Discovery and validation of a compound to target ewing’s sarcoma

Ellie Esfandiari Nazzaro, Fahad Y. Sabei, Walter K. Vogel, Mohamad Nazari, Katelyn S. Nicholson, Philip R. Gafken, Olena Taratula, Oleh Taratula, Monika A. Davare, Mark Leid

Research output: Contribution to journalArticlepeer-review

Abstract

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; how-ever, 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 nanopar-ticles, 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.

Original languageEnglish (US)
Article number1553
JournalPharmaceutics
Volume13
Issue number10
DOIs
StatePublished - Oct 2021

Keywords

  • Cancer
  • Chemotherapy
  • Drug discovery
  • Ewing’s sarcoma
  • High-throughput screening
  • ML111
  • Nanoparticle drug delivery

ASJC Scopus subject areas

  • Pharmaceutical Science

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