Trainee Spotlight: Anna Kiseleva
Unlike some lucky people who know what career path to choose, I became a scientist almost by accident. Until the very last year at high school, I was attracted by logic and deduction and considered a future in studying and practicing law. That was until I met a biology professor who convinced me that the same principles that attracted me to the law could be used to investigate the fundamentals of biological processes. This experience inspired me to enroll in a molecular biology program at Kazan Federal University in Russia. Upon graduation in 2014, I extended my studies at Kazan and joined a biochemistry PhD program. During my graduate studies, I got an opportunity to work in Dr. Elena Pugacheva’s group at West Virginia University where, besides studying the molecular mechanisms of cancer progression, I developed a strong interest in investigating the primary cilium – a single, antenna-like structure on the cell surface that plays an important role in intracellular signal transduction. To continue working with primary cilium, I joined Dr. Erica Golemis’ laboratory at Fox Chase Cancer Center in 2016 to study autosomal-dominant polycystic kidney disease (ADPKD) – one of the most common genetic human disorders associated with mutations of the genes encoding cilia proteins. In my current work, we discovered that we can significantly improve the ADPKD phenotype following direct manipulation of cilia stability. Although there is no cure for this ADPKD, and I hope that one day my research will help to make a real difference for the ADPKD patients. The results of this study laid a foundation for my PhD thesis which I have recently defended, and soon I am going to join Dr. Jonathan Epstein's group as a postdoctoral fellow at the University of Pennsylvania, where I am planning to continue studying molecular mechanisms of human genetic disorders.
My research is focused on primary cilium with the goal of identifying therapeutic strategies to treat cilia-associated human disorders. Cilia serve as communication hubs that undergo dynamic assembly and disassembly in a cell cycle dependent manner. Disruption of ciliary structure and function, due to mutations of ciliary genes, result in severe developmental disorders termed ciliopathies.
One of the most common ciliopathies that affects approximately 1 in 1000 individuals in western countries is autosomal dominant polycystic kidney disease (ADPKD). ADPKD is caused by mutations in the ciliary proteins polycystin-1 and polycystin-2, PKD1 or PKD2 respectively. In healthy cells, PKD1 and PKD2 function as an ion channel to transduce extracellular signals to regulate growth and survival. Loss of function mutations of PKD1 or PKD2 result in disruption of the ion channel and the uncontrolled proliferation of renal epithelial cells giving rise to renal cysts and interfere with normal kidney function.
To date, there is a desperate need for an effective ADPKD therapy. Recent studies have shown that disruption of PKD1 or PKD2-associated signaling transduction triggers a variety of alterations in activity of protein kinases, such as AURKA, EGFR, HER2, ERK, and many others. Surprisingly, these same kinases are also mis-regulated in transformed cells suggesting that the underlying signaling changes may be conserved between ADPKD and cancer. Therefore, we investigated whether anti-cancer drugs that target misregualted kinases might also be effective in treating ADPKD. Using this approach, we identified that several clinical anti-cancer compounds, including alisertib and ganetspib, not only brings the activity of certain kinases, such as Aurora A, PI3K and Erk, back to the normal, but also affect ciliary presence, promoting or inhibiting its’ resorption. Intriguingly, a compound promoting cilia disassembly, HSP90 inhibitor ganetespib, significantly improves the phenotype of ADPKD, proposing that a complete removal of cilia with mutated PKDs from cilia surface is beneficial to slow down the ADPKD. On the contrary, a compound stabilizing cilium, Aurora A inhibitor alisertib, showed the opposite effect, making ADPKD progression worse.
In the present work, we extended our previous studies by screening a library of 178 inhibitors and identified another 11 compounds that affect ciliary assembly or disassembly. In particular, we identified sunitinib, a drug widely used in the clinic to treat renal cell carcinoma. We found that sunitinib stimulates cilia disassembly, leading to a decrease of abnormal signaling levels in PKD mutants and reduction of renal cysts. Overall, the results of our studies contribute to a better understanding of mechanisms controlling the cilia-related human disorders and suggest that repurposing of established drugs may be a novel and effective strategy for the ADPKD therapy.