# Therapeutic targeting for translocation renal cell carcinoma

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2024 · $368,288

## Abstract

SUMMARY
Translocation Renal Cell Carcinoma (tRCC) represents a rare subtype of kidney cancer associated with
aggressive behavior and poor clinical outcome. The prevalence of this disease is high in pediatric kidney
cancer, representing 20-40% of total cases of RCC. Noteworthy, the true incidence of this disease in adults
is likely underestimated, as a significant number of patients undergoes histological misclassification. TRCC is
characterized by gene fusions resulting from chromosomal rearrangement involving TFE3 (Xp11.2) locus or
TFEB (6p21 locus), with various partner genes. Despite the identification of multiple TFE3 gene fusions in
tRCC (i.e. SFPQ-TFE3, NONO-TFE3, and PRCC-TFE3) there are no effective targeted therapies for patients
with tRCC. In preliminary results supported by the DOD (W81XWH1810586), our group has generated SFPQ-
TFE3, NONO-TFE3, and PRCC-TFE3 TFE3-Os and established their oncogenic potential. Knocking down
TFE3-wild type or full length (TFE3-wt) inhibited the proliferation of tRCC. By using Fluorescence Resonance
Energy Transfer (FRET) microscopy imaging our data suggest that TFE3-Os dimerize TFE3-wt and screened
compounds have anti-proliferative effect by inhibiting this protein-protein interaction. Thus, this proposal aims
to identify small molecules that selectively bind the leucine zipper domain and disrupt the TFE3-Os/TFE3
interaction. Our central hypothesis is that TFE3 chimeric proteins (TFE3-Os) play a key biological role in
translocation renal cell carcinoma (tRCC) and represent a rational target for therapeutic interventions. Our
hypothesis is that inhibiting the protein-protein homo and/or hetero dimerization of TFE3-Os/TFE3-wt may
offer a novel therapeutic opportunity. Our central hypothesis aims to accomplish the objectives of this
application by pursuing the following specific aims: Aim 1: To optimize tool compounds and to identify new
small molecule inhibitors targeting TFE3-O dimerization. Aim 2: To test the biological and antitumor effects
of new small molecule inhibitors targeting TFE3-O dimerization. Aim 1 proposes to optimize lead
compound recently identified in our lab, terfernadine and its metabolite fexofenadine. It will also screen for
novel compounds targeting TFE3 dimers with a customized cell-based antiproliferation assay that
simultaneously monitors TFE3 dimerization status through FRET. Validated hit molecules comprising
synthetically tractable scaffolds will be subject to medicinal chemistry optimization for structure-activity
relationship, lipophilicity, oral bioavailability and other essential properties. To accelerate the generation of
compounds for biological testing, our aim is to employ computer-aided docking of lead compounds with
relevant human TFE3 homology models for focused rational drug design. Aim 2 will utilize our established in
vitro models to determine the antitumor effect of the optimized tool compounds identified in Aim 1 which
disrupt TFE3-Os protein-protein interaction....

## Key facts

- **NIH application ID:** 10944705
- **Project number:** 1R01CA292851-01
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Roberto Pili
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $368,288
- **Award type:** 1
- **Project period:** 2024-07-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944705

## Citation

> US National Institutes of Health, RePORTER application 10944705, Therapeutic targeting for translocation renal cell carcinoma (1R01CA292851-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10944705. Licensed CC0.

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