tbuckley/cabot-search huggingface dataset:
Abstract 5109: Beyond malaria: Second career of artesunate as cancer drug
Authors: Thomas A. Efferth
Journal: Cancer Research (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 1848: Autocrine IGF1 signaling mediates the survival of pancreatic cancer cells following the ablation of oncogenes
Authors: Nirakar Rajbhandari
Journal: Cancer Research (2017)

Abstract Pancreatic cancer is an extremely lethal disease, which is mostly associated with the gain-of-function mutation in KRAS gene. Due to a very high frequency of activating mutations within the KRAS gene, mutant KRAS is considered a rational therapeutic target in pancreatic cancer. In line with the existing idea that oncogenic KRAS is required for the maintenance of pancreatic cancer, we show a complete macroscopic regression of both primary and orthotopically transplanted tumors in our ligand-regulatable (Doxycycline) mouse model of KRASG12D-driven pancreatic cancer. This finding indicate that the expression, and provides a strong rationale for the development of KRAS targeted therapy for the treatment of pancreatic cancer. However, in our current study, despite the complete macroscopic regression of PDACs upon downregulation of oncogenic KRAS, few cancer cells always survived and remained dormant for a protracted duration. These residual cancer cells were responsible for the rapid recurrence upon KRAS reactivation. Using a genome-wide gene expression (RNA-Seq) analysis of in vivo-derived bulk and residual cancer cells followed by biochemical analysis, we identified a significant increase in autocrine IGF-1/AKT signaling in residual cancer cells. We also identified IGF1 signaling as a common survival mechanism of residual cancer cells in c-MYC-driven pancreatic tumor model. Pharmacological inhibition of IGF-1R signaling significantly delayed the tumor recurrence in both the tumor models, suggesting the crucial role of IGF-1R signaling in the survival of cancer cells in the absence of oncogenic drivers. Our findings from animal models were also validated in human pancreatic cancer cell lines harboring KRAS mutations, by demonstrating a compensatory increase in IGF1 signaling in response to a conditional knockdown of KRAS in vitro and in vivo. Collectively, all our findings from mouse model and human cancer cell studies strongly indicate that residual cancer cells can survive in the absence of tumor driving oncogenes by upregulation of autocrine IGF1 signaling loop. Thus, targeting oncogenic drivers along with IGF-1R signaling might be an effective strategy for prevention of tumor recurrence in pancreatic cancer. Citation Format: Nirakar Rajbhandari. Autocrine IGF1 signaling mediates the survival of pancreatic cancer cells following the ablation of oncogenes [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 1848. doi:10.1158/1538-7445.AM2017-1848
Abstract 896: Long term exposure to Oroxylin A inhibits cell migration via suppressing CCL2 in oral squamous cell carcinoma cells
Authors: Jiun-Jia Tung, Tony Jer-Fu Lee, Wei-Ting Ku, Kuo-Chu Lai
Journal: Cancer Research (2017)

Abstract Oral squamous cell carcinoma (OSCC) is the sixth most common cancer in the world. Like other cancers, the major causes of OSCC-related death are cervical node and distant metastasis. Therefore, it is a critical need to identify new potential therapeutic agents against OSCC migration, invasion, and metastasis. Oroxylin A, a main bioactive flavonoids extracted from Scutellaria radix, has been reported to inhibit migration in breast and non-small-cell lung cancer. In this study, we explored the anti-migration effects of oroxylin A on OSCC cells and investigated its underlying mechanisms. A 24-hour exposure (short-term) of OSCC cells to oroxylin A at noncytotoxic concentrations (5-20 μM) significantly suppressed cell migration using