Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib
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 exqu...
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2015
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| Online Access: | http://hdl.handle.net/1721.1/96675 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826200871135870976 |
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| author | Wagle, N. Grabiner, Brian C. Van Allen, E. M. Hodis, Eran Jacobus, S. Supko, J. G. Stewart, M. Choueiri, T. K. Gandhi, L. Cleary, J. M. Elfiky, A. A. Taplin, M. E. Stack, E. C. Signoretti, S. Loda, Massimo Shapiro, G. I. Gabriel, Stacey B. Kantoff, Philip W. Garraway, Levi A. Rosenberg, J. E. Sabatini, David Lander, Eric Steven |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Wagle, N. Grabiner, Brian C. Van Allen, E. M. Hodis, Eran Jacobus, S. Supko, J. G. Stewart, M. Choueiri, T. K. Gandhi, L. Cleary, J. M. Elfiky, A. A. Taplin, M. E. Stack, E. C. Signoretti, S. Loda, Massimo Shapiro, G. I. Gabriel, Stacey B. Kantoff, Philip W. Garraway, Levi A. Rosenberg, J. E. Sabatini, David Lander, Eric Steven |
| author_sort | Wagle, N. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:43:02Z |
| format | Article |
| id | mit-1721.1/96675 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:43:02Z |
| publishDate | 2015 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/966752022-09-27T21:24:44Z Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib Wagle, N. Grabiner, Brian C. Van Allen, E. M. Hodis, Eran Jacobus, S. Supko, J. G. Stewart, M. Choueiri, T. K. Gandhi, L. Cleary, J. M. Elfiky, A. A. Taplin, M. E. Stack, E. C. Signoretti, S. Loda, Massimo Shapiro, G. I. Gabriel, Stacey B. Kantoff, Philip W. Garraway, Levi A. Rosenberg, J. E. Sabatini, David Lander, Eric Steven Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Sabatini, David M. Lander, Eric S. 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. National Human Genome Research Institute (U.S.) (5U54HG003067-11) 2015-04-17T17:39:44Z 2015-04-17T17:39:44Z 2014-03 2013-12 Article http://purl.org/eprint/type/JournalArticle 2159-8274 2159-8290 http://hdl.handle.net/1721.1/96675 Wagle, N., B. C. Grabiner, E. M. Van Allen, E. Hodis, S. Jacobus, J. G. Supko, M. Stewart, et al. “Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib.” Cancer Discovery 4, no. 5 (March 13, 2014): 546–553. https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1158/2159-8290.cd-13-0353 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research PMC |
| spellingShingle | Wagle, N. Grabiner, Brian C. Van Allen, E. M. Hodis, Eran Jacobus, S. Supko, J. G. Stewart, M. Choueiri, T. K. Gandhi, L. Cleary, J. M. Elfiky, A. A. Taplin, M. E. Stack, E. C. Signoretti, S. Loda, Massimo Shapiro, G. I. Gabriel, Stacey B. Kantoff, Philip W. Garraway, Levi A. Rosenberg, J. E. Sabatini, David Lander, Eric Steven Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib |
| title | Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib |
| title_full | Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib |
| title_fullStr | Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib |
| title_full_unstemmed | Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib |
| title_short | Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib |
| title_sort | activating mtor mutations in a patient with an extraordinary response on a phase i trial of everolimus and pazopanib |
| url | http://hdl.handle.net/1721.1/96675 https://orcid.org/0000-0002-1446-7256 |
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