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.

Recurrence of retroperitoneal localized perivascular epithelioid cell tumor two years after initial diagnosis: case report

“…At the end of the first year, the tumor had regressed almost completely, while at the end of the 16 th month they reported that both the treatment and the response remained the same. 3 In our case, we achieved minimal regression with everolimus.…”

“…The majority of these tumors are benign with a good prognosis. [1][2][3] In this report, we present a patient who was operated to treat a retroperitoneal mass that was diagnosed as a benign PEComa, and who developed abdominal recurrence and pulmonary lymphangioleiomyomatosis.…”

Treatment of Advanced Malignant Uterine Perivascular Epithelioid Cell Tumor with mTOR Inhibitors: Single-institution Experience and Review of the Literature

“…Current chemotherapy strategies have not been successful in advanced disease, and recent focus has been drawn to targeting the mTOR pathway, which is up-regulated in PEComas. There are several reports in the medical literature describing a total of seven patients with uterine or 'gynecologic' PEComas who received treatment with mTOR inhibitors, with varying degrees of success [50%-100% response rates (8)(9)(10)(11)(12)]. Given this robust response and the plausible theoretical basis behind it, we proceeded to manage three cases of advanced PEComas with mTOR inhibitors.…”

“…Tumors in the PEComa group are rare and usually sporadic. However, they can be associated with tuberous-sclerosis complex (TSC), and both sporadic and TSC-related cases demonstrate similar genetic alterations of the TSC1 or TSC2 locus (8,9). The TSC1 and TSC2 gene products form a complex which negatively regulates mammalian target of rapamycin complex 1 (mTORC1) and therefore PEComas as well as LAM and AML, have constitutive activation of the mTOR pathway.…”

Recently characterized soft tissue tumors that bring biologic insight

“…23 Recent data indicate that this is of clinical relevance as drugs targeting the mTOR pathway (such as rapamycin, also known as sirolimus) may be effective in palliating patients with metastatic PEComa. 24,25 Spindle cell liposarcoma Spindle cell liposarcoma is a somewhat controversial entity, first described more than 15 years ago, which, until recently, had been thought to represent an unusual variant of atypical lipomatous tumor. 26,27 These lesions, which are not rare in our experience, occur mostly in adults and show a striking predilection to arise in somatic soft tissue but arise only exceptionally at visceral locations (such as retroperitoneum).…”