the wound healing assay. Furthermore, a 30-days exposure (long-term) to oroxylin A (20 μM), which still had no cytotoxic effect on OSCC cells, but significantly suppressed more cell migration than that of short-term oroxylin A exposed OSCC cells. To uncover the molecular mechanisms involved in the inhibitory effect of oroxylin A on OSCC migration, cDNA microarray technique and Ingenuity software were used. There were 468 differentially expressed genes, including 112 upregulated and 356 downregulated genes identified in long-term oroxylin A exposed cells compared to untreated OSCC cells. Among them, 77 genes have been reported to be associated with cancer cell migration. Consistent with results from cDNA microarray, we revealed that the expressions of several cell migration-related genes, such as CCL2, S100A9, LCN2, and THBS1 were significantly decreased in long-term oroxylin A exposed OSCC cells using QPCR assay. Western blotting and ELISA results also demonstrated that CCL2 expressions at mRNA and protein levels were significantly decreased in long-term oroxylin A exposed OSCC cells compared to untreated OSCC cells. In the meantime, the expressions of downstream targets of CCL2, including p-ERK, NFκB, MMP2, and MMP9 were also decreased in long-term oroxylin A exposed OSCC cells. These results suggest that long-term oroxylin A treatment inhibits migration may via suppressing CCL2 in OSCC cells. Citation Format: Jiun-Jia Tung, Tony Jer-Fu Lee, Wei-Ting Ku, Kuo-Chu Lai. Long term exposure to Oroxylin A inhibits cell migration via suppressing CCL2 in oral squamous cell carcinoma 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 896. doi:10.1158/1538-7445.AM2017-896
Myeloma Cells Induce High Level of TAF12 Expression in Bone Marrow Stromal Cells, Resulting in Increased Osteoclastogenesis and Myeloma Cell Growth in Response to 1,25(OH)2D3
Authors: Yasuhisa Ohata, John M Chirgwin, Jolene J Windle, G. David Roodman, Noriyoshi Kurihara
Journal: Blood (2016)
Abstract 354: Inhibition of Smad3 signaling with a TAT fusion peptide prevented TGF-β-induced fibronectin expression and cell migration in malignant gliomas
Authors: Jeonghan Kang
Journal: Cancer Research (2017)

Abstract Malignant primary brain tumors represent one of the most common causes of cancer death in the world. Grade IV gliomas (glioblastoma multiform, GBM) are routinely resistant to current chemoradiationchemo radiation therapy with a median progression-free and overall survival for glioblastoma following current chemoradiation of ~7 and 15 months, respectively. While TGF-β functions as a growth inhibitor for most normal cell types, many tumors (including GBMs) have lost this inhibitory response and TGF-β now functions to promote tumor progression and/or dissemination. As aberrant TGF-β signaling is often considered a hallmark of high-grade gliomas, we examined whether inhibition of specific components would impact the malignant phenotype of glioblastoma. The primary mediators of TGF-β action are the Smad proteins (R-Smads), Smad2 and Smad3. Following receptor activation and R-Smad phosphorylation, they translocate to the nucleus to modulate gene expression. Since we previously determined that a cell penetrating peptide conjugate of the HIV TAT protein fused to a 30 amino acid sequence from sorting nexin 9 (SNX9) prevented Smad3, but not Smad2, nuclear import and target gene expression in models of organ fibrosis, we further investigated whether it might similarly impact aspects of GBM proliferation. To that end, twenty-one patient-derived xenografts (PDXs) were examined for their responsiveness to TGF-β. Of those, TGF-β stimulated migration and fibronectin expression in seven (33%), which was prevented by inhibiting Smad3 signaling with the TAT-SNX9 peptide but not a control peptide unable to block Smad3 action. These findings indicate that the