bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5089: Antitumor activities elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1
Authors: Numasaki Muneo , Tsukamoto Hiroki , Tomioka Yoshihisa 
Published: July 2017

Abstract
Interleukin (IL)-28A/IFN-λ2 and IL-29/IFN-λ1 have been demonstrated to elicit direct and indirect antitumor actions. In this study, we constructed an adenovirus vector expressing either IL-28A/IFN-λ2 (AdIL-28A) or IL-29/IFN-λ1 (AdIL-29) to evaluate the therapeutic properties of intratumoral injection of recombinant adenovirus to apply for the clinical implementation of cancer gene therapy. Despite the lack of antiproliferative effect on MCA205 and B16-F10 cells, a retarded growth of established subcutaneous tumors was observed following multiple injections of either AdIL-28A or AdIL-29 when compared with AdNull. In vivo cell depletion experiments displayed that both NK cells and CD8+ T cells play a major role in AdIL-28A-mediated tumor growth suppression. A significant increase in the number of infiltrating CD8+ T cells into the tumors treated with either AdIL-28A or AdIL-29 was observed. Moreover, specific antitumor cytotoxic T lymphocyte reactivity was detected in spleen cells from animals treated with either AdIL-28A or AdIL-29. In IFN-γ deficient mice, the antitumor activity of AdIL-28A was completely impaired, indicating that IFN-γ is critically involved in the tumor growth inhibition triggered by AdIL-28A. IL-12 provided an additive antitumor effect when combined with AdIL-28A. These results indicate that AdIL-28A and AdIL-29 could be successfully utilized as an alternative cancer gene therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Muneo Numasaki, Hiroki Tsukamoto, Yoshihisa Tomioka. Antitumor activities elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1 [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 5089. doi:10.1158/1538-7445.AM2017-5089
Abstract 5097: An industrial method of manufacturing a novel RNAi anticancer drug, DFP-10825, for the treatment of peritoneal disseminated gastric cancer
Authors: Ishida Tatsuhiro , Ando Hidenori , Fukushima Masakazu , Huang Cheng-Long , Wada Hiromi 
Published: July 2017

Abstract
We have developed an RNAi based anticancer drug, DFP-10825 [a cationic liposome and short-hairpin RNAi molecule for thymidylate synthase (TS shRNA)] and here established an industrial method of manufacturing the formulation. The therapeutic efficacy of the DFP-10825 was examined in a MKN45 human gastric carcinoma xenograft mouse model (peritoneal disseminated gastric cancer model). The mice were received intraperitoneal injection with 5 doses of DFP-10825 or control formulation (short-hairpin RNA for luciferase) (1 mg shRNA/kg/day) once every 3 days. The treatment with DFP-10825 obviously prolonged survival time of the mice compared to control formulation and significantly suppressed the target mRNA level in the peritoneal disseminated tumors. We recently reported that DFP-10825 showed a significant therapeutic efficiency in the human malignant pleural mesothelioma orthotopic xenograft model. Accordingly, DFP-10825 may lead a clinical benefit to patients with pulmonary malignant mesothelioma or disseminated peritoneal tumor. In addition, we established an industrial method of manufacturing DFP-10825, which provides a large scale preparation. Water solution of TS shRNA was gently mixed at an optimal ratio with ethanol solution of cationic lipids, composed of DC-6-14 (a cationic lipid), DOPE and DOPC. Then, the mixture was lyophilized under optimal condition. The freeze-dried cake provided a ready for injection formulation by a one-step hydration with saline. Physicochemical properties of the obtained DFP-10825 such as particle size, zeta-potential, and size distribution were almost comparable with those of conventionally prepared DFP-10825, which prepared with conventional preparation method, mixing TS shRNA solution and cationic liposomes. Our findings in this study demonstrate that intraperitoneal chemotherapy with a simple freeze-dried RNAi medicine, DFP-10825, showing an equivalent pharmaceutical and therapeutic potency with conventionally prepared DFP-10825, meets a criteria to use for clinical settings and will have a clinical benefit to treat patients with disseminated peritoneal and pulmonary cancers.
