#2242 mTORi: edging closer to targeted therapy in tuberous sclerosis complex
Authors: Cara Anila , Iatrino Rossella , Porata Giulia , Cozzolino Mario Gennaro 
Published: May 2024

Abstract

Background and Aims
Tuberous sclerosis complex (TSC) is an autosomal dominant condition with an estimated incidence of 1 in 6000 births. TSC is caused mostly by mutations in either TSC1 or TSC2 genes, with 70–80% of cases resulting from sporadic mutations; however in 10-15% of cases no mutations are identified. A dysregulation of these genes that encode the hamartin and tuberin proteins, respectively, results in an aberrant signaling of the mammalian target of the rapamycin (mTOR) pathway and subsequent tumor growth. Indeed, the clinical features of TSC are characterized by the proliferation of different types of hamartomas in various organs, including brain, heart, skin, lungs, eyes, bone, kidneys and less frequently pancreas.
TSC is mainly diagnosed clinically according to diagnostic criteria with genetic testing performed in cases of diagnostic uncertainty or/and to support the clinic diagnosis.
Renal angiomyolipomas (AMLs), observed in more than 80% of patients with TSC, are benign, mostly bilateral tumors, composed of immature smooth muscle cells, abnormal blood vessels and fat cells in variable portions. Their size and the prevalence of their vascular component are directly associated with risk of acute bleeding that in 25% of cases may require embolization or nephrectomy. As a consequence, renal complications are the leading cause of death in adult TSC patients and AML-related surgery is performed in a high percentage of these patients.
In the last decade, mTOR inhibitor (mTOR-i) therapy has demonstrated to be a potential alternative to embolization and nephrectomy for managing TSC-AML.
The aim of this study was to evaluate over time, potential changes in the relative tissue composition of renal AMLs and their overall size following the initiation of mTOR-i therapy based on MRI measurements.

Method
From August 2011 to May 2023, 86 potentially eligible adult TSC patients with AML, across a great part of Italy were referred for assessment and monitoring at our center. 14 of these patients were eligible for mTOR-i therapy. An ethics committee approved its use as a compassionate therapy as mTOR-is are not approved as a conventional therapy for renal AMLs in Italy. These patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a regular follow-up with MRI scan every 6-9 months after initiation of therapy. Dose titration was guided by trough levels, side effects and lesion radiological responsiveness on MRI.

Results
No AML bleeding events were documented during the study. None of the 14 patients on treatment discontinued therapy. Overall, 5 of them (35.7%) required dose adjustments during the course of treatment due to adverse events (40%), sub-optimal trough levels (40%) or minimal radiological response (20%). Radiologic assessment with MRI confirmed a halted growth trend in all treatment-naive cases (100%) and in 64% of them, a regression in AML volume and a reduction of their vascular component within the first year of treatment.

Conclusion
Our experience confirmed results that emerged from different clinical studies evaluating mTOR inhibition in TSC patients conducted in the last decade. For renal angiomyolipoma, mTOR-i treatment, carefully monitored, fundamentally changed the approach from preventive embolization or even partial nephrectomy to pharmacological treatment; drastically limiting the number of urgent interventional procedures that TSC patients often might undergo.
In conclusion, mTOR-i therapy represents a valid and important therapeutic strategy to arrest the growth or regress of renal AMLs.