TGB-b/Smad3 axis is a potentially important mediator of glioma cell invasion in a significant minority of GBM models. specifically targeting Smad3 might be effective in a subset of gliomas. This work was supported by Public Health Service grants GM-055816 and GM-054200 from the National Institutes of General Medical Sciences and P50 CA-108961 Developmental Pilot Award from the National Cancer Institute. Citation Format: Jeonghan Kang. Inhibition of Smad3 signaling with a TAT fusion peptide prevented TGF-β-induced fibronectin expression and cell migration in 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 354. doi:10.1158/1538-7445.AM2017-354
Analyses of a Mutant Foxp3 Allele Reveal BATF as a Critical Transcription Factor in the Differentiation and Accumulation of Tissue Regulatory T Cells
Authors: Norihito Hayatsu, Takahisa Miyao, Masashi Tachibana, Ryuichi Murakami, Akihiko Kimura, Takako Kato, Eiryo Kawakami, Takaho A. Endo, Ruka Setoguchi, Hiroshi Watarai, Takeshi Nishikawa, Takuwa Yasuda, Hisahiro Yoshida, Shohei Hori
Journal: Immunity (2017)
Abstract 5183: The radioenhancer NBTXR3 brings anticancer efficacy to the cisplatin-based chemoradiationin vitroandin vivo
Authors: Agnès Pottier, Sonia Vivet, Sébastien Paris, Bo Lu
Journal: Cancer Research (2017)

Abstract NBTXR3 is a radioenhancer composed of functionalized hafnium oxide nanoparticles, designed to enhance the radiation dose deposit within the cancer cells when activated by ionizing radiations. NBTXR3 is intended for single intratumor administration and is currently evaluated in cancer clinical trials including soft tissue sarcoma, head and neck (H&amp;N), prostate, liver and rectum. Cisplatin (CDDP) is a cytotoxic agent considered to be a radiosensitizer and inhibits the repair of sublethal damage from irradiation. Concurrent chemoradiation using CDDP is the mainstream treatment for high risk H&amp;N, cervix and non-small cell lung cancer patients. We hypothesized that adding NBTXR3 to radiation treatment (RT) may improve significantly anticancer effect of the chemoradiation combination In vitro, no specific clonogenic toxicity was observed for the cells exposed only to NBTXR3. For the combined treatment CDDP was used at its IC50 concentrations. A marked and enhanced cell destruction (DEF) was observed with the CDDP combined treatment (added 6h or 16h prior to RT) and NBTXR3 (800µM, added 16h prior to RT) at ≥2Gy when compared to the single agent. TreatmentCell line (DEF*)CDDPNBTXR3IrradiationFaDuNCI-H460-Luc26h-2 Gy1.0±0.061.2±0.06-16h1.4±0.151.3±0.256h16h1.4±0.141.6±0.1216h-1.0±0.121.9±0.32-16h1.2±0.131.5±0.1716h16h1.8±0.232.6±0.456h-4 Gy1.3±0.082.2±0.16-16h2.2±0.241.9±0.416h16h3.1±0.643.8±0.4816h-1.2±0.192.9±0.52-16h2.1±0.312.8±0.3916h16h5.3±0.977.6±2.76 *For a given radiation dose, the DEF value was obtained by taking the ratio of the survival fraction in the control (radiotherapy alone) and the survival fraction of the treatment. In vivo, NBTXR3 enhanced the fractionated radiation treatment (5x2Gy) when injected intratumorally at 25% of tumor volume. NBTXR3 activated with ionizing radiation in combination with low dose of CDDP (1mg/kg administered 5 consecutive days, 2 hours prior to RT) delayed tumor growth when compared to single agent CDDP in combination with RT. These results strongly support the concurrent chemoradiotherapy regimen with NBTXR3 nanoparticles as an effective radioenhancer to increase the anticancer effect. A new phase I/II trial with H&amp;N cancers patient receiving radiotherapy plus CDDP has been started evaluating the optimal dose, safety and preliminary efficacy of NBTXR3. Citation Format: Agnès Pottier, Sonia Vivet, Sébastien Paris, Bo Lu. The radioenhancer NBTXR3 brings anticancer efficacy to the cisplatin-based chemoradiation in vitro and in vivo [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 5183. doi:10.1158/1538-7445.AM2017-5183
