bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5100: AB61, a new potent nucleoside cytostatic: Molecular mechanisms of action and preclinical activity
Authors: Dzubak Petr , Hajduch Marian , Perlikova Pavla , Rylová Gabriela , Naus Petr , Elbert Tomas , Tloustova Eva , Bourderioux Aurelie , Slavetinska Lenka , Motyka Kamil , Dolezal Dalibor , Znojek Pawel , Nova Alice , Harvanova Monika , Siler Michal , Hlavac Jan , Hocek Michal 
Published: July 2017

Abstract
7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, the formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK- OV-3, BT-549, HT-29 and MDA-MB231 xenografts. The results indicate that AB61 is a promising compound with the unique mechanism of action and deserves further development as an anticancer agent. This work was supported by the Ministry of Education of the Czech Republic (LO1304).
Citation Format: Petr Dzubak, Marian Hajduch, Pavla Perlikova, Gabriela Rylová, Petr Naus, Tomas Elbert, Eva Tloustova, Aurelie Bourderioux, Lenka Slavetinska, Kamil Motyka, Dalibor Dolezal, Pawel Znojek, Alice Nova, Monika Harvanova, Michal Siler, Jan Hlavac, Michal Hocek. AB61, a new potent nucleoside cytostatic: Molecular mechanisms of action and preclinical 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 5100. doi:10.1158/1538-7445.AM2017-5100
Abstract 5106: In vitro and in vivo evaluation of WAC-224, a novel quinolone class of topoisomerase II inhibitor for cancer therapy
Authors: Ueshima Taichi , Yamaguchi Tomonori , Itoh Kenji , Kashimoto Naoki , Hirano Tatsuya , Shimabara Rumiko , Kawakubo Yohei , Sato Masayuki , Yamashita Junpei , Yazaki Akira , Tamura Koichi 
Published: July 2017

Abstract
Introduction: DNA topoisomerases (Topo) are classical but still attractive targets for drug therapy in multiple types of cancers. Topo inhibitors, such as Etoposide and Daunorubicin, have been effectively used; however, their clinical use is often limited by drug resistance in cancer cell population. Therefore, the development of a novel chemical class of Topo inhibitors has been desired to overcome drug resistance. Recently, Vosaroxin (QINPREZO) is identified as a first-in-class anti-cancer quinolone derivative targeting Topo II, which is under development for relapsed or refractory acute myeloid leukemia (AML). In this study, we evaluated the in vitro and in vivo activities of WAC-224, a novel quinolone derivative for Topo II inhibition, for various cancer cell lines including multi-drug resistant cells and in mouse xenograft models, respectively.
Materials and Methods: In vitro anti-proliferative activities against over 20 cell lines were determined using WST cell proliferation reagent. Apoptosis was measured by Annexin-V staining. In vivo anti-tumor activity was determined in immunodeficient mice bearing multi-drug resistant human uterine sarcoma MES-SA/DX5.
Results: WAC-224 accomplished extensive anti-proliferative activities for cancer cell lines including multi-drug resistant ones with the EC50 range of 0.001 to 1 microM. Especially, in MV4-11 AML cell line, WAC-224 showed a potent and superior anti-proliferative activity compared with Doxorubicin (EC50: 1.4 nM for WAC-224 v.s. 2.5 nM for Doxorubicin). Molecular and cellular mechanisms of WAC-224 were defined as inhibition of human Topo II, induction of G2/M phase cell cycle arrest and apoptosis. Additionally, significant antitumor effects of WAC-224 were confirmed in mouse xenograft models. Furthermore, WAC-224 showed no toxic effect on small intestinal crypts in mice.
Conclusion: This study demonstrated that WAC-224 has strong in vitro activities against broad cancer cell types along with the potent in vivo efficacy and well tolerability, without gastrointestinal toxicity. These results indicate that WAC-224 is promised to provide a new therapeutic option for various cancers including multi-drug resistant and hematological ones.
