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Abstract: SA-PO026

Targeting BH3 Domains in iPSC-Derived Tuberous Sclerosis Kidney Organoids for the Development of Novel Therapies for Renal Angiomyolipoma

Session Information

  • Bioengineering
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bioengineering

  • 300 Bioengineering

Authors

  • Lemos, Dario R., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • López-Marfil, Marta, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Kuo, Ting-Chun, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Wang, Xichi, Brigham and Women's Hospital, Boston, Massachusetts, United States

Group or Team Name

  • Lemos Lab HMS
Background

Kidney organoids can recapitulate genetic kidney diseases allowing the identification of novel druggable targets. Among those diseases, kidney tumors known as renal angiomyolipomas (AMLs) occur in a majority of patients with Tuberous Sclerosis (TS). Rapamycin analogs with cytostatic and pro-apoptotic activity, are the main therapy for AML. Rapalogs partially shrink AMLs by inhibiting mTORC1 activity, but tumor size stabilizes over time, making life-long treatment necessary. Tumor re-growth is often observed after treatment is interrupted due to adverse effects. A lack of appropriate experimental models, has precluded the development of more effective therapies.

Methods

We have developed a kidney organoid model that recapitulates kidney AML in vitro and in vivo, using patient-derived TSC2−/− iPSCs. Orthotopic transplantation of AML organoids allowed us to identify previously unknown molecular mechanisms and to test the effect of candidate compounds with prospective anti-tumor activity in immunodeficient rodents.

Results

Consistent with the genetic mechanisms observed in TS patients, kidney organoids generated from iPSCs carrying bi-allelic inactivating mutations in the TSC2 gene (i.e. TSC2-/-) recapitulated key anatomical and molecular features of renal AML (Hernandez J. et al. Nat. Commun. 2021 Nov 11;12(1):6496). Transcriptional analysis of AML organoids against kidney AML transcriptomes further identified gene sets and major signaling mechanisms shared in common with kidney AML tumors. Among those mechanisms, we identified upregulation of anti-apoptotic members of the BCL-2 family of proteins as a putative mechanism of tumor resistance. Transplantation of TSC2-/- renal organoids into the kidneys of immunodeficient rats allowed us to investigate AML mechanisms in vivo for the first time. Using these novel tools, we have identified the BCL-2 inhibitor drug Venetoclax as a prospective novel therapy, inducing iPSC-derived AML cell death and AML organoid xenograft ablation in vivo.

Conclusion

Our TSC2-/- iPSC-derived AML organoid xenograft model allowed us to elucidate previously unknown tumor resistance mechanisms in TS-associated kidney AML, and to identify the BH3 mimetic molecule Venetoclax as an prospectively efficacious new therapy.

Funding

  • Private Foundation Support