Development of Mithramycin Analogs for Ewing sarcoma
Background
A promising drug target for Ewing’s sarcoma is a protein called EWS-FLI1. This is a type of protein called a transcription factor which is thought by many to be an “undruggable target.”
Project Goal
The focus of this study is to develop a compound called EC8042 as a bona fide inhibitor of EWS-FLI1. We will show that the drug blocks EWS-FLI1 using sophisticated sequencing technologies on a genome-wide scale. In addition, we will use animal models to optimize the suppression of EWS-FLI1 in vivo. We will use Positron Emission Tomography (PET) imaging to follow EWS-FLI1 suppression in the tumors of the mice. Together, these results will provide the data to justify and guide the development and translation of this compound to the clinic as an EWS-FLI1 inhibitor.
Project Update - June 2020
It has been known for more than 20 years that Ewing sarcoma cells depend on a protein called EWS-FLI1 for cell survival. The goal of this proposal is to understand how a derivative of the drug mithramycin, called EC8042, works to block EWS-FLI1. If we understand how it works, it will make the molecule more attractive for companies to develop and bring to patients. In addition, we will be able to more effectively administer the drug to patients. In year one, we made major progress towards the goal of understanding how it works and optimized the experiments needed to complete these studies. In addition, we have shown that giving the parent drug, mithramycin, continuously is more effective in xenograft models than more standard dosing. Therefore, in year two, we will show that these effects translate to EC8042. Together, the data generated in year two will complete the goals of the proposal.