Citation Format: Taichi Ueshima, Tomonori Yamaguchi, Kenji Itoh, Naoki Kashimoto, Tatsuya Hirano, Rumiko Shimabara, Yohei Kawakubo, Masayuki Sato, Junpei Yamashita, Akira Yazaki, Koichi Tamura. In vitro and in vivo evaluation of WAC-224, a novel quinolone class of topoisomerase II inhibitor for cancer 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 5106. doi:10.1158/1538-7445.AM2017-5106
Abstract 5111: Norcantharidin impairs tumor growth in vivo and inhibits stemness of triple-negative breast cancer cells
Authors: Berardi Damian E. , Cicuttin Guido , Taruselli Maria A. , Cirigliano Stefano M. , Joffé Elisa D. Bal de Kier , Urtreger Alejandro J. , Todaro Laura B. 
Published: July 2017

Abstract
Triple-negative breast cancer (TNBC) is characterized by an abundance of treatment-resistant cancer stem cells (CSC). The absence of a molecular target, coupled with its highly aggressiveness, leads to the lack of an effective therapy for TNBC. Norcantharidin (NCTD) is a synthetic demethylated small-molecule analog of the naturally occurring cantharidin isolated from blister beetles (Mylabris phalerata Pall). Unlike the conventional chemotherapeutics, NCTD toxicity is higher to cancer cells than normal ones, making this small molecule promising for cancer treatment.
The aims of this work were: A) To study the effect of NCTD on 4T1 cell line proliferation in vitro. B) To analyze the effect of NCTD on 4T1 derived CSC on self-renewal and clonogenic capacity. C) To evaluate the effect of NCTD on 4T1 tumor growth in vivo.
We employed the well-known 4T1 triple-negative breast cancer cell model, which presents a huge proportion of CSC.
We observed that NCTD treatment during 96 h significantly reduced 4T1 cell proliferation in vitro. In addition, the IC50 value of NCTD was 27.35 ± 2.83 μM.
Related to CSC, NCTD pre-treatment for 96 h impaired CSC self-renewal (Number of secondary mammospheres: Control: 276±39; NCTD: 163±18; p≤0.05) as well as the clonogenic capacity (Number of colonies: Control: 359±38; NCTD: 122±11; p≤0.05). By q-PCR, we observed that NCTD treatment for 48 h significantly induced an increase of Gli-1 and Smooth in CSC, keys member of Sonic Hedgehog pathway.
Finally, we performed an in vivo assay, where 4T1 cells were orthotopically inoculated on mammary gland of BALB/c mice, and NCTD was i.p. inoculated twice a week (5mg/kg). We observed that NCTD treatment significantly reduced tumor growth in vivo.
Our data suggest that NCTD treatment reduces tumor growth both in vitro and in vivo, possibly through the direct effect on CSC self-renewal and clonogenic capacity, by modulating Sonic Hedgehog pathway.
