Results of an abbreviated phase-II study with the Akt Inhibitor MK-2206 in Patients with Advanced Biliary Cancer

Abstract

Biliary cancers (BC) are rare, chemoresistant and are associated with a poor prognosis. Targeting the Akt pathway is of significance in BC. We hypothesized that the allosteric inhibitor MK-2206 will be active in BC. This was a multi-institutional phase II study of MK-2206 given to patients with advanced, refractory BC. The primary end point was overall response rate. We also characterized pharmacokinetic profiles of MK-2206 in these patients and explored its potential correlation with clinical outcomes. Eight patients were enrolled prior to early termination of the trial. All patients had received prior systemic therapy. The best response observed was stable disease, exceeding 12 weeks in two patients. Toxicities were mild and tolerable. MK-2206 exhibited a pharmacokinetic profile with an apparent slow absorption followed by biphasic elimination in these patients with BC. No significant association was observed between the pharmacokinetic properties of MK-2206 and clinical outcomes. MK-2206 as a single-agent in BC is tolerable with pharmacokinetic properties similar to patients with other solid tumors. No clinical activity was observed in this limited population. Further development of Akt inhibitors may need to focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy and prospective patient selection.

Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data

“…We focussed on MK-2206, a selective inhibitor of AKT1 in clinical trials in solid tumours4041. MiSL identified several predictive biomarkers for MK-2206 (Fig.…”

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

“…While early studies investigating novel agents targeting relevant signaling pathways demonstrated interesting antitumor activity in a small proportion of patients, the overall results have been disappointing, with outcomes largely similar to chemotherapy agents in the refractory setting ( Table 2) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). This may be in part due to the utilization of non-selected trials, where patients are eligible for enrollment regardless of their tumor genomic alterations.…”

MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome

“…Here, we found a dysregulated AKT-MDM2-P53 pathway in Fmr1 KO aNPCs, and that inhibiting either AKT or MDM2-P53’s interaction restored the P53 levels and rescued NPC proliferation and differentiation deficits in Fmr1 KO NPCs. AKT signaling is frequently dysregulated in human cancers, and MK-2206, a potent allosteric inhibitor of all AKT isoforms, has been used to treat patients with tumors in several clinical trials (examples(49, 50)). Although our study might extend the reach of MK-2206 to FXS, one concern is the molecule’s broad effects on many cellular processes in many types of cells.…”