Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies

Abstract

Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

“…Akt is important for a wide range of cellular functions and interacts with an immense number of substrates [52]. Only a few Akt inhibitors have been developed, and they have not produced convincing effects in AML [131,132]. Results from selected representative and relatively large clinical studies of PI3K-Akt-mTOR inhibitors were recently reviewed by Herscbein and Liesveld [133], and Table 1 represents the most relevant studies.…”

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

“…The treatment had an acceptable toxicity profile and correlative studies demonstrated a significant reduction in the levels of pAKT (Ser473) and pBAD (Ser112). 52 While no objective responses were documented, stable disease among 17 patients suggested a potential role for this inhibitor. 52 The phospholipid analog, perifosine, inhibits AKT by altering lipid rafts and preventing the membrane localization of AKT, resulting in apoptosis of AML cell lines and enhancement of etoposide cytotoxicity.…”

“…52 While no objective responses were documented, stable disease among 17 patients suggested a potential role for this inhibitor. 52 The phospholipid analog, perifosine, inhibits AKT by altering lipid rafts and preventing the membrane localization of AKT, resulting in apoptosis of AML cell lines and enhancement of etoposide cytotoxicity. 53 These results provided the impetus for ongoing clinical studies of perifosine in refractory AML and other malignancies (NCT00391560).…”

“…52 Based on preclinical evidence of AKT inhibition, triciribine was evaluated among 41 patients with advanced hematological malignancies, including 36 patients with AML. The treatment had an acceptable toxicity profile and correlative studies demonstrated a significant reduction in the levels of pAKT (Ser473) and pBAD (Ser112).…”

Two acute myeloid leukemia patient subsets are identified based on the constitutive PI3K-Akt-mTOR signaling of their leukemic cells; a functional, proteomic, and transcriptomic comparison

“…Akt is important for a wide range of cellular functions and interacts with an immense number of substrates [122]. Only a few Akt inhibitors have been developed, and they have not produced convincing effects in AML [187,188]. ___________________________________________________________________________ Results from selected representative and relatively large clinical studies of PI3K-Akt-mTOR inhibitors were recently reviewed by Herscbein-Liesveld and colleagues [189] and Table 3 represents the most relevant studies.…”