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New Treatment Alleviates Kidney Disease in Mice

Study suggests new potential therapy for polycystic kidney disease, according to scientists at Fox Chase

PHILADELPHIA, PA (July 15, 2013)—Results from the Fox Chase study could eventually lead to the first treatment for autosomal dominant polycystic kidney disease (ADPKD)—a life-threatening and debilitating condition, and the most common inherited kidney disease.  A new compound reduces the symptoms of ADPKD in a mouse model, according to research from Fox Chase Cancer Center that will appear in the July 15, 2013 issue of the Proceedings of the National Academy of Sciences.

ADPKD affects between one in 400-1,000 people, making it one of the most commonly inherited life-threatening diseases. Along with cysts, ADPKD can cause the kidneys to swell to the point where they become visible to others, and patients experience abdominal or flank pain. Other complications include blood in the urine and infections of the cysts.
Half of patients develop kidney failure, typically around their fifth or sixth decade, requiring a transplant or dialysis for the rest of their lives. Many also are at increased risk of additional problems, such as high blood pressure, cardiac disease or brain vessel abnormalities.

After administering a new experimental compound once weekly for 10 weeks to mice bred to develop ADPKD, the researchers saw fewer signs of disease, including the tell-tale kidney cysts and enlarged kidneys.  In mice with previously established ADPKD, the cysts progressed more slowly during the treatment.  Importantly, kidney function also appeared to improve.

"We were very excited about these results," said study author Tamina Seeger-Nukpezah, MD, postdoctoral associate in the lab of Erica A. Golemis, PhD, Deputy Chief Scientific Officer and vice president at Fox Chase.

With respect to side effects, their biggest concern was weight loss, since the compound may cause diarrhea. "Thankfully, we didn't see any significant changes in body weight," said Seeger-Nukpezah.

“Ultimately, the therapy would work best if targeted to patients who were most likely to develop kidney failure,” she added. "We need to find biomarkers that signal which patients have a form of the disease that is quickly progressive, since they will benefit most from the compound."

The compound, known only as STA-2842, blocks the heat shock protein 90 (HSP90), a chaperone protein which helps fold and stabilize other proteins involved in ADPKD. Previous research has attacked some of those proteins individually, says Seeger-Nukpezah, "but by targeting HSP90, STA-2842 simultaneously affects many different proteins driving the disease."

Seeger-Nukpezah and her colleagues began studying STA-2842 in collaboration with Synta Pharmaceuticals, which developed the compound. Although STA-2842 is in the early stages of investigation it is closely related to Synta’s lead HSP90 inhibitor, ganetespib, currently in Phase 3 clinical trials for the treatment of advanced lung cancer and in other earlier stage trials for the treatment of other malignancies.  

“We had hypothesized that the same compound might target both cancer and ADPKD since many proteins affected by HSP90 appear to play a key role in both diseases, which have some common characteristics like uncontrolled cell proliferation, said Seeger-Nukpezah.  “The study offers an important example of how drugs developed for one type of condition - cancer - can sometimes provide benefits for other diseases.”

“The next step is to continue to test STA-2842 in different animal models of ADPKD,” said Seeger-Nukpezah. "If patients have a fast progressive form of ADPKD that will likely progress to renal failure, weekly or even every other week therapy that could slow down the disease and ease their symptoms would offer a big advantage."

Seeger-Nukpezah's co-authors include Brian L. Egleston, Anna S. Nikonova, Tatiana Kent, Kathy Q. Cai, Harvey H. Hensley, Ilya G. Serebriiskii, and Erica A. Golemis at Fox Chase, and David A. Proia, Weiwen Ying, and Dinesh Chimmanamada at Synta Pharmaceuticals, in Lexington, MA.

Fox Chase Cancer Center, part of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence four consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach.  For more information, call 1-888-FOX CHASE or (1-888-369-2427).

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