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.

Public Health Relevance

ADPKD poses a substantial public health burden, affecting approximately 1:500 individuals (~600,000 individuals in the United States alone). At present, while some clinical trials have shown promise in limiting the rate of disease progression, there is still no cure, strongly motivating efforts to better understand and target critical disease mechanisms. In this application, the exploration of the signaling interactions between ADPKD- associated mutations, control of ciliary dynamics, and clinical agents with potential efficacy in ADPKD, is intended to optimize therapeutic options for patients with ADPKD, leading to a better quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK108195-01A1
Application #
9185461
Study Section
Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
Program Officer
Rasooly, Rebekah S
Project Start
2016-08-29
Project End
2021-04-30
Budget Start
2016-08-29
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
$401,625
Indirect Cost
$176,625
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Golemis, Erica A; Scheet, Paul; Beck, Tim N et al. (2018) Molecular mechanisms of the preventable causes of cancer in the United States. Genes Dev 32:868-902
Nikonova, Anna S; Deneka, Alexander Y; Kiseleva, Anna A et al. (2018) Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD). FASEB J 32:2735-2746
Korobeynikov, Vladislav; Deneka, Alexander Y; Golemis, Erica A (2017) Mechanisms for nonmitotic activation of Aurora-A at cilia. Biochem Soc Trans 45:37-49