Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing...

Area of Science:

• Pharmacology
• Oncology
• Molecular Biology

Background:

• MLN0128 is an investigational small molecule inhibitor targeting the serine/threonine kinase mTOR.
• The mechanistic target of rapamycin (mTOR) pathway is crucial in cell growth and proliferation, making it a target for cancer therapy.

Purpose of the Study:

• To evaluate the in vitro and in vivo efficacy of MLN0128 in preclinical cancer models.
• To determine the anti-cancer activity of MLN0128 against a panel of solid tumors and acute lymphoblastic leukemia (ALL) xenografts.

Main Methods:

• In vitro testing of MLN0128 across a concentration range of 0.1 nM to 1 µM.
• In vivo evaluation using the Patient-Derived Xenograft (PDX) tumor models (PPTP) at an oral dose of 1 mg/kg daily for 28 days.

Main Results:

• The median relative IC50 concentration in vitro was 19 nM.
• MLN0128 demonstrated significant differences in event-free survival (EFS) in 77% (24/31) of solid tumor models.
• No significant activity was observed in 0/7 ALL xenografts.

Conclusions:

• MLN0128 exhibits modest preclinical activity against solid tumors but lacks efficacy in ALL xenografts.
• The observed activity profile is comparable to other TOR kinase inhibitors, suggesting a need for further investigation into its therapeutic applications.