Citation Format: Damian E. Berardi, Guido Cicuttin, Maria A. Taruselli, Stefano M. Cirigliano, Elisa D. Bal de Kier Joffé, Alejandro J. Urtreger, Laura B. Todaro. Norcantharidin impairs tumor growth in vivo and inhibits stemness of triple-negative 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 5111. doi:10.1158/1538-7445.AM2017-5111
Abstract 5119: Evaluation of Minnelide as potential targeted therapy for triple negative breast cancer
Authors: Singh Mahendra K. , Shah Soham , Sharma Nikita Satish , Giri Bhuwan , Banerjee Sulagna , Saluja Ashok 
Published: July 2017

Abstract
Recent advances in diagnostics and better understanding of molecular mechanism underlying breast cancer has let to the better therapeutic options and disease outcome for majority of breast cancer patients. However, ~10 - 20% of all breast cancers often referred to as “triple negative” as they lack expression of the estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors convey a poor prognosis due in part to a lack of targeted therapies. The aim of the current study is to evaluate whether triptolide and its water soluble analog Minnelide is effective against triple negative breast cancer cells. We have previously shown that triptolide/Minnelide not only reduces tumor growth in various cancer models but it also regulates epithelial -mesenchymal transition (EMT), an important mechanism underlying metastasis. In our preliminary findings using three triple negative breast cancer (TNBC) cell lines, MDA-MB-231, MDA-MB-468, and MDA-MB-157, we demonstrate that triptolide not only inhibits the proliferation of TNBC cells but also regulates the protein levels of EMT markers including β-Catenin and Vimentin. In order to elucidate the mechanism underlying triptolide mediated inhibition of cellular proliferation and regulation of EMT markers in TNBC cells, we identified Src kinase and Aurora kinase A as two new targets for triptolide action in TNBC cells. By targeting Src and Aurora kinase, triptolide disrupts the integrity of focal adhesion structures and reduces cell spreading via regulating FAK activity. Our preliminary findings regarding potential use of triptolide/Minnelide in TNBC based on in vitro experiments are promising. However, considering the complex pathophysiology of breast cancer and other biological factors playing role in a disease setting, in-vivo experiments to test the efficacy of Minnelide in relevant mouse models for mammary cancers are currently underway.
Citation Format: Mahendra K. Singh, Soham Shah, Nikita Satish Sharma, Bhuwan Giri, Sulagna Banerjee, Ashok Saluja. Evaluation of Minnelide as potential targeted therapy for triple negative breast 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 5119. doi:10.1158/1538-7445.AM2017-5119
Abstract 5128: Induction of immunogenic cell death and tumor regression in murine animal models by a novel cytolytic compound, LTX-401
Authors: Mauseth Brynjar , Eike Liv-Marie , Shi Ji-Hua , Camilio Ketil , Zhou Heng , Sauvat Allan , Gomes-da-Silva Lígia C , Durand Sylvèr , Forveille Sabrina , Iribarren Kristina , Yamazaki Takahiro , Souquere Sylvie , Bezu Lucillia , Müller Kevin , Leduc Marion , Liu Peng , Zhao Liwei , Marabelle Aurélien , Zitvogel Laurence , Kepp Oliver , Kroemer Guido , Rekdal Øystein , Line Pål-Dag , Sveinbjørnsson Baldur 
Published: July 2017

Abstract
LTX-401 is a de novo designed cytolytic compound that shares many chemical features with anticancer peptides, such as amphipathicity, hydrophobicity and overall net charge. In vitro cytotoxicity studies revealed that LTX-401 was highly active against a panel of malignant cells including murine and human cancer cell lines while displaying selectivity towards human red blood cells. Furthermore, LTX-401 was found to induce immunogenic cell death as demonstrated by the release of Damage-Associated Molecular Pattern molecules, or ‘danger signals’, such as High-Mobility Group Box-1 protein, ATP and cytochrome c. Flow cytometric and confocal microscopy studies also demonstrated reduced signal from lysosomal dye Lysotracker-DND-26, hence indicating loss of lysosomal integrity upon induction of cell death. The latter was supported using transmission electron microscopy, showing distinct morphological characteristics of necrosis. Moreover, at low concentrations, LTX-401 selectively enriched in the Golgi apparatus and initiated a lethal signaling event that in part could be inhibited by Brefeldin A. Complete tumor regression has been obtained in several rodent models, including the B16 mouse melanoma model and the JM1 rat hepatocellular carcinoma model by intratumoral injection with LTX-401. Additionally, previously cured animals showed protection against rechallenge with live tumor cells, indicating the induction of tumor-specific immune memory. The increased survival benefit of LTX-401-treated animals provides a rationale for further evaluation of the compound as an immunotherapeutic agent against solid malignancies.
