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

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.

Fig 1.

Computed tomography images of perivascular epithelioid cell tumors (PEComas; left panels) at baseline and (right panels) after treatment with sirolimus. All images are chosen to show the maximal size of the lesions indicated by arrows; other lesions may be out of phase in the two studies. (A) Retroperitoneal PEComa before and after 1 year of treatment. (B) Renal PEComa before and after 9 months of treatment. (C, top) Metastatic uterine PEComa in lung before and after 6 weeks of treatment; some lesions are improved, whereas others remain stable. (C, bottom, left) Before and (right) 3 weeks after treatment with sorafenib.

Fig 2.

Perivascular epithelioid cell tumor (PEComa) histology and immunohistochemical stains. Formalin-fixed paraffin-embedded sections stained with (A) hematoxylin and eosin, (B) antiphospho-S6 antibody, and (C) anti-TSC2 antibody.

Fig 3.

Mulitplex ligation-dependent probe amplification (MLPA) and fluorescent in situ hybridization (FISH) assays of TSC1 and TSC2 in perivascular epithelioid cell tumor (PEComa) samples. Genomic DNA from (A-C) tumor or (D) peripheral blood assessed for copy number by mulitplex ligation-dependent probe amplification (MLPA). Signals were normalized to values from control tissues. (E) FISH using (green) TSC1-specific DNA probes, (red) chromosome 16 centromeric probes, and nuclei isolated from uterine PEComa tissue.

Fig A1.

Validation of anti-TSC2 antibody. TSC2-null TRI-102 cells and TSC2-expressing TRI-103 cells were grown on coverslips, were fixed, and were stained with anti-TSC2 antibody followed by horseradish peroxidase detection.