mTOR inhibitors for the treatment of lymphoma

Patients with non-Hodgkin lymphoma (NHL) or Hodgkin disease (HD) who relapse after conventional chemoimmunotherapy and/or stem cell transplantation are usually incurable. New agents are needed for this group of diseases. The phosphatidylinositol- 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway integrates signals from multiple receptor tyrosine kinases and regulates many cellular processes, including proliferation, growth and survival. In lymphoma cells this pathway has been shown to be upregulated.1 For example, a pathologic hallmark of mantle cell lymphoma (MCL) is the characteristic overexpression of cyclin D1 in the MCL tumor cells.2 Cyclin D1 is one of the proteins whose translation is under the control of the PI3K signal transduction pathway and is downstream of mTOR.1 Several drugs are now in clinical use or in trial that inhibit mTOR. The first member of this class of drugs is rapamycin (sirolimus) which was originally isolated from a strain of Streptomyces hygroscopicus found in the soil of the Vai Atore region of Easter Island.3,4 Oral sirolimus is approved for the prophylaxis of kidney transplant rejection. Temsirolimus, a dihydroester of the selective mTOR inhibitor rapamycin (Wyeth Pharmaceuticals), is approved by the US FDA for the treatment of renal cell carcinoma because of its demonstrated anti-tumor activity at a dose of 25 mg IV weekly.5,6 Everolimus (Novartis) is an oral agent also based on the structure of rapamycin. It is available in Europe as an anti-rejection agent and is undergoing clinical trial in various cancers. As a class, the mTOR inhibitors are generally well-tolerated. The side effects to be aware of are myelosuppression (especially thrombocytopenia), dysgeusia, hyperglycemia and hyperlipidemia and less commonly pulmonary infiltrates, rash, and oral ulcers.