Development of inhibitors of the IGF-IR/PI3K/Akt/mTOR pathway.
Progress has been made towards the development of agents targeting tyrosine kinase receptors and other molecules involved in signalling pathways important for cell proliferation, motility, and apoptosis. Inhibitor molecules designed to be highly specific with the aim of decreasing toxicity have proven to be generally well tolerated. However, the efficacy of targeted agents may be impacted by cross-talk between pathways and downregulation of negative feed-back loops. That is the case of the IGF-IR/PI3K/Akt/mTOR pathway. This issue raises the question of how these targeted agents could be combined to prevent or delay resistance without significantly increasing toxicity. Several mTOR inhibitors have been approved for cancer therapy, and late-stage clinical trials of IGF-IR inhibitors are underway. The outcome of ongoing clinical studies of IGF-IR, PI3K, Akt and mTOR inhibitors as well as further testing of the combination of these agents will be key for the development of therapeutic options in a wide range of oncology indications.
Hixon
Mary L
ML
Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Paccagnella
Luisa
L
Millham
Robert
R
Perez-Olle
Raul
R
Gualberto
Antonio
A
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015534:Trans-Activators; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases