# Interaction of protein-targeted therapeutics and ciliary dynamics

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $420,750

## Abstract

Project Summary
 Autosomal polycystic kidney disease (ADPKD) patients typically experience hypertension and other
cardiovascular symptoms commencing in their 20s, and develop an increasing burden of fluid-filled renal cysts
in middle age, culminating typically in end stage renal disease (ESRD) and the need for dialysis or kidney
replacement in later life. The goal of this application is to gain mechanistic insights that will improve clinical
outcomes in patients with ADPKD. ADPKD arises from mutations reducing or eliminating function of the PKD1
or PKD2 genes, which encode polycystins: large transmembrane proteins that heterodimerize at cell cilia, and
influence activity of multiple downstream signaling proteins. Pre-clinical experiments and clinical trials have
shown that targeting polycystin-dependent signaling defects can slow disease progression. Our preliminary
studies in mouse models have shown that inhibition of the protein chaperone HSP90 is extremely beneficial in
reducing ADPKD symptoms, while inhibition of Aurora-A (AURKA) is deleterious, and begun to define related
signaling mechanisms. Interestingly, recent reports indicate that severe manifestation of ADPKD depends in
part on the maintenance of intact cilia, while we have found that AURKA inhibition stabilizes cilia. This
suggests use of inhibitors of AURKA and proteins with similar activity may be harmful in ADPKD patients.
Conversely, our studies of HSP90, its protein clients, and polycystin-regulated signaling effectors indicate
these may act in part by contributing to ciliary resorption. This proposal will explore the mechanisms of action
of these drugs in the context of a ciliary model for ADPKD cystogenesis, testing the hypothesis that part of their
activity arises from control of ciliary dynamics, and perform preclinical tests intended to suggest improved
therapy for ADPKD. In this proposal, Aim 1 will use mouse models to evaluate the HSP90 inhibitor ganetespib
in combination with other promising therapies for efficacy in ADPKD versus in non-ADPKD cystic syndromes,
and will use recently developed multiplexed kinase inhibitor beads (MIBs) technology to profile the interaction
of ganetespib with ADPKD-specific signaling. Aim 2 will complement this aim, evaluating how ganetespib alone
and in therapeutic combinations influences ciliary dynamics and cilia-dependent signaling, in ADPKD versus
non-ADPKD renal cells and tissue. Finally, 35-40% of individuals with ADPKD will develop some form of
cancer in their lifetime, and many will be treated with systemic cancer therapies. Inhibitors of AURKA and
functionally related proteins are becoming common in cancer therapy. Aim 3 will use mouse models to test the
idea that AURKA inhibitors and other drugs predicted to stabilize cilia pose risks for patients with ADPKD.

## Key facts

- **NIH application ID:** 9927617
- **Project number:** 5R01DK108195-05
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** ERICA A. GOLEMIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,750
- **Award type:** 5
- **Project period:** 2016-08-29 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927617

## Citation

> US National Institutes of Health, RePORTER application 9927617, Interaction of protein-targeted therapeutics and ciliary dynamics (5R01DK108195-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9927617. Licensed CC0.

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