The PI3K/AKT/mTOR (PAM) signaling pathway is frequently mutated in prostate cancer. Specific AKT inhibitors are now in advanced clinical trials and this study investigates the effect of MK2206, a non-ATP competitive inhibitor, on the cellular metabolism in the context of prostate cancer. A significant reduction in cell motility and aerobic glycolysis was observed in prostate cancer cells with treatment. These changes were not accompanied by a reduction in the ratio of high-energy phosphates or a change in total protein levels of enzymes (e.g., Hexokinase) and transporters (e.g., Glut1) involved in glycolysis. However, a decreased ratio of NAD+/NADH was observed, motivating the use of hyperpolarized magnetic resonance spectroscopy (HP-MRS) to detect treatment response. Spectroscopic experiments were performed on tumor spheroids, 3D structures that self-organize in the presence of an extracellular matrix (ECM). Treated spheroids showed decreased lactate production with on-target inhibition confirmed using immunohistochemistry (IHC) for phosphorylated AKT, demonstrating that HP-MRS can be used to probe treatment response in prostate cancer spheroids.
Hyperpolarized MRS (HP-MRS) can now be performed on self-organizing 3D cultures. Treatment of these spheroids with an AKT inhibitor reduces hyperpolarized lactate formation from pyruvate, demonstrating that HP-MRS can provide a biomarker for treatment response.
Molecular cancer research : MCR. 2018 Jan 12 [Epub ahead of print]
Sui Seng Tee, Izabela Suster, Steven Truong, Sangmoo Jeong, Roozbeh Eskandari, Valentina Di Gialleonardo, Julio A Alvarez, Hannah N Aldeborgh, Kayvan Keshari
Radiology, Memorial Sloan Kettering Cancer Center., Chemistry, Hunter College., Radiology, Memorial Sloan Kettering Cancer Center .