Targeting Melanoma with Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitors

Abstract

Phosphoinositide 3-kinase (PI3K)/protein kinase B/Akt and Ras/mitogen-activated protein kinase pathways are often constitutively activated in melanoma and have thus been considered as promising drug targets. Exposure of melanoma cells to NVP-BAG956, NVP-BBD130, and NVP-BEZ235, a series of novel, potent, and stable dual PI3K/ mammalian target of rapamycin (mTOR) inhibitors, resulted in complete G1 growth arrest, reduction of cyclin D1, and increased levels of p27 KIP1 , but negligible apoptosis. In contrast, treatment of melanoma with the pan-class I PI3K inhibitor ZSTK474 or the mTORC1 inhibitor rapamycin resulted only in minor reduction of cell proliferation. In a syngeneic B16 mouse melanoma tumor model, orally administered NVP-BBD130 and NVP-BEZ235 efficiently attenuated tumor growth at primary and lymph node metastatic sites with no obvious toxicity. Metastatic melanoma in inhibitor-treated mice displayed reduced numbers of proliferating and significantly smaller tumor cells. In addition, neovascularization was blocked and tumoral necrosis increased when compared with vehicle-treated mice. In conclusion, compounds targeting PI3K and mTOR simultaneously were advantageous to attenuate melanoma growth and they develop their potential by targeting tumor growth directly, and indirectly via their interference with angiogenesis. Based on the above results, NVP-BEZ235, which has entered phase I/II clinical trials in patients with advanced solid tumors, has a potential in metastatic melanoma therapy. (Mol Cancer Res 2009;7(4):601-13)

The Akt signaling pathway

“…NVP-BEZ235, an imidazoquinoline derivative inhibiting both PI3K and mTOR by binding to the ATP binding site, has been tested in preclinical models of melanoma. 44,130 In preclinical studies, blocking PI3K with ZSTK474 or blocking mTOR with rapamycin yielded promising results. 44,130 It is promising that NVP-BEZ235 was found to be more potent than the combination of ZSTK474 and rapamycin with respect to inhibition of melanoma cell proliferation.…”

“…130 Furthermore, oral administration of NVP-BBD130 and NVP-BEZ235 efficiently inhibited B16 melanoma tumor growth in primary tumors and in lymph node metastasis. 130 Currently, NVP-BEZ235 is being evaluated in Phase I/II clinical trials for the treatment of metastatic melanoma. 130 OSI-027 (Osi Pharmaceuticals) and OXA-01 are novel inhibitors of mTORC1 and mTORC2.…”

“…For example, targeting PI3K and mTOR with NVP-BAG956, NVP-BBD130 or NVP-BEZ-235 induced G 1 growth arrest mediated by p27 thereby reducing cyclin D1 in melanoma cells. 130 However, inhibition of either PI3K or mTOR alone using ZSTK474 or rapamycin, respectively, only marginally reduced cell proliferation. 130 Furthermore, oral administration of NVP-BBD130 and NVP-BEZ235 efficiently inhibited B16 melanoma tumor growth in primary tumors and in lymph node metastasis.…”

“…130 However, inhibition of either PI3K or mTOR alone using ZSTK474 or rapamycin, respectively, only marginally reduced cell proliferation. 130 Furthermore, oral administration of NVP-BBD130 and NVP-BEZ235 efficiently inhibited B16 melanoma tumor growth in primary tumors and in lymph node metastasis. 130 Currently, NVP-BEZ235 is being evaluated in Phase I/II clinical trials for the treatment of metastatic melanoma.…”

“…130 Currently, NVP-BEZ235 is being evaluated in Phase I/II clinical trials for the treatment of metastatic melanoma. 130 OSI-027 (Osi Pharmaceuticals) and OXA-01 are novel inhibitors of mTORC1 and mTORC2. 131 Preclinical studies using 75 mg/kg OXA-01 demonstrated retardation of xenografted MDA-MB-231 tumor development.…”