Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors

Wagner, A. J., Malinowska-Kolodziej, I., Morgan, J. A., Qin, W., Fletcher, C. D., Vena, N., Ligon, A. H., Antonescu, C. R., Ramaiya, N. H., Demetri, G. D., Kwiatkowski, D. J., Maki, R. G. (February 2010) Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol, 28 (5). pp. 835-40. ISSN 1527-7755 (Electronic)0732-183X (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/20048174
DOI: 10.1200/JCO.2009.25.2981

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.

Item Type: Paper
Uncontrolled Keywords: Administration, Oral Aged Antibiotics, Antineoplastic/administration & dosage/adverse effects/*therapeutic use Female Humans Immunohistochemistry In Situ Hybridization, Fluorescence Intracellular Signaling Peptides and Proteins/analysis/*antagonists & inhibitors Male Middle Aged Multiprotein Complexes Perivascular Epithelioid Cell Neoplasms/chemistry/*drug therapy/genetics/radiography/secondary Protein-Serine-Threonine Kinases/analysis/*antagonists & inhibitors Proteins Sirolimus/administration & dosage/adverse effects/*therapeutic use TOR Serine-Threonine Kinases Time Factors Tomography, X-Ray Computed Transcription Factors/analysis/*antagonists & inhibitors Treatment Outcome Tumor Suppressor Proteins/analysis/genetics United States
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > mTORC1
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 10 February 2010
Date Deposited: 21 Oct 2016 16:49
Last Modified: 21 Oct 2016 16:49
PMCID: PMC4810029
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33715

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