Defining the Magnetic Resonance Features of Renal Lesions and Their Response to Everolimus in a Transgenic Mouse Model of Tuberous Sclerosis Complex

Shubhangi Agarwal; Emilie Decavel-Bueff; Yung-Hua Wang; Hecong Qin; Romelyn Delos Santos; Michael J Evans; Renuka Sriram

doi:10.3389/fonc.2022.851192

Defining the Magnetic Resonance Features of Renal Lesions and Their Response to Everolimus in a Transgenic Mouse Model of Tuberous Sclerosis Complex

Front Oncol. 2022 Jun 23:12:851192. doi: 10.3389/fonc.2022.851192. eCollection 2022.

Authors

Shubhangi Agarwal¹, Emilie Decavel-Bueff¹, Yung-Hua Wang¹, Hecong Qin¹, Romelyn Delos Santos¹, Michael J Evans^{1

2

3}, Renuka Sriram¹

Affiliations

¹ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States.
² Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, United States.
³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.

Abstract

Tuberous sclerosis complex (TSC) is an inherited genetic disorder characterized by mutations in TSC1 or TSC2 class of tumor suppressers which impact several organs including the kidney. The renal manifestations are usually in the form of angiomyolipoma (AML, in 80% of the cases) and cystadenomas. mTOR inhibitors such as rapamycin and everolimus have shown efficacy in reducing the renal tumor burden. Early treatment prevents the progression of AML; however, the tumors regrow upon cessation of therapy implying a lifelong need for monitoring and management of this morbid disease. There is a critical need for development of imaging strategies to monitor response to therapy and progression of disease which will also facilitate development of newer targeted therapy. In this study we evaluated the potential of multiparametric ¹H magnetic resonance imaging (mpMRI) to monitor tumor response to therapy in a preclinical model of TSC, the transgenic mouse A/J Tsc2^+/- . We found 2-dimensional T₂-weighted sequence with 0.5 mm slice thickness to be optimal for detecting renal lesions as small as 0.016 mm³. Baseline characterization of lesions with MRI to assess physiological parameters such as cellularity and perfusion is critical for distinguishing between cystic and solid lesions. Everolimus treatment for three weeks maintained tumor growth at 36% from baseline, while control tumors displayed steady growth and were 70% larger than baseline at the end of therapy. Apparent diffusion coefficient, T₁ values and normalized T₂ intensity changes were also indictive of response to treatment. Our results indicate that standardization and implementation of improved MR imaging protocols will significantly enhance the utility of mpMRI in determining the severity and composition of renal lesions for better treatment planning.

Keywords: AML; MRI; TSC; everolimus; kidney; mTOR; mp-MRI.