Abstract 5399: Investigating phenotypic plasticity in breast cancer with high-throughput nanogrid single-nucleus RNA sequencing
Authors: Ruli Gao, Charissa Kim, Emi Sei, Jie Yang, Leo Chan, Maithreyan Srinivasan, Hong Zhang, Funda Meric-Bernstam, Nicholas E. Navin
Journal: Cancer Research (2017)

Abstract Single-cell RNA sequencing (RNA-seq) is a powerful tool for investigating rare tumor subpopulations and resolving intra-tumor heterogeneity, but is low throughput, expensive, and requires fresh tissue samples. To address these limitations, we developed a 5’ high-throughput single-nucleus RNA sequencing (SNRS) approach that uses nanogrid technology to perform single-cell imaging and sequencing of 500-2500 nuclei in parallel. The automated image scanning procedure allowed us to exclude doublets and select live cells with DAPI/PI staining. This approach allows the transcriptomic profiling of frozen tissue samples, in which the cytoplasmic membrane is ruptured in cells, but leaves the nuclear membrane intact. We validated SNRS in a breast cancer cell line (SK-BR-3) and compared the transcriptomes of 500 nuclei to 500 whole cells, which revealed a high concordance in the number of genes expressed as well as their expression levels. We also performed bulk RNA-seq of isolated nuclear and cellular fractions from 5 breast cancer cell lines, which showed a high concordance in genes and expression levels. Differentially expressed genes in the nucleus mainly included lincRNAs, pseudogenes and mitochondria genes, but did not affect most cancer genes and pathway analysis. We further applied SNRS to sequence 500 nuclei from a triple-negative breast cancer patient and identified diverse phenotypes in tumor cells, including variation in cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition. These studies demonstrated the technical feasibility of using a nanogrid platform to perform high-throughput single-cell RNA sequencing and showed that nuclei from cell lines and tumors can be used to study signaling pathways and gene networks that play an important role in tumor progression. Citation Format: Ruli Gao, Charissa Kim, Emi Sei, Jie Yang, Leo Chan, Maithreyan Srinivasan, Hong Zhang, Funda Meric-Bernstam, Nicholas E. Navin. Investigating phenotypic plasticity in breast cancer with high-throughput nanogrid single-nucleus RNA sequencing [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 5399. doi:10.1158/1538-7445.AM2017-5399
Abstract 9208: Association of Polymorphism in Glutamate-Cysteine Ligase Modifier Subunit Gene with Idiopathic Dilated Cardiomyopathy
Authors: Ken-ichi Kawabata, Tsuyoshi Kobayashi, Daisuke Fujioka, Shyun Tamaru, Yousuke Watanabe, Kazuhiro Watanabe, Hideto Mishina, Keita Sano, Takamitsu Nakamura, Yukio Saito, Yoshinobu Kitta, Jyun-ei Obata, Kiyotaka Kugiyama
Journal: Circulation (2011)

Myocardial mitochondrial dysfunction due to oxidative stress contributes to the pathogenesis of cardiomyopathy. Reduced glutathione (GSH) plays a crucial role in antioxidant defense mechanisms, and it is synthesized by glutamate-cysteine ligase (GCL) which is composed of catalytic (GCLC) and modifier (GCLM) subunits. We have found a polymorphism (-588C/T) in the 5’-flanking region of the GCLM gene in which the T allele showed lower promoter activity (40% of C allele) in response to oxidants and is associated with lower plasma GSH levels. This study examined the hypothesis that this polymorphism of GCLM gene may be associated with dilated cardiomyopathy (DCM). And, we studied potential role of GCLM in myocardial mitochondrial function using GCLM deficient (GCLM -/- ) mice. Methods and Results: The frequency of the polymorphism (-588C/T) of the GCLM gene was determined in 205 consecutive patients with non-familial idiopathic DCM and age- and sex-matched 253 normal healthy subjects. The