Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia

Abstract

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase whose activity contributes to leukemia proliferation and survival. Compounds targeting the mTOR active site inhibit rapamycin-resistant functions and have enhanced anti-cancer activity in mouse models. MLN0128 (formerly known as INK128) is a novel, orally active mTOR kinase inhibitor currently in clinical development. Here we evaluated MLN0128 in preclinical models of B-cell acute lymphoblastic leukemia (B-ALL). MLN0128 suppressed proliferation of B-ALL cell lines in vitro and reduced colony formation by primary human leukemia cells from adult and pediatric B-ALL patients. MLN0128 also boosted the efficacy of dasatinib in Philadelphia Chromosome-positive (Ph+) specimens. In a syngeneic mouse model of lymphoid BCR-ABL+ disease, daily oral dosing of MLN0128 rapidly cleared leukemic outgrowth. In primary xenografts of Ph+ B-ALL specimens, MLN0128 significantly enhanced the efficacy of dasatinib. In non-Ph B-ALL xenografts, single agent MLN0128 had a cytostatic effect that was most pronounced in mice with low disease burden. In all in vivo models, MLN0128 was well tolerated and did not suppress endogenous bone marrow proliferation. These findings support the rationale for clinical testing of MLN0128 in both adult and pediatric B-ALL and provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors.

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

“…The lack of cell killing as a single-agent suggests that combination treatment, with standard of care agents or other targeted therapies, may be required to achieve cell death and tumor regression in patients with solid tumors. Other combinations with mTOR kinase inhibitors have been reported (26,27) and the combination of CC-223 with Erlotinib or CC-486, an oral formulation of azacitidine, is under clinical study in NSCLC (28). In addition, the combination of CC-223 with CC-122 (immunomodulator), with and without rituximab, is being evaluated in DLBCL (29).…”

Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels

“…The few studies that have previously explored the involvement of PI3K/Akt constitutive activation in adult B-ALL did so in a very limited number of patients 6 or focused on mTOR [8][9][10] rather than Akt. However, mTOR activation is only very indirectly regulated by PI3K and it can be affected by several upstream cues that are PI3K-independent.…”

“…However, mTOR activation is only very indirectly regulated by PI3K and it can be affected by several upstream cues that are PI3K-independent. 10 Therefore, we opted to study Akt phosphorylation, a more direct PI3K effector and central player in the pathway. Our data, using a reasonable number of cases (n=21), clearly revealed that adult B-ALL cells displayed constitutive hyperactivation of PI3K/Akt signaling pathway.…”

“…However, little is known about the levels of activation of this pathway in B-ALL, especially in adult cases, 6,7 with most studies focusing on the PI3K/Akt downstream target mTOR and its respective effectors. [8][9][10] Yet, mTOR is part of a complex network that does not necessarily reflect the levels of activation of PI3K/Akt pathway, since it can be regulated by other upstream events. 11,12 The activity of PI3K/Akt signaling can be inhibited by the tumor suppressor phosphatase and tensin homologue (PTEN), which converts phosphatidylinositol 3,4,5-trisphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2).…”

First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014

“…TORC1/2 inhibitors that are currently under phase I evaluation or have completed phase I evaluation include AZD2014 (15), INK-128/MLN-128 (16,17), DS-3078a (18), OSI-027 (19,20), and AZD8055 (21,22).…”