scholarly journals Replication Study: Systematic identification of genomic markers of drug sensitivity in cancer cells

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
John P Vanden Heuvel ◽  
Ewa Maddox ◽  
Samar W Maalouf ◽  
Elizabeth Iorns ◽  
Rachel Tsui ◽  
...  

In 2016, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Vanden Heuvel et al., 2016), that described how we intended to replicate selected experiments from the paper ‘Systematic identification of genomic markers of drug sensitivity in cancer cells’ (Garnett et al., 2012). Here we report the results. We found Ewing’s sarcoma cell lines, overall, were more sensitive to the PARP inhibitor olaparib than osteosarcoma cell lines; however, while the effect was in the same direction as the original study (Figure 4C; Garnett et al., 2012), it was not statistically significant. Further, mouse mesenchymal cells transformed with either the EWS-FLI1 or FUS-CHOP rearrangement displayed similar sensitivities to olaparib, whereas the Ewing’s sarcoma cell line SK-N-MC had increased olaparib sensitivity. In the original study, mouse mesenchymal cells transformed with the EWS-FLI1 rearrangement and SK-N-MC cells were found to have similar sensitivities to olaparib, whereas mesenchymal cells transformed with the FUS-CHOP rearrangement displayed a reduced sensitivity to olaparib (Figure 4E; Garnett et al., 2012). We also studied another Ewing’s sarcoma cell line, A673: A673 cells depleted of EWS-FLI1 or a negative control both displayed similar sensitivities to olaparib, whereas the original study reported a decreased sensitivity to olaparib when EWS-FLI1 was depleted (Figure 4F; Garnett et al., 2012). Differences between the original study and this replication attempt, such as the use of different sarcoma cell lines and level of knockdown efficiency, are factors that might have influenced the outcomes. Finally, where possible, we report meta-analyses for each result.

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
John P Vanden Heuvel ◽  
Jessica Bullenkamp ◽  

The Reproducibility Project: Cancer Biology seeks to address growing concerns about the reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (<xref ref-type="bibr" rid="bib7">Errington et al., 2014</xref>). This Registered Report describes the proposed replication plan of key experiments from “Systematic identification of genomic markers of drug sensitivity in cancer cells” by Garnett and colleagues, published in Nature in 2012 (<xref ref-type="bibr" rid="bib9">Garnett et al., 2012</xref>). The experiments to be replicated are those reported in Figures 4C, 4E, 4F, and Supplemental Figures 16 and 20. Garnett and colleagues performed a high throughput screen assessing the effect of 130 drugs on 639 cancer-derived cell lines in order to identify novel interactions for possible therapeutic approaches. They then tested this approach by exploring in more detail a novel interaction they identified in which Ewing’s sarcoma cell lines showed an increased sensitivity to PARP inhibitors (Figure 4C). Mesenchymal progenitor cells (MPCs) transformed with the signature EWS-FLI1 translocation, the hallmark of Ewing’s sarcoma family tumors, exhibited increased sensitivity to the PARP inhibitor olaparib as compared to MPCs transformed with a different translocation (Figure 4E). Knockdown mediated by siRNA of EWS-FLI1 abrogated this sensitivity to olaparib (Figure 4F). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.


2014 ◽  
Author(s):  
TABREZ A. MOHAMMAD ◽  
Aparna Gorthi ◽  
Andrew Robles ◽  
Xavier Bernard ◽  
Tzu-hung Hsiao ◽  
...  

2007 ◽  
Vol 103 (4) ◽  
pp. 1344-1354 ◽  
Author(s):  
Cristina Zanini ◽  
Giuliana Giribaldi ◽  
Giorgia Mandili ◽  
Franco Carta ◽  
Nicoletta Crescenzio ◽  
...  

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1553
Author(s):  
Ellie Esfandiari Nazzaro ◽  
Fahad Y. Sabei ◽  
Walter K. Vogel ◽  
Mohamad Nazari ◽  
Katelyn S. Nicholson ◽  
...  

Ewing’s sarcoma, characterized by pathognomonic t (11; 22) (q24; q12) and related chromosomal ETS family translocations, is a rare aggressive cancer of bone and soft tissue. Current protocols that include cytotoxic chemotherapeutic agents effectively treat localized disease; however, these aggressive therapies may result in treatment-related morbidities including second-site cancers in survivors. Moreover, the five-year survival rate in patients with relapsed, recurrent, or metastatic disease is less than 30%, despite intensive therapy with these cytotoxic agents. By using high-throughput phenotypic screening of small molecule libraries, we identified a previously uncharacterized compound (ML111) that inhibited in vitro proliferation of six established Ewing’s sarcoma cell lines with nanomolar potency. Proteomic studies show that ML111 treatment induced prometaphase arrest followed by rapid caspase-dependent apoptotic cell death in Ewing’s sarcoma cell lines. ML111, delivered via methoxypoly(ethylene glycol)-polycaprolactone copolymer nanoparticles, induced dose-dependent inhibition of Ewing’s sarcoma tumor growth in a murine xenograft model and invoked prometaphase arrest in vivo, consistent with in vitro data. These results suggest that ML111 represents a promising new drug lead for further preclinical studies and is a potential clinical development for the treatment of Ewing’s sarcoma.


Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 879
Author(s):  
Giacomo Domenici ◽  
Rodrigo Eduardo ◽  
Helena Castillo-Ecija ◽  
Gorka Orive ◽  
Ángel Montero Carcaboso ◽  
...  

Ewing’s Sarcoma (ES) is the second most frequent malignant bone tumour in children and young adults and currently only untargeted chemotherapeutic approaches and surgery are available as treatment, although clinical trials are on-going for recently developed ES-targeted therapies. To study ES pathobiology and develop novel drugs, established cell lines and patient-derived xenografts (PDX) are the most employed experimental models. Nevertheless, the establishment of ES cell lines is difficult and the extensive use of PDX raises economic/ethical concerns. There is a growing consensus regarding the use of 3D cell culture to recapitulate physiological and pathophysiological features of human tissues, including drug sensitivity. Herein, we implemented a 3D cell culture methodology based on encapsulation of PDX-derived ES cell spheroids in alginate and maintenance in agitation-based culture systems. Under these conditions, ES cells displayed high proliferative and metabolic activity, while retaining the typical EWSR1-FLI1 chromosomal translocation. Importantly, 3D cultures presented reduced mouse PDX cell contamination compared to 2D cultures. Finally, we show that these 3D cultures can be employed in drug sensitivity assays, with results similar to those reported for the PDX of origin. In conclusion, this novel 3D cell culture method involving ES-PDX-derived cells is a suitable model to study ES pathobiology and can assist in the development of novel drugs against this disease, complementing PDX studies.


2015 ◽  
Vol 12 (3) ◽  
pp. 3359-3364 ◽  
Author(s):  
WEIHUA LI ◽  
YUXIA LI ◽  
JIANKUO GUO ◽  
HUAGANG PAN ◽  
YONGLE ZHANG ◽  
...  

1991 ◽  
Vol 57 (1) ◽  
pp. 19-30 ◽  
Author(s):  
Ken Kodama ◽  
Osamu Doi ◽  
Masahiko Higashiyama ◽  
Yoichi Mori ◽  
Takeshi Horai ◽  
...  

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