Case 2017-517
UCLA researchers have identified and characterized mTORC2-specific inhibitors useful as a novel treatment of glioblastoma.
BACKGROUND
Glioblastoma (GBM) is a highly malignant and invasive primary brain tumor that is difficult to treat with total surgical resection or chemotherapy. Two-year survival rate of GBM is only 30%, and patients that do survive typically develop drug resistance. Thus, there is an urgent need for novel therapeutic options.
Mammalian target of rapamycin (mTOR) is an important target for molecular therapeutics in GBM. mTOR is a common element in 2 separate kinase complexes, mTORC1 (regulates cell size and growth) and mTORC2 (regulates cell growth and cell cycle-dependent cytoskeleton assembly). However, current efforts utilizing mTOR inhibitors as a potential targeted therapy for the treatment of GBM have failed in the clinic. This is due to the disruption of mTORC1-dependent feedback signaling loops, which results in mTOR inhibitor resistance. Recently it was found that mTORC2 activity is essential for the transformation and invasive characteristics of GBM, making mTORC2-specific inhibitors a promising therapeutic option.
INNOVATION
UCLA researchers have identified novel inhibitors that specifically block mTORC2 signaling, leaving mTORC1-dependent feedback loops intact, thus circumventing drug resistance facilitated by mTORC1. These inhibitors demonstrate significant anti-glioblastoma effects both in cell culture and animal models.
APPLICATIONS
The primary application of this invention is for treatment of glioblastoma.
ADVANTAGES
- mTORC2 is known to be hyperactive in approximately 75% of GBM patients
- Inhibitor is specific for mTORC2 and does not affect mTORC1 activity
- Doesn’t activate the mTORC1-dependent drug resistance signaling pathway
STATE OF DEVELOPMENT
These mTORC2 inhibitors were tested in vitro and in vivo. They were proven to be specific for mTORC2 activity. They demonstrated significant anti-tumor properties.
RELATED MATERIALS
- Benavides-Serrato, Angelica, et al. "Specific blockade of Rictor-mTOR association inhibits mTORC2 activity and is cytotoxic in glioblastoma." PloS one 12.4 (2017): e0176599.m