The main challenge in the treatment of acute myeloid leukemia (AML) is overcoming resistance to chemotherapy. We have shown that AML cells express high levels of AKT, a kinase known to promote survival and proliferation, and this is associated with poor overall survival. These data provide a rationale for use of AKT selective inhibitors with the goal to eliminate AKT-expressing AML cells. In our preclinical models, novel AKT allosteric inhibitor MK-2206 inhibited cell growth and induced apoptosis at concentrations achievable in vivo. The ongoing Phase I/II studies in solid tumors have demonstrated acceptable safety profile and sustained target inhibition at 200mg doses of MK-2206 weekly, and this regimen produced higher anti-tumor activity in tumor xenograft studies. Based on these findings, we will conduct Phase II clinical trial in patients with relapsed or refractory AML to investigate the safety and anti-leukemia efficacy of MK-2206. We have designed optional laboratory studies to measure changes in signaling pathways in leukemic cells from easily accessible peripheral blood and bone marrow sources (Aim 2). This will be conducted using new proteomic technique Reverse Phase Protein Array (RPPA). We have vast experience using RPPA in pre-clinical studies and for assessment of the prognostic significance of the expression levels of certain proteins. We will further determine the potential of MK-2206 to inhibit leukemic progenitor and stem cells by performing clonogenic assays and multicolor flow cytometry following treatment with MK-2206 of leukemic blasts obtained as a baseline prior to MK-2206 administration. We anticipate determining association of clinical responses with modulation of protein expression and/or viability outcomes. We have further identified B-subunits of AKT phosphatase PP2A as a potential biomarker of AKT inhibition, and will validate these findings in the ongoing clinical trial. It is our belief that demonstration of target inhibition and studying the effects on other potential biomarkers associated with cell death may serve as a guide for future studies with AKT or PI3K inhibitors in AML, alone or in combination with chemotherapy or with tyrosine kinase inhibitors (e.g., FLT3, c-KIT, Ras/MEK). If successful, this approach of targeting key pro-survival pathway, alone or in combination with other chemotherapeutic or targeted agents, may significantly impact AML therapy and ultimately improve outcomes of patients.
In acute myeloid leukemia (AML), the effectiveness of novel treatment modalities has increased, but we have not, after initial successes, made substantial progress to improve the survival of most patients. AKT is a molecule that provides the signal required for protection against various cellular stresses, and is constitutively activated in leukemic but not in normal cells. In this study supported by CTEP, we will investigate the safety and anti-leukemia efficacy of novel AKT inhibitor MK-2206 in patients with relapsed or refractory AML (Aim 1);and characterize molecular markers associated with response (Aim 2).
|Konopleva, Marina Y; Walter, Roland B; Faderl, Stefan H et al. (2014) Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia. Clin Cancer Res 20:2226-35|
|Rosen, David B; Harrington, Kimberly H; Cordeiro, James A et al. (2013) AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin. PLoS One 8:e53518|