MK-2206 Causes Growth Suppression and Reduces Neuroendocrine Tumor Marker Production in Medullary Thyroid Cancer Through Akt Inhibition

Background

Development of targeted therapies for medullary thyroid cancer (MTC) has focused on inhibition of the rearranged during transfection (RET) proto-oncogene. Akt has been demonstrated to be a downstream target of RET via the key mediator phosphoinositide-3-kinase. MK-2206 is an orally administered allosteric Akt inhibitor that has exhibited minimal toxicity in phase I trials. We explored the antitumor effects of this compound in MTC.

Methods

Human MTC-TT cells were treated with MK-2206 (0–20 μM) for 8 days. Assays for cell viability were performed at multiple time points with MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). The mechanism of action, mechanism of growth inhibition, and production of neuroendocrine tumor markers were assessed with Western blot analysis.

Results

MK-2206 suppressed MTC cell proliferation in a dose-dependent manner (p ≤ 0.001). Levels of Akt phosphorylated at serine 473 declined with increasing doses of MK-2206, indicating successful Akt inhibition. The apoptotic proteins cleaved poly (ADP-ribose) polymerase and cleaved caspase-3 increased in a dose-dependent manner with MK-2206, while the apoptosis inhibitor survivin was markedly reduced. Importantly, the antitumor effects of MK-2206 were independent of RET inhibition, as the levels of RET protein were not blocked.

Conclusions

MK-2206 significantly suppresses MTC proliferation without RET inhibition. Given its high oral bioavailability and low toxicity profile, phase II studies with this drug alone or in combination with RET inhibitors are warranted.     

Invasive IPMN and MCN: Same Organ, Sifferent Outcomes?

Background

The efficacy of surgery for invasive mucinous neoplasms is unclear. We examined the natural history of invasive mucinous cystic neoplasms (MCN) and invasive intraductal papillary mucinous neoplasms (IPMN) in patients who underwent pancreatic resection.

Methods

The Surveillance, Epidemiology, and End Results (SEER) database (1996–2006) was queried for cases of resected invasive MCN and IPMN. Demographics, tumor characteristics, and overall survival were examined using log-rank analysis and multivariate Cox regression model.

Results

Of 185 MCN cases and 641 IPMN cases, 73% and 48%, respectively, were women (P < 0.0001). Most (73%) IPMN were in the head of the pancreas; most (64%) MCN were in the tail/body (P < 0.0001). Lymph node metastasis was more common for IPMN than MCN (46% vs. 24%, P < 0.0001). Overall survival after resection was better for patients with stage I MCN vs. stage I IPMN (P = 0.0005), and it was better for patients with node-negative MCN vs. node-negative IPMN (P = 0.0061). There was no significant difference in survival of patients with stage IIA MCN vs. stage IIA IPMN (P = 0.5964), stage IIB MCN vs. stage IIB IPMN (P = 0.2262), or node-positive MCN vs. node-positive IPMN (P = 0.2263). Age older than 65 years (hazards ratio (HR) 1.71, P = 0.0046), high tumor grade (HR 2.68, P < 0.0001), higher T stage (HR 2.11, P < 0.0001), and IPMN histology (HR 1.90, P = 0.0040) predicted worse outcome in node-negative patients.

Conclusions

Our findings suggest that survival is better after resection of invasive MCN versus invasive IPMN when disease is localized within the pancreas, but this difference disappears in the presence of nodal metastasis or extrapancreatic extension.