The Applicability of mTOR Inhibition in Solid Tumors

Abstract

The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin-pathway (PI3K/AKT/mTOR-pathway) plays a role in the regulation of cell proliferation, cell survival, angiogenesis and resistance to anti-tumor treatments. In many tumor types the PI3K/AKT/mTOR-pathway is found activated through several different underlying mechanisms. Since this pathway is believed to largely drive the malignant behavior of several of these tumors, mTOR-inhibition is considered an attractive means to apply as anti-tumor treatment. Currently, four mTOR-inhibitors are explored for clinical use: rapamycin, temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573). As monotherapy, mTOR-inhibitors yield interesting anti-tumor activity against various tumor types at the expense of relatively mild toxicities. This recently resulted in the registration of two mTOR-inhibitors for patients with metastatic renal cell carcinoma (RCC) while randomized studies in other tumors are currently in progress. Furthermore, mTOR-inhibitors are well-suited drugs to combine with other anti-tumor drugs as in preclinical models mTOR-inhibition overcomes chemoresistance. Consequently, mTOR-inhibitor-containing multidrug regimens are subject to clinical studies. As holds true for all anti-tumor therapies, identification of patients who are likely to respond to mTOR-inhibitor-containing therapies is of utmost importance to avoid over- or undertreatment. Preliminary results suggest that several factors reflecting activation of mTOR in tumors may be used for this purpose. This review addresses the mechanism of action and current clinical experience with mTOR-inhibitors as well as their role in overcoming resistance to conventional therapies. Additionally, potential predictors of outcome to mTOR-inhibition are discussed.

Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

“…Accordingly, inhibitors have been developed to treat this and other malignancies clinically and pre-clinically. [23][24][25] MTOR exists in at least 2 distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, with each complex containing at least several distinctive proteins. 26,27 MTORC1, or the rapamycin-sensitive mTOR complex, is assembled by mTOR, raptor, and G protein b subunit-like (GbL) among others.…”

Autophagy Induction with RAD001 Enhances Chemosensitivity and Radiosensitivity through Met Inhibition in Papillary Thyroid Cancer

“…PTC is intrinsically resistant to cytotoxic chemotherapies, partly due to defects in apoptosis (16). This is relevant to a variety of malignancies, many with known deficiencies in apoptosis that are resistant to conventional cytotoxic chemotherapy, such as gemcitabine-refractory metastatic pancreatic cancer (31)(32)(33)(34)(35)(36)(37).…”

Interferon alpha and rapamycin inhibit the growth of pheochromocytoma PC12 line in vitro

“…These signalling alterations promote tumourigenesis, as hyperactivity of mTOR pathway is a well established factor leading to different neoplasms [3] and increased angiogenesis has been shown to be associated with the development of metastases, poor prognosis and reduced survival in many tumours [4]. The invasiveness of pheochromocytoma also correlated with the number of tumour blood vessels and increased VEGF (vascular endothelial growth factor) immunoreactivity [5].…”

“…The antiangiogenic and antitumour activity of rapamycin was found later [3,10] and gave rise to the use of mTOR inhibition in cancer treatment, which has proved to be effective in a number of neoplasms [3], including neuroendocrine tumours [11]. In 2011, the FDA (Food and Drug Administration) approved an mTOR inhibitor, everolimus, for the treatment of progressive pancreatic neuroendocrine tumours (PNETs) (NCI; http://www.…”