Citation Format: Brynjar Mauseth, Liv-Marie Eike, Ji-Hua Shi, Ketil Camilio, Heng Zhou, Allan Sauvat, Lígia C Gomes-da-Silva, Sylvèr Durand, Sabrina Forveille, Kristina Iribarren, Takahiro Yamazaki, Sylvie Souquere, Lucillia Bezu, Kevin Müller, Marion Leduc, Peng Liu, Liwei Zhao, Aurélien Marabelle, Laurence Zitvogel, Oliver Kepp, Guido Kroemer, Øystein Rekdal, Pål-Dag Line, Baldur Sveinbjørnsson. Induction of immunogenic cell death and tumor regression in murine animal models by a novel cytolytic compound, LTX-401 [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 5128. doi:10.1158/1538-7445.AM2017-5128
Abstract 5161: Inhibition of TBK1/IKBKE impacts tumor growth of KRAS-mutant colorectal cancers
Authors: Stinson Susanna , He Jianhua , Jia Zhiheng , Walker Katie S. , Cui Zhi-Hua , Kaplan Joshua A. , Venkataramani Chandrasekar , Wang Yujin , Guevara Fatima , Nelson Timothy , Sicinska Ewa , Ng Kimmie , Fuchs Charles S. , Dornan David 
Published: July 2017

Abstract
Mutations in RAS occur in an estimated one third of all human cancers. While direct targeting of RAS remains challenging, targeting downstream RAS effector molecules has been shown to impact the oncogenic function of RAS and elicit anti-tumor activity. TANK Binding Kinase 1 (TBK1) and I-Kappa B Kinase Epsilon (IKBKE) serine/threonine kinases are non-canonical IKK family members. TBK1 is directly downstream of the RAS effector Ral Guanine Nucleotide Dissociation Stimulator (RALGDS) and may be required for RAS to elicit its full oncogenic potential.
To explore this possibility, we identified a potent and selective TBK1/IKBKE inhibitor to determine whether inhibition of TBK1 impacts the growth of RAS-mutant cancer models. KRAS-mutant cancer cell lines showed preferential sensitivity to TBK1/IKBKE inhibition over KRAS wild-type cell lines. The TBK1/IKBKE inhibitor was then evaluated in vivo with two KRAS-mutant colorectal cancer patient-derived xenograft (PDX) models, one of which harbors co-occurring PIK3CA and KRAS mutations. The TBK1/IKBKE inhibitor caused moderate tumor growth inhibition in comparison to vehicle in both PDX models. Since RAS exerts its oncogenic effects via additional effectors, such as RAF, and that inhibition of MEK1/2 resulted in compensatory activation of TBK1 in a KRAS-mutant cancer cell line, we tested if inhibition of TBK1/IKBKE in combination with the MEK inhibitor, trametinib, would result in superior efficacy in PDX models. The combination of a TBK1/IKBKE inhibitor and trametinib resulted in greater than 90% tumor growth inhibition within both of these KRAS mutant PDX models compared to either single agent alone. We also tested TBK1/IKBKE inhibition in a KRAS wild-type colorectal PDX model containing a BRAF mutation. In this model, TBK1/IKBKE did not inhibit tumor growth and, although there was significant tumor growth inhibition with trametinib alone, there was no further enhancement of efficacy with the addition of a TBK1/IKBKE inhibitor.
Together, these data suggest that a TBK1/IKBKE inhibitor in combination with a MEK inhibitor may impact KRAS-mutant cancers.
