Study suggests enzyme safely starves cancer cells

Dr. John DiGiovanniA University of Texas at Austin research team that includes Dr. John DiGiovanni, professor of pharmacology and toxicology, has engineered an enzyme that safely treats prostate and breast cancer in animals, and also lengthens the lifespan of models that develop chronic lymphocytic leukemia. The new treatment and results from preclinical trials are described in a paper published recently in Nature Medicine.

Many cancers depend on the non-essential amino acid cysteine to grow, survive, and even resist many chemotherapeutics. George Georgiou, a professor of molecular biosciences and chemical engineering, and Everett Stone, a research assistant professor in molecular biosciences, led a team that was able to capitalize upon these observations by engineering a human enzyme to systemically degrade cysteine.  The two researchers partnered with labs directed by DiGiovanni in pharmacy and Peng Huang of the UT MD Anderson Cancer Center to  demonstrate that injection of their cysteine-degrading enzyme into animals leads to the elimination of cysteine in blood and thus deprives the tumor cells of what it needs to grow.

“With this treatment approach, cancers build up toxic molecules of their own making because we took away their ability to make an antioxidant that is really important to them—but not necessarily important to a normal cell,” Stone says. “A very important component of our result is that there are no apparent side effects.”

Cysteine is considered a non-essential amino acid in healthy cells because it is produced by most tissues and does not have to be taken up in the diet. It plays a central role in the defense of cells against oxidation. Numerous tumors are known to be oxidatively stressed, in part because of their fast growth; for this reason, they require cysteine, which they take up from blood.

“Cancer cells are often very stressed and toxic to themselves because of abnormal metabolism,” says Stone. “With the enzyme that we engineered, we are pushing them over the edge by increasing oxidative stress to levels that they cannot recover from. This cancer-selective starvation gives us a new way to target cancer in addition to conventional approaches such as surgery, radiation or chemotherapy.”

The results of the preclinical trials showed that using the engineered enzyme to selectively eliminate cysteine had no adverse effects on healthy cells yet effectively impacted a variety of cancer types, inhibiting their growth and survival.

The new product is being developed under the trade name AEB3103 by Aeglea Biotherapeutics, Inc, a biotechnology company cofounded by Georgiou and Stone.

“Preclinical findings showed that AEB3103 had