# Elucidation of Tumor Resistance Mechanisms in Tuberous Sclerosis Complex-Associated Renal Angiomyolipoma for the Design of Novel Nanotherapies

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $364,979

## Abstract

Summary
A majority of patients with Tuberous Sclerosis Complex (TSC) develop benign kidney tumors known as renal
angiomyolipoma (AML) that can cause renal insufficiency and spontaneous life-threatening hemorrhages. The
main therapy for AML is everolimus, a rapamycin analog inhibitor of the kinase mTOR with cytostatic activity that
only partially reduces tumor size. AMLs become stable over time, and tumor re-growth is often occurs after
treatment is interrupted due to side effects. Therefore, there is an urgent need to elucidate mechanisms of
tumor resistance for the development of more efficacious therapies.
 Efforts to recapitulate AML experimentally have failed for the past 20+ years, precluding the study of AML
biology. To address this problem, we have used genetically engineered patient-derived induced pluripotent stem
cells (iPSCs) to generate AML organoids. Organoids generated from iPSCs carrying biallelic inactivating
mutations in the TSC2 locus (i.e. TSC2-/-) faithfully recapitulated key anatomical and molecular features of human
kidney AML (reported in Hernandez JOR et al. Nat Commun. 2021 Nov 11;12(1):6496). Some of those features
included the presence of myomelanocytic AML-like cells co-expressing smooth muscle and melanocyte markers,
and the transcriptional activation of signaling pathways shared with kidney AML. Transplantation of TSC2-/- AML
organoids into the kidneys of immunodeficient rodents resulted in fully vascularized human AML xenografts for
mechanistic studies and for drug testing testing in vivo. Using these novel tools we identified potential
mechanisms of tumor resistance driven by p21CIP1 and by BCL-2 apoptosis modulators, preventing AML cell
death induced by rapalogs. Our in vivo experiments also indicated that drug delivery via nanocarriers may
increase the efficacy of anti-tumor therapy while reducing undesired effects in other tissues. The objective of this
proposal is to elucidate anti-apoptotic mechanisms driven by p21CIP1 and BCL-2 proteins for the development of
novel anti-tumor therapies combining BCL-2 protein inhibitor drugs and rapalogs, that can be co-delivered using
tissue-targeting nanoparticles. Our long-term goal is to design new therapies for AML with increased efficacy
and specificity. The central hypothesis is that antiapoptotic mechanisms driven by p21CIP1 and BCL-2
apoptosis inhibitors sustain AML cell survival promoting tumor resistance to rapalog therapy. Our three
aims are: Aim 1: To investigate anti-apoptotic mechanisms of tumor resistance driven by p21CIP1 in renal AML;
Aim 2: To elucidate the role of IGFBP2 in stabilizing p21CIP1 promoting AML cell survival; Aim 3: To study the
contribution of BCL-2 proteins to AML cell survival through pharmacologic blockage of BH3 domain interaction.
Collectively, these studies will provide much needed insight into the mechanisms of AML and will assess the
efficacy of BCL-2 inhibitor therapy alone or in combination with rapalogs in AML-targeting nanoparticl...

## Key facts

- **NIH application ID:** 10850649
- **Project number:** 5R01CA269583-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Dario Lemos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $364,979
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850649

## Citation

> US National Institutes of Health, RePORTER application 10850649, Elucidation of Tumor Resistance Mechanisms in Tuberous Sclerosis Complex-Associated Renal Angiomyolipoma for the Design of Novel Nanotherapies (5R01CA269583-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10850649. Licensed CC0.

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