title: Targeting the PI3K/AKT/mTOR pathway in non-Hodgkin's lymphoma: results, biology, and development strategies.
abstract: Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in non-Hodgkin's lymphoma (NHL), prompting evaluation of the rapamycin-analog (rapalog) mTOR inhibitors in multiple clinical trials. The drugs show activity as single agents, and the rapalog temsirolimus is now accepted as a therapeutic option in relapsed/refractory mantle cell lymphoma. Response rates, however, are typically below 50%, resulting in remissions that are neither complete nor durable. Results of preclinical studies shed important new light on resistance mechanisms that may explain results. Looking ahead, it is likely PI3K/AKT/mTOR inhibition will find expanded roles in NHL therapy due to 1) assessments of the rapalogs in combination with other therapies and in less heavily pretreated patients, 2) the development and evaluation of multiple novel inhibitors of the pathway that may increase specificity and potency, 3) alternative treatment strategies able to bypass particular resistance mechanisms, and 4) increased efforts to identify biomarkers for better pretreatment patient stratification.
authors.affiliation: Department of Medicine and Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York 10065, USA. schatzj@mskcc.org
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Schatz
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human