Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Wagle, N, Grabiner, BC, Van Allen, EM, Hodis, E, Jacobus, S, Supko, JG, Stewart, M, Choueiri, TK, Gandhi, L, Cleary, JM, Elfiky, AA, Taplin, MEllen, Stack, EC, Signoretti, S, Loda, M, Shapiro, GI, Sabatini, DM, Lander, ES, Gabriel, SB, Kantoff, PW, Garraway, LA, Rosenberg, JE |
Journal | Cancer Discov |
Volume | 4 |
Issue | 5 |
Pages | 546-53 |
Date Published | 2014 May |
ISSN | 2159-8290 |
Keywords | Aged, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Transitional Cell, Drug Administration Schedule, Everolimus, Female, High-Throughput Nucleotide Sequencing, Humans, Lymphatic Metastasis, Male, Middle Aged, Mutation, Precision Medicine, Pyrimidines, Radionuclide Imaging, Sequence Analysis, DNA, Sulfonamides, TOR Serine-Threonine Kinases, Urinary Bladder Neoplasms |
Abstract | Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR. |
URL | http://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24625776 |
DOI | 10.1158/2159-8290.CD-13-0353 |
Pubmed | |
Alternate Journal | Cancer Discov |
PubMed ID | 24625776 |
PubMed Central ID | PMC4122326 |
Grant List | U54 HG003067 / HG / NHGRI NIH HHS / United States P30 CA014051 / CA / NCI NIH HHS / United States T32 GM007753 / GM / NIGMS NIH HHS / United States T32 CA009172 / CA / NCI NIH HHS / United States 5U54HG003067-11 / HG / NHGRI NIH HHS / United States T32GM007753 / GM / NIGMS NIH HHS / United States P50 CA127003 / CA / NCI NIH HHS / United States |
Cancer Discov DOI:10.1158/2159-8290.CD-13-0353
Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.
Recent Broad Publications
News at the broad
News / 03.8.18
News / 04.19.18