mTORC1 Inhibition Is an Effective Treatment for Sporadic Renal Angiomyolipoma.

Introduction: Renal angiomyolipoma (AML) is the most common benign renal tumor. Despite a generally benign histology, AML can result in significant morbidity, from intra-abdominal hemorrhage and reduction in kidney function. While classically associated with the autosomal dominant disorder tuberous sclerosis complex (TSC) or with pulmonary lymphangioleiomyomatosis, most AMLs are sporadic. Mammalian target of rapamycin complex 1 (mTORC1) inhibitors (e.g., sirolimus) have been found to be effective in treating TSC- or lymphangioleiomyomatosis-associated AML, but to date it is unknown whether this strategy is effective for sporadic AML.

Methods: We stained tumor specimens of sporadic AML patients for pS6 to assess for mTORC1 activation.

Results: We detected strong activation of the mTORC1 pathway, similar to TSC-associated AML. Consequently, we showed that in vitro treatment with sirolimus results in significant growth inhibition of the human sporadic AML cell line SV7Tert, similar to the effect seen when the same treatment is applied to the human TSC-associated AML cell line UMBSV-tel. To further investigate the potential of mTORC1 inhibition for treating sporadic AML and assess whether the in vitro results are clinically relevant, we identified a patient with sporadic, bilateral AMLs, showing continued tumor growth following a partial nephrectomy. Using immunostaining, we detected strong mTORC1 activation in the patient's AML tissue. Accordingly, upon treatment with sirolimus, we noted significant reduction in the patient's tumor volume and resolution of hydronephrosis, without any significant side effects.

Conclusion: We propose mTORC1 inhibition as an effective treatment option for patients with sporadic AML, which represents the vast majority of patients with this tumor.