given the genomic instability of cancer cells, the genetic load could be substantial if the instability indeed leads to loss of cell fitness. We hypothesize that because aneuploidy and copy number variations (CNVs) are the most common forms of genome instability, their fitness consequences may determine the genetic load in cancer cells. To test this hypothesis, we randomly selected single cells from a HeLa cell line and measured the cell growth rate via daily cell counting and an MTT cell proliferation assay. We then measured the genetic changes and resulting growth rate variation. We observed rapid generation of heterogeneity in the growth rate within the population. The growth rate of different progeny cells was stable indicating that it is genetically determined. Next, using whole genome sequencing of recently descended clones of a single HeLa cell, we found that cells with fewer newly acquired CNVs have higher proliferation rates vice versa. This indicated that CNV accumulation decreased cell fitness systematically. We next estimated the rate of CNV mutation by measuring the growth rate of two daughter cells from single proliferation and found that there is approximately 1 deleterious mutation in every 4 cell divisions. We speculated that due to a high, deleterious CNV mutation rate, tumor cells inevitably accumulate deleterious CNVs and a large percentage of tumor cells are genetically defective. Accordingly, we observed that the average growth rate of tumor cell populations decreased in the short term since defective cells accumulated in the population and the variation of cellular growth rates within the population increased. By modeling the process of mutation accumulation and measuring cell growth rate, we estimated that the deleterious mutation rate in HeLa cells is about 0.26-0.31 per cell division, and that HeLa cells reduce roughly 5%-6% of fitness for every cell division. The observations of a high proliferation rate and high genetic load in this representative tumor cell line indicates a “high risk, high reward” evolution strategy for tumor cells and suggests that increasing the level of genomic instability may cause the meltdown of tumor cell population by forcing cells to accelerate the cell cycle.
Citation Format: Yuezheng Zhang, Xu Shen, Yawei Li, Tianqi Zhu, Yong Tao, Tao Li, Di Wang, Xueying Li, Qin Ma, Xuemei Lu, Hurng-Yi Wang, Chung-I Wu. Genetic load in cancer cell populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 514. doi:10.1158/1538-7445.AM2017-514
Abstract 5140: Encapsulation of the atypical retinoid ST1926 in nanoparticles prolongs the survival of acute myeloid leukemia xenografted mice at multiple folds lower concentrations than the naked drug
Authors: El-Houjeiri Leeanna , Saad Walid , Hayar Berthe , Aouad Patrick , Tawil Nadim , Abdel-Samad Rana , Pisano Claudio , Bazarbachi Ali , Hajj Hiba El , Darwiche Nadine 
Published: July 2017

Abstract
Acute myeloid leukemia (AML) represents one of the most complex types of leukemia. It is a clinically and genetically heterogeneous disorder of hematopoietic progenitor cells, which have lost their ability to differentiate normally. Retinoids regulate vital biological processes including development, differentiation, proliferation, and cell death of hematopoietic progenitor cells. The natural retinoid all-trans retinoic acid (ATRA) became the paradigm for the treatment of acute promyelocytic leukemia (APL), an AML subtype. However, in non-APL AML patients, ATRA is possibly only effective in patients with Nucleophosmin-1 mutations without FMS-like tyrosine kinase 3 internal tandem duplication (FLT-3 ITD). Therefore, synthetic retinoids, specifically the adamantyl ST1926, emerged as potential alternatives. However, despite its lack of toxicity, ST1926 development in clinic was limited due to its rapid glucuroconjugation resulting in low plasma concentrations. Nanomedicine enables more efficient drug delivery and bioavailability. Here, we investigate the pre-clinical efficacy of ST1926 and polymer stabilized ST1926 nanoparticles in AML in vitro and in vivo models. We show that ST1926, at low sub-µM concentrations, potently inhibited the growth of human non-APL ATRA-resistant AML cell lines and AML patient cells while sparing resting and activated normal leukocytes at ten- to hundred-fold higher concentrations. ST1926 induced early DNA damage and massive apoptosis in all tested AML cell lines. To optimize the drug’s bioavailability burden, polymer stabilized ST1926 nanoparticles were developed using Flash NanoPrecipitation, and were shown to display comparable anti-growth activities to the naked drug in vitro. In murine AML xenograft model, ST1926 and ST1926 nanoparticles significantly prolonged survival. Strikingly, ST1926 encapsulated in nanoparticles extended survival in AML xenografted mice at four-fold lower concentrations than the naked drug. These results highlight the promise of ST1926 in AML therapy and warrant further clinical development of this adamantly retinoid.
Citation Format: Leeanna El-Houjeiri, Walid Saad, Berthe Hayar, Patrick Aouad, Nadim Tawil, Rana Abdel-Samad, Claudio Pisano, Ali Bazarbachi, Hiba El Hajj, Nadine Darwiche. Encapsulation of the atypical retinoid ST1926 in nanoparticles prolongs the survival of acute myeloid leukemia xenografted mice at multiple folds lower concentrations than the naked drug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5140. doi:10.1158/1538-7445.AM2017-5140