mTOR inhibitors: A novel class of anti-cancer agents

Recent development has made cancer treatment move on from conventional cytotoxic drugs to agents that target specific proteins like mTOR called mTOR inhibitors. A very common mTOR inhibitor, rapamycin, is a bacterial product that inhibits mTOR by associating with its intracellular receptor [5]. [Currently, two mTOR inhibitors, temsirolimus and everolimuswhich are derivatives of rapamycin, temsirolimus(Torisel: Wyeth-Ayerst, Charlotte, NC, U.S.A.) and everolimus(Certican: Novartis Pharmaceuticals, St. Louis, MO, U.S.A.) ] are approved for the treatment of patients with advanced renal cell carcinoma (RCC) and mantle cell lymphoma, effectively translating this paradigm into the clinical setting [6].mTOR inhibitors (like other drugs) have an adverse effect profile. Clinical trials have had mixed opinions regarding drug efficacy [7]. Examples of the neoplasias with promising results include pancreatic neuroendocrine tumors, follicular lymphoma, renal cell carcinoma and mantle cell lymphoma while the ones with negative results include glioblastoma multiforme and small cell carcinoma of lung. Although relatively safe, these drugs are associated with some unique adverse side effects, such as hyperlipidemia, hyperglycemia, and pneumonitis, which require monitoring and may require clinical intervention [6]. Clinical utility of mTOR inhibitors depends on appropriate selection of patients and type of cancer. Mutations in the mTOR pathway of cancer cells may result in resistance to mTOR inhibition and prevent any action of the mTOR inhibitors. Examples include mutations of FKBP-12 proteins, mammalian 14-3-3 proteins ATM (ataxia telangiectasia, mutated) cells, all responsible for growth of cancer cells.A new wave of clinical trials has commenced using a second generation of mTORC1 and mTORC2 inhibitors. First generation of mTOR inhibitors like rapamycin, showed certain limitations by blocking only C1 isoform, inducing feedback activation of Akt and showing resistance to mTORC2 [8