Citation Format: Tatsuhiro Ishida, Hidenori Ando, Masakazu Fukushima, Cheng-Long Huang, Hiromi Wada. An industrial method of manufacturing a novel RNAi anticancer drug, DFP-10825, for the treatment of peritoneal disseminated gastric 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 5097. doi:10.1158/1538-7445.AM2017-5097
Abstract 510: Topoisomerase IIβ silencing increases R loops at specific genomic loci associated with an increase of γH2AX and cell cycle progression delay in human cancer cells
Authors: Delcuratolo Maria , Marinello Jessica , Capranico Giovanni 
Published: July 2017

Abstract
DNA topoisomerases (Top) are important players in maintaining the genome stability of cells by removing negative and positive DNA supercoils during transcription, replication and other DNA transactions. Recent evidence demonstrated that Top 1 silencing and poisoning by camptothecin affect the formation of R-loops, which are RNA/DNA hybrid structures involved in genome instability and are favored by negative supercoils of the DNA. The findings overall demonstrate that Top 1 reduces R loop levels during transcription whereas it favors R loop formation at early origins of DNA replication. Here, we address the question of whether DNA topoisomerase IIβ can also contribute to steady-state levels of R loop structures in the genome of U2OS cancer cells. We have then investigated the effects of Top2β silencing and Top2 poisons, doxorubicin and etoposide, on R loops and DNA damage in human U2OS cancer cells. Similarly to published data with camptothecin (Marinello et al., Nucleic Acids Research, 2013), Top2 poisons increase cellular R loops by IF after short treatment times and reduce them after 1 hour of treatment. The bi-phasic effect of poisons is mainly dependent on transcription. Moreover, we have determined the changes of R-loop levels by IF after Top2β silencing and the findings demonstrate that the enzyme can strongly modulate the formation of R loops as a full Top2β depletion increases nuclear R-loop levels. In addition, Top2β depletion leads to a slight increase of phosphorylation of H2AX histone along with cell cycle delay and eventually cell death. Thus, Top2β depletion can trigger genomic DNA breakage through alterations of R-loops. In order to establish which are the genomic regions of altered R loop levels, we have mapped Top2β-dependent R loop alterations by the DRIP method showing that specific genomic sites are affected by Top2β. Bioinformatic analyses of R loop maps in U2OS cells will be presented and discussed at the meeting. Altogether the findings demonstrate a critical role of Top2β in governing R loop structures in human cancer cells indicating that DNA torsional tension is a main driving factor of R loop formation and hence genome instability in cancer cells.
Citation Format: Maria Delcuratolo, Jessica Marinello, Giovanni Capranico. Topoisomerase IIβ silencing increases R loops at specific genomic loci associated with an increase of γH2AX and cell cycle progression delay in human 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 510. doi:10.1158/1538-7445.AM2017-510
Abstract 5103: Development of MJ-66 as a novel anticancer agent for the treatment of malignant gliomas
Authors: Hour Mann-Jen , Chen Tai-Lin , Gean Po-Wu , Lee Hong-Zin 
Published: July 2017

Abstract
Malignant glioma is the most common aggressive adult primary tumor of the central nervous system. Treatments of malignant gliomas include surgery, radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. However, inherent- and acquired resistance to TMZ present major obstacles to successful treatment, and the prognosis of patients with malignant gliomas remains very poor.
MJ-66, a synthetic qunazoline compound, was identified in our study as a potent anti-proliferative agent especially on human glioma with IC50 of approximately 60 nM. In intracranial glioma xenograft model, MJ-66 (0.14 mg/kg in saline, i.p., q.d., 10 days) significantly inhibited tumor growth and increased the survival of the experimental mice, however, did not decrease the body weight of mice.
Currently, there is a profound unmet medical need for a new drug in the treatment of malignant brain tumor. The MJ-66 demonstrated superior efficacy to TMZ that are the only first-line-drug in clinical use. MJ-66 is suggested to be a promising anticancer candidate.