Citation Format: Susanna Stinson, Jianhua He, Zhiheng Jia, Katie S. Walker, Zhi-Hua Cui, Joshua A. Kaplan, Chandrasekar Venkataramani, Yujin Wang, Fatima Guevara, Timothy Nelson, Ewa Sicinska, Kimmie Ng, Charles S. Fuchs, David Dornan. Inhibition of TBK1/IKBKE impacts tumor growth of KRAS-mutant colorectal cancers [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 5161. doi:10.1158/1538-7445.AM2017-5161
Abstract 5213: Aberrant tumor metabolism enables GR takeover in enzalutamide-resistant prostate cancer
Authors: Li Jianneng 
Published: July 2017

Abstract
It is well known that castration resistant prostate cancer (CRPC) is still driven by the androgen axis. Therefore, the advent of new AR-targeting drugs, such as Enzalutamide (ENZ), has been beneficial for many patients with CRPC. ENZ is a potent FDA-approved AR antagonist which prolongs survival for patients with CRPC, even after docetaxel chemotherapy. Unfortunately, although ENZ has proven effective clinically, treatment resistance eventually arises in nearly all patients with CRPC. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. Hence, we hypothesize that similar to metabolic mechanisms that elicit dihydrotestosterone (DHT) synthesis, which in turn stimulate AR in CRPC, a role for GR in ENZ resistance would be accompanied by a tumor metabolic switch that provides sustained tissue cortisol concentrations which enable GR activation. Here, we found that long-term ENZ treatment sustains tumor cortisol concentrations in models of prostate cancer and patient tissues by using [3H]-cortisol and high performance liquid chromatography. Further investigations with immunoblot, co-immunoprecipitation as well as in vitro ubiquitination assays in ENZ resistant prostate cancer models demonstrated that autocrine motility factor receptor (AMFR), an ubiquitin E3-ligase, and one of its adaptors, Erlin-2, mediate loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which sustains tumor cortisol concentrations, resulting in the continuous stimulation of GR and ENZ resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses ENZ resistance in mouse xenograft tumors.
Together, these findings reveal a surprising metabolic mechanism of ENZ resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.
Citation Format: Jianneng Li. Aberrant tumor metabolism enables GR takeover in enzalutamide-resistant prostate 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 5213. doi:10.1158/1538-7445.AM2017-5213
Abstract 524: Characterizing the in vitro and in vivo effects of the PIM kinase inhibitor HS140 in triple-negative human breast cancer
Authors: Cobb Michael , Hunter Lucas , Carlson David , Darr David , Haystead Timothy , Baines Antonio T. 
Published: July 2017

Abstract
Triple-negative breast cancer (TNBC) lacks expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, making it the worse subtype of all breast cancers. Currently, there are no molecular targeted therapies for this cancer and chemotherapy is only successful in a limited number of patients. Recent studies suggest that members of the oncogenic PIM kinase family, especially PIM-1, play a significant role in the growth of TNBC. However, there is very limited information on the role other PIM family members have in the growth and development of TNBCs. As an attempt to address this concern, we treated a panel of TNBC cell lines with HS140, a PIM-2 kinase inhibitor developed in the laboratory. Using cytotoxicity assays, we were able to demonstrate a decrease in anchorage-dependent growth of cell lines at different concentrations of HS140. Also, a triple negative breast cancer GEMM (C3TAg) was used for an efficacy study. Mice (FVB/N background) have C(3)SV40 T-antigen resulting in inactivation of p53 and Rb. Nine mice received HS140 treatment (80mg/kg BIW IP) and 14 left untreated for control (non-treatment [NT]). All mice were monitored for weight loss and timespan to tumor development 5 times weekly. Tumor volumes at 21 days were significantly (Mann-Whitney, p=0.0002) reduced in the treated cohort with a mean of 109mm3 (range of 0-5000) compared to untreated 1393mm3 (0-239). We observed no toxicities with body mass stable at the treatment dose of 80mg/kg. Additionally, three mice from untreated and three mice from treated cohorts were chosen for blood sampling pre- and post-treatment via a submandibular bleed; no significant differences were noted in WBC, RBC, PLT, or HGB between untreated and treated cohorts. Overall, these results suggest that other members of the PIM kinase family, including PIM-2, have an important function in the growth and development of TNBC and may serve as a potential molecular target for future therapeutics.
Citation Format: Michael Cobb, Lucas Hunter, David Carlson, David Darr, Timothy Haystead, Antonio T. Baines. Characterizing the in vitro and in vivo effects of the PIM kinase inhibitor HS140 in triple-negative human breast 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 524. doi:10.1158/1538-7445.AM2017-524