Methods for Enhancing GBM Treatment Through Inhibition of Autophagy Mediator ATG4B

NU 2019-106

INVENTORS

Shi-Yuan Cheng*
- Feinberg School of Medicine, Department of Neurology
Bo Hu
Tianzhi Huang

SHORT DESCRIPTION

A novel autophagy inhibitor to enhance the efficiency of standard cancer treatments

BACKGROUND

Glioblastoma (GBM), an incurable, lethal disease, exhibits a poor 5-year survival rate. The usual treatment approach comprises surgical removal of the tumor, followed by a regimen of combined chemotherapy and radiation, typically involving temozolomide (TMZ). Nevertheless, despite these interventions, GBM often returns within a few months. Autophagy, a cellular mechanism to degrade damaged proteins, is frequently utilized by cancer cells to discard damaged organelles. Current front-line GBM treatments instigate this autophagic response, which aids in the development of treatment resistance in these cancers. Incorporating a treatment approach that targets autophagy might reduce such resistance, enhancing patient outcomes.

ABSTRACT

Northwestern scientists have shown that NCS185058 (NCS), an autophagy inhibitor, significantly reduces tumor growth and extends lifespan in mice injected with GBM when paired with radiation, TMZ, or both. NCS targets ATG4B, a key cysteine protease crucial for autophagy activation, which has been observed to increase in cancer patients. Crucially, NCS can infiltrate xenografted tumors in mouse brains, bypassing the blood-brain barrier, and it showed no toxic effects. These results strongly support that NCS could potentially serve as a part of combined treatment for GBM.

APPLICATIONS

Combination treatment of glioblastoma

ADVANTAGES

Exhibited no relevant tissue toxicity of NSC-treated mice, excellent brain/BBB penetration
Sustained levels that were effective on inhibiting brain tumors in the brain and the plasma
Displayed high specific activities against autophagy
Provided better inhibitory effects compared to currently used treatments

PUBLICATION

Huang T, Wan X, Alvarez AA, James CD, Song X, Yang Y, Sastry N, Nakano I, Sulman EP, Hu B, Cheng SY. MIR93 (microRNA -93) regulates tumorigenicity and therapy response of glioblastoma by targeting autophagy. Autophagy. 2019 Jun;15(6):1100-1111.

IP STATUS