Identification of DNA Polymerase Theta Inactivation Mechanism

Unmet Need
Loss of DNA repair is an early and frequent event in the growth of tumors, occurring in 40 to 50% of breast, lung and ovarian cancer patients. The inability to repair damaged DNA provides a selective growth advantage to tumor cells as this results in genetic instability and enhanced mutation rates, which can drive tumor growth.  These DNA repair–deficient cancers often become dependent on backup DNA repair pathways, which can be exploited to eliminate cancer cells.  The development of inhibitors that target DNA repair in tumors has recently gained interest as a new focus in advancing cancer treatments.  DNA Polymerase theta (Pol Φ) is a repair enzyme specifically expressed in tumors and associated with poor clinical outcomes.  Importantly, disruption of Pol Φ sensitizes cancer cells to radiotherapy and has been shown to be lethal in animal models of BRCA-deficient cancer.  Therefore, the development of methods to identify and develop inhibitors to Pol Φ could be medically and economically important.

Technology Overview
Hopkins inventors have identified a mutation in the active site of Pol Φ that has reduced its activity more than 3,000-fold.  Using patented technology developed previously at Johns Hopkins, the inventors plan to screen libraries of molecules as potential irreversible inhibitors of Pol Φ.

Stage of Development
Conceptual

Publications
Laverty, DJ, et al. ACS Chemical Biology 12(6), 1584-1592, 2017
 

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