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.
Publication types
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Case Reports
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Clinical Trial, Phase I
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Carcinoma, Transitional Cell / drug therapy*
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Carcinoma, Transitional Cell / genetics
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Drug Administration Schedule
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Everolimus / administration & dosage*
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Everolimus / pharmacokinetics
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Everolimus / therapeutic use
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Female
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High-Throughput Nucleotide Sequencing
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Humans
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Indazoles
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Lymphatic Metastasis / diagnostic imaging
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Lymphatic Metastasis / genetics
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Male
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Middle Aged
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Mutation
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Precision Medicine
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Pyrimidines / administration & dosage*
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Pyrimidines / pharmacokinetics
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Pyrimidines / therapeutic use
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Radionuclide Imaging
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Sequence Analysis, DNA
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Sulfonamides / administration & dosage*
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Sulfonamides / pharmacokinetics
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Sulfonamides / therapeutic use
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / chemistry
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TOR Serine-Threonine Kinases / genetics*
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Urinary Bladder Neoplasms / drug therapy*
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Urinary Bladder Neoplasms / genetics
Substances
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Antineoplastic Agents
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Indazoles
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Pyrimidines
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Sulfonamides
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pazopanib
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Everolimus
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MTOR protein, human
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TOR Serine-Threonine Kinases