T allele was highly frequent in patients with DCM, compared with control subjects (CT and TT genotypes: 36.2% in DCM vs. 18.6% in controls; P &lt; 0.0001), and it was a significant risk factor for DCM, that was independent of hypertension, diabetes, smoking and BMI (OR 3.13, 95% CI 2.28 to 4.44; P &lt; 0.0001). The mitochondrial GSH levels in myocardium were lower in GCLM -/- mice (39% of baseline GCLM +/+ ). Mitochondrial respiratory function in the myocardium of GCLM -/- mice had a reduction in the ADP-stimulated state 3 activity (60% of GCLM +/+ ). Hypoxia re-oxygenation induced greater mitochondrial damages in cultured GCLM -/- cardiomyocytes than GCLM +/+ cardiomyocytes, as evidenced by reduced membrane potential, increased protein carbonyl content, and increased GSSG/GSH rate in the isolated mitochondria. After myocardial ischemia-reperfusion, GCLM -/- mice had a greater dilation and systolic dysfunction of left ventricle (LV) than GCLM +/+ mice. Conclusions: The -588T polymorphism of the GCLM gene is associated with non-familial idiopathic DCM. This association is supported by the animal study that GCLM deletion increased susceptibility of myocardial mitochondria to oxidative damage through mitochondrial GSH reduction, which may potentially contribute to LV dysfunction.
Abstract 1187: Synthetic lethality screening reveals ATR as responsible for oxaliplatin resistance in colorectal cancer cells
Authors: Eve Combes, Augusto Faria-Andrade, Diego Tosi, Pierre Martineau, Maguy Del Rio, Roderick Beijersbergen, Nadia Vie, Céline Gongora
Journal: Cancer Research (2017)

Abstract Despite the recent advances achieved in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. Our work was aimed to determine the molecular mechanisms involved in the resistance to oxaliplatin, an anticancer agent widely used in colorectal cancer treatment. To this end, we establish an oxaliplatin-resistant cellular model from the colon adenocarcinoma cell line HCT-116. Among cellular clones obtained, we used one displaying mild resistance (10 fold called HCT116-R1) to perform short hairpin RNA-based loss of function genetic screen in order to identify genes that can modulate the cellular response to oxaliplatin by revealing genes the silencing of which causes drug sensitivity (synthetic lethal interactions with the drug). Using this screen, we have identified ATR (Ataxia-telangiectasia mutated and rad3 related), a protein that plays a key role in the repair of DNA double-strand breaks induced by various DNA damaging agents, including platinum derivatives. We further validated ATR implication in oxaliplatin resistance by showing that (i) shRNA-mediated repression of ATR in HCT116-R1 oxaliplatin-resistant CRC cells sensitizes such cells to the drug; (ii) co-incubation with the ATR inhibitor VE-822 (or VX-970) and oxaliplatin led to a dramatic synergistic effect in six different CRC cell lines (two oxaliplatin-sensitives: HCT116 and SW48; and four oxaliplatin-resistant: HCT116-R1, HCT116-R2, SW48-R1 and SW48-R2) using 2D and 3D cell growth inhibition assays and in vivo. The synergistic effect was evaluated using dose matrix data (an algorithm that was implemented in our group); (iii) the synergistic effect of oxaliplatin and VE-822 was accompanied by an increase of ssDNA, DNA double-strand breaks, growth arrest and apoptosis induction. In conclusion, our preliminary data confirm the results of our screen by demonstrating for the first time the functional role of ATR in the sensitivity to oxaliplatin. Citation Format: Eve Combes, Augusto Faria-Andrade, Diego Tosi, Pierre Martineau, Maguy Del Rio, Roderick Beijersbergen, Nadia Vie, Céline Gongora. Synthetic lethality screening reveals ATR as responsible for oxaliplatin resistance in colorectal 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 1187. doi:10.1158/1538-7445.AM2017-1187