Allosteric Modulation of PARP1-DNA Binding with Small Molecule Inhibitors: A Potential Non-Synthetic Lethal Therapeutic Strategy for Treating Ewing Sarcoma and Other Solid Tumors

Case ID:
2756
Web Published:
7/29/2019
Description:

Allosteric Modulation of PARP1-DNA Binding with Small Molecule Inhibitors: A Potential Non-Synthetic Lethal Therapeutic Strategy for Treating Ewing Sarcoma and Other Solid Tumors

OHSU Tech ID 2756

 

Technology Overview

Ewing sarcoma is the second most common type of bone cancer in children. Treatment options are limited to surgery and general chemotherapy; however, relapse often occurs in children with metastatic disease. In these cases, prognosis is especially dismal-less than 30% survival. It occurs because of the aberrant expression of a chimeric protein known as EWS/FLI-1, which is a potent driver of transformation. EWS/FLI-1 itself has eluded drug discovery efforts, and unlike other cancers, Ewing sarcoma has no obvious candidate drug targets. Previous studies have shown that Ewing sarcoma cells are sensitive to drugs (e.g. irinotecan, an FDA-approved DNA topoisomerase I inhibitor) that induce replication stress. Combining irinotecan with an inhibitor of an enzyme known as PARP1 causes cell death in Ewing sarcoma cells. However, the general cytotoxicity and poor pharmacokinetic properties of irinotecan limit the effectiveness of this combination therapy.

 

To address this medical need, Researchers at Oregon Health & Science University have identified novel PARP1 inhibitors that exhibit a unique mechanism of action-allosteric modulation of DNA binding, which induces replication stress in a similar way to irinotecan. Because these novel PARP1 inhibitors also inhibit the catalytic activity of PARP1, they induce rapid cell death in Ewing sarcoma cells. Therefore, the dual mode of action of the inhibitors allow them to be used as a potential monotherapy for Ewing sarcoma and likely, certain other solid tumors such as prostate cancer, and ovarian cancer.

 

Publication

Manuscript submitted for peer review.

 

Intellectual Property

Provisional patent application filed.

 

Licensing Opportunity

OHSU Tech ID 2756 is available for licensing, please contact OHSU Technology Transfer at techmgmt@ohsu.edu or by calling (503) 494-8200.

 

Patent Information:
Category(s):
Therapeutics
For Information, Contact:
Travis Cook
Senior Technology Development Manager
Oregon Health & Science University
cooktr@ohsu.edu
Inventors:
Moriah Arnold
Michael Cohen
Anang Shelat
Keywords:
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