Abstract
PURPOSE Perivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus. PATIENTS AND METHODS Patients with advanced PEComa were treated with sirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined by computed tomography scans obtained at the clinical discretion of the treating physicians. Tumors were assessed for immunohistochemical evidence of mTORC1 activation and genetic evidence of alterations in TSC1 and TSC2. Results Radiographic responses to sirolimus were observed in all patients. PEComas demonstrated loss of TSC2 protein expression and evidence of baseline mTORC1 activation. Homozygous loss of TSC1 was identified in one PEComa. CONCLUSION Inhibition of mTORC1, pathologically activated by loss of the TSC1/TSC2 tumor suppressor complex, is a rational mechanistic target for therapy in PEComas. The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex.
Publication types
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Case Reports
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Multicenter Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Aged
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Antibiotics, Antineoplastic / administration & dosage
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Antibiotics, Antineoplastic / adverse effects
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Antibiotics, Antineoplastic / therapeutic use*
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Female
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Humans
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Immunohistochemistry
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In Situ Hybridization, Fluorescence
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Intracellular Signaling Peptides and Proteins / analysis
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Male
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Mechanistic Target of Rapamycin Complex 1
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Middle Aged
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Multiprotein Complexes
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Perivascular Epithelioid Cell Neoplasms / chemistry
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Perivascular Epithelioid Cell Neoplasms / diagnostic imaging
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Perivascular Epithelioid Cell Neoplasms / drug therapy*
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Perivascular Epithelioid Cell Neoplasms / genetics
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Perivascular Epithelioid Cell Neoplasms / secondary
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Protein Serine-Threonine Kinases / analysis
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Proteins
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Sirolimus / administration & dosage
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Sirolimus / adverse effects
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Sirolimus / therapeutic use*
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TOR Serine-Threonine Kinases
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Time Factors
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Tomography, X-Ray Computed
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Transcription Factors / analysis
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Transcription Factors / antagonists & inhibitors*
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Treatment Outcome
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / analysis
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Tumor Suppressor Proteins / genetics
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United States
Substances
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Antibiotics, Antineoplastic
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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Proteins
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TSC1 protein, human
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TSC2 protein, human
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Transcription Factors
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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MTOR protein, human
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Sirolimus