Note: This abstract was not presented at the meeting.
Citation Format: Mann-Jen Hour, Tai-Lin Chen, Po-Wu Gean, Hong-Zin Lee. Development of MJ-66 as a novel anticancer agent for the treatment of malignant gliomas [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 5103. doi:10.1158/1538-7445.AM2017-5103
Abstract 5104: A novel N-mustard-quinoline conjugate is a potent agent against colorectal cancer
Authors: Chen Tai-Lin , Chen Yan-Bo , Shen Chia-Ning , Su Tsann-Long , Lee Te-Chang 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the third leading cancer worldwide. The prognosis of patients diagnosed with CRC at the stage IV is poor with a 5-year survival rate less than 10%. Combination chemotherapy with platinum-based drugs and 5-fluorouracil (5-FU) remains the first line treatment, while the chemotherapy combined target therapeutic agents were decreasing the mortality of CRC patients. However, the efficacy of platinum-based drugs has often been limited because of the substantial risk for severe toxicities, including nephrotoxicity or neurotoxicity. Therefore, there is an unmet need to develop a novel drug for improving the treatment of advance colorectal cancer. We have previously designed and synthesized several series of DNA-directed alkylating agents with potent antitumor activity. Recently, one derivative of N-mustard-quinoline conjugates with hydrazinecarboxamide as a linker, designated as SL-1, was selected to explore its anti-colorectal cancer (CRC) activity because it was highly cytotoxic to a panel of CRC cell lines in culture. Flow cytometric analysis showed that treatment of CRC cells with SL-1 induced G2/M arrest and triggered apoptosis. We further demonstrated that SL-1 preferentially targeted on the selective guanine sequence by sequencing gel electrophoresis. By the aid of comet assay, SL-1 in combination with 5-FU resulted in increased DNA tail moments and induced more DNA damage. Evaluation of the potency of antitumor activity both in culture and in xenograft models, we observed that SL-1 was more potent than 5-FU and oxaliplatin against SW620, RKO and RKO-E6 (an oxaliplatin resistant-subline) cells. Notable, SL-1+5-FU were more efficacious than oxalipatin+5-FU in suppression the growth of RKO or SW620 in xenograft models. We further found that SL-1 enhanced 5-FU and induced more apoptosis by c-caspase 3 and TUNNEL staining. Additionally, histopathological examination showed that SL-1 by itself has no obvious kidney and liver toxicity in ICR mice comparing to cisplatin, oxaliplatin or 5-FU. Taken together, SL-1 alone or in combination with 5-FU may warrant our further development as a potential antitumor agent for the treatment of CRC patients.
Citation Format: Tai-Lin Chen, Yan-Bo Chen, Chia-Ning Shen, Tsann-Long Su, Te-Chang Lee. A novel N-mustard-quinoline conjugate is a potent agent against colorectal 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 5104. doi:10.1158/1538-7445.AM2017-5104
Abstract 5105: Structure-activity relationship study of pyrrolo[2,3- d]pyrimidines as microtubule targeting antitumor agents
Authors: Gangjee Aleem , Quadery Tasdique M. , Mooberry Susan L. 
Published: July 2017

Abstract
Microtubules are cytoskeleton protein polymers composed of αß-tubulin heterodimers which play pivotal roles in cell division, cellular transport and cell signaling. Interfering with microtubule dynamics is a well-established strategy for the treatment of cancer. However, clinical utility of microtubule targeting agents (MTAs) in cancer chemotherapy is often limited by the emergence of drug resistance. Expression of P-glycoprotein (Pgp) or the βIII isotype of tubulin, are two clinically established drug resistance mechanisms. We previously reported that compound AG346 binds to the colchicine site of tubulin and has microtubule depolymerization activity in A-10 cells (EC50 = 365 nM). Molecular modeling and docking studies of this compound in the X-ray crystal structure of tubulin (PDB: 402B) suggested that the pyrrole NH can be substituted with alkyl chains of optimal length to obtain an altered binding conformation which can facilitate interaction with the hydrophobic pocket formed by amino acid Val181 of side chain A, and Lys352 and Thr314 of side chain B. We designed and synthesized a variety of pyrrole NH-alkyl substituted compounds and determined that the compound AG473 shows a 43-fold improved microtubule depolymerization potency (EC50 = 8.4 nM) in A-10 cells, compared to the lead compound. In addition, this compound inhibited the growth of human melanoma cancer cell line MDA-MB-435 in culture with an IC50 of 7.2 nM, which is a 5-fold improvement in potency over the parent compound. These analogs also circumvented resistance mediated by Pgp and βIII-tubulin. These attributes provide the impetus for further preclinical development of these compounds as microtubule targeted antitumor agents in vivo and these studies are currently underway.
