We will test novel targeted strategies to modulate the emergence and evolution of drug resistance using the NEDD8-activating enzyme (NAE) inhibitor MLN4924.
Aim 1 focuses on evaluating how treatment-associated on-target mutations influence regression and relapse in spontaneous disease models. Ex-vivo strategies designed to control the types and frequencies of known MLN4924-resistance mechanisms will be compared to in vivo treatment-associated relapse to delineate how selective pressure by a strongly mono-targeted drug drives cancer cell evolution.
Aim 2 tests a strategy that uses a less selective NAE inhibitor to transiently suppress MLN4924 resistance by providing a low level, secondary selective pressure.
Aim 3 determines how providing distinct selective pressures at a known drug resistance hotspot in NAE influence the type and frequency of MLN4924 treatment-emergent resistance mechanisms. Collectively, our studies using the clinical NAE inhibitor MLN4924 will establish new rational paradigms for targeted therapies designed to suppress and potentially reverse treatment-emergent drug resistance.

Public Health Relevance

The NEDD8-activating enzyme inhibitor has recently begun testing in humans for hematological and advanced non-hematological malignancies. In this R01 application, we propose new investigations into molecular mechanisms of treatment-emergent resistance during MLN4924 therapy and devise innovative strategies to overcome these to restore the drug's anti-cancer efficacy.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA180150-02
Application #
8719960
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Kondapaka, Sudhir B
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037