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Dr. El-Deiry made important contributions in cell death signaling and our understanding of the sensitivity of tumors to chemotherapy including the original discovery of TRAIL death receptor 5 (DR5) as a p53 target and mediator of extrinsic cell death after DNA damage. This work, published in Nature Genetics in 1997 linked the p53 tumor suppressor to the innate immune pathway of suppression of cancer and its metastases. Later work unraveled various determinants of sensitivity to TRAIL as a therapeutic, brought out the tumor susceptibility and inflammation phenotype of DR5-knockout mice, and suggested various combinatorial therapeutic strategies including sorafenib plus TRAIL or TRAIL receptor agonist antibodies.
He discovered and brought first-in-class TRAIL-pathway activating small-molecule ONC201/TIC10 into clinical trials for patients with cancer. The first manuscript on the new drug was published in Science Translational Medicine in 2013 and this demonstrated that TIC10 (later called ONC201) treatment of tumor cells led to transcriptional upregulation of the TRAIL gene, independent of the p53 status of tumor cells, through a pathway involving ERK and Akt inhibition, dephosphorylation and nuclear translocation of Foxo3a and transcriptional activation of the TRAIL gene. By 2016 in work published in Science Signaling, the lab discovered that ONC201 activates an integrated stress response, involving eIF2-alpha kinases PKR and HRI, ATF4 induction and CHOP-dependent DR5 transcriptional activation. These results suggested that ONC201 activates both the TRAIL gene and the DR5 gene in priming cancer cells for drug-induced cell death. ONC201 entered clinical trials by 2014 and has been found to have anti-tumor activity in patients with GBM (DIPG with H3K27M mutations), prostate cancer, endometrial cancer and other tumor types.
He discovered and brought first-in-class TRAIL-pathway activating small-molecule ONC201/TIC10 into clinical trials for patients with cancer. The first manuscript on the new drug was published in Science Translational Medicine in 2013 and this demonstrated that TIC10 (later called ONC201) treatment of tumor cells led to transcriptional upregulation of the TRAIL gene, independent of the p53 status of tumor cells, through a pathway involving ERK and Akt inhibition, dephosphorylation and nuclear translocation of Foxo3a and transcriptional activation of the TRAIL gene. By 2016 in work published in Science Signaling, the lab discovered that ONC201 activates an integrated stress response, involving eIF2-alpha kinases PKR and HRI, ATF4 induction and CHOP-dependent DR5 transcriptional activation. These results suggested that ONC201 activates both the TRAIL gene and the DR5 gene in priming cancer cells for drug-induced cell death. ONC201 entered clinical trials by 2014 and has been found to have anti-tumor activity in patients with GBM (DIPG with H3K27M mutations), prostate cancer, endometrial cancer and other tumor types.
研究兴趣
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Nature Cancer (2024)
Tej Tummala, Ashley S. Sevilla Uruchurtu, Nicholas R. Liguori, E. Abbas, Christopher G. Azzoli,Wafik S. El-Deiry
Cancer Researchno. 6_Supplement (2024): 4550-4550
Tej Tummala, Arielle De La Cruz,Ash Uruchurtu,Nicholas R. Liguori,Abbas E. Abbas,Leiqing Zhang, Chistopher G. Azzoli,Lanlan Zhou,Wafik S. El-Deiry
Nature Cancerpp.1-9, (2024)
bioRxiv (Cold Spring Harbor Laboratory) (2024)
Nature Cancerpp.1-9, (2024)
PATHOLOGYno. 2 (2024): 228-238
Khaldoun Almhanna,Rimini Breakstone,Alexander Raufi,Roxanne Wood, Amy Webber, Sopha Dionson, Lindsay Cavanagh,Attila A Seyhan,Howard Safran,Wafik El-Deiry
Translational gastroenterology and hepatology (2024): 15-15
Nicholas A. Zorko, Allison Makovec,Andrew Elliott, Samuel Kellen,John R. Lozada,Ali T. Arafa,Martin Felices, Madison Shackelford,Pedro Barata,Yousef Zakharia,Vivek Narayan,Mark N. Stein,
Prostate Cancer and Prostatic Diseasespp.1-9, (2024)
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