Citation Format: Aleem Gangjee, Tasdique M. Quadery, Susan L. Mooberry. Structure-activity relationship study of pyrrolo[2,3- d]pyrimidines as microtubule targeting 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 5105. doi:10.1158/1538-7445.AM2017-5105
Abstract 5109: Beyond malaria: Second career of artesunate as cancer drug
Authors: Efferth Thomas A. 
Published: July 2017

Abstract
More than a decade ago, we initiated a research program on the molecular pharmacology of phytochemicals derived from Chinese medicinal herbs. Bioactive plant extracts have been fractionated by chromatographic techniques. We isolated bioactive compounds and elucidated their chemical structures by nuclear magnetic resonance and mass spectrometry. A promising compounds was artemisinin from Artemisia annua L. and its semisynthetic compound artesunate. Artemisinin and artesunate are anti-malarial drugs. Our data indicated profound activity against cancer cells, but also against various viruses, Schistosoma, Trypanosoma, and even plant crown gall tumors. To elucidate the molecular mode of actions against cancer, we applied molecular biological and pharmacogenomic approaches in vitro and in vivo. Different signaling pathways were identified not only in cancer cells but also in cells infected with viruses, e.g. HCMV, HSV1 and others. To translate the experimental results in cell lines and animals to the bedside, we report on the compassionate use of artesunate in single cancer patients as well as on our efforts to initiate several clinical phase I/II trials in veterinary tumors as well as in human cervix or colorectal carcinoma. These pilot studies indeed indicate that artesunate is not only useful as antimalarial drug, but also exerts activity against cancer and viral diseases. Clinical results will also be presented that not only artesunate as semisynthetic chemical derivative of artemisinin, but also herbal extracts from Artemisia annua are active in veterinary and human tumor patients. Artesunate represents an illustrative example for the therapeutic potential of medicinal herbs and drugs derived from traditional Chinese medicine.References 1. Efferth et al.: Journal of Molecular Medicine 2002;80:233-42. 2. Efferth: Drug Resistance Updates 2005;8:85-97. 3. Efferth et al.: Molecular Cancer Therapeutics 2008;7:152-61. 4. Li et al.: Cancer Research 2008;68:4347-51. 5. Shapira et al.: Clinical Infectious Diseases 2008;46:1455-7. 6. Efferth et al.: Clinical Infectious Diseases 2008;47:804-11. 7. Krishna et al.: Ebiomedicine 2014;2:82-90. 8. Saeed et al.: Pharmacological Research 2016;110:216-226.
Citation Format: Thomas A. Efferth. Beyond malaria: Second career of artesunate as cancer 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 5109. doi:10.1158/1538-7445.AM2017-5109
Abstract 5116: Identification of new treatment options for Merkel cell carcinoma using high throughput chemical screening
Authors: Gelb Tara , Urban Daniel , Daily Kenneth , Xiao Ying , Shen Min , Hall Matthew , Brownell Isaac 
Published: July 2017

Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer with limited treatment options. Approximately 80% of MCC tumors have Merkel cell polyomavirus (MCPyV) DNA integrated into the host genome, and viral oncogenes are thought to drive carcinogenesis. In contrast, MCPyV-negative (MCPyV-) tumors have higher rates of proto-oncogene mutations. Transcriptome differences between MCPyV+ and MCPyV- tumors further suggests divergent underlying pathologies. In order to develop efficacious treatments for MCC and elucidate the pathophysiologies underlying MCPyV+ and MCPyV- MCC, we screened the effects of mechanistically annotated drug libraries on MCC cell viability (CellTiter-Glo). We screened ~4,500 compounds including the NCGC Pharmaceutical Collection of approved and investigational drugs and the oncology-focused MIPE (Mechanism Interrogation PlatE) library against six MCC cell lines (3 MCPyV+ and 3 MCPyV-). We ran follow-up screens on the above cell lines as well as non-MCC control cells to identify agents that specifically reduced viability in MCC. DNA topoisomerase inhibitors, proteasome inhibitors, and PI3K inhibitors potently and efficaciously reduced viability in all MCC cell lines tested. Moreover, using hierarchical clustering we found that viral status impacted pharmacological responses. For example, a subset of HDAC inhibitors were more potent in MCPyV+ than MCPyV- MCC cells. In contrast, a dual RasGAP/ERK inhibitor more potently reduced viability in MCPyV- MCC cells relative to MCPyV+ MCC cells. Together these results identify existing drugs that can be repurposed for treating MCC. Moreover, they help elucidate the distinct pathophysiology driving MCPyV+ and MCPyV- MCC.
Citation Format: Tara Gelb, Daniel Urban, Kenneth Daily, Ying Xiao, Min Shen, Matthew Hall, Isaac Brownell. Identification of new treatment options for Merkel cell carcinoma using high throughput chemical screening [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 5116. doi:10.1158/1538-7445.AM2017-5116
Abstract 5118: A novel polyamine sulfonamide with anti-leukemic activity
Authors: Vijay Vindhya , Meacham Amy , Drusbosky Leylah , Wise Elizabeth , Cogle Christopher 
Published: July 2017

Abstract
The greatest challenge in treating Acute Myeloid Leukemia (AML) is refractory disease. Although 60-80% of AML patients achieve complete remission after induction chemotherapy, majority of these patients relapse and die of progressive disease. New treatment options targeting the vulnerabilities of AML biology are highly critical for disease regression, in particular the chemo-resistant leukemia-initiating population, to ensure relapse-free survival in patients. Identifying novel druggable targets that are selective to AML despite their location in the vascular niche is thus highly warranted. We developed an in vitro co-culture model consisting of AML cells and Bone Marrow- derived Endothelial Cells (BMECs), mimicking the protective effect of the vascular niche in the bone marrow microenvironment. Using this unique model, and taking advantage of combinatorial chemistry, we performed high-throughput chemical-phenotypic screening of approximately 30 million novel compounds and identified a novel polyamine sulfonamide 2470-51 that can selectively kill AML cells by overcoming the protective effect of the BMECs. In addition to AML blasts, 2470-51 also exhibited highly selective activity against the leukemic stem and progenitor cell population while sparing normal hematopoietic stem and progenitor cells. In vivo studies using patient-derived xenograft models indicated significant regression in AML engraftment post 2470-51 treatment. Target identification experiments involving unbiased label-free shotgun proteomic analysis in combination with targeted Selected Ion Monitoring (SIM) revealed covalent drug binding targets of 2470-51. By performing differential protein expression analysis using ITRAQ analysis, we identified downstream mechanisms that led to mitotic cell cycle arrest and cell death. Collectively, our findings display the in vitro as well as in vivo efficacy of a novel polyamine sulfonamide in eliminating AML, including the leukemia initiating compartment. We also uncover a novel mechanism in AML that can be taken advantage of for selective toxicity. Furthermore, we establish the role of 2470-51 as a potential therapeutic agent in treating AML.
Citation Format: Vindhya Vijay, Amy Meacham, Leylah Drusbosky, Elizabeth Wise, Christopher Cogle. A novel polyamine sulfonamide with anti-leukemic activity [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 5118. doi:10.1158/1538-7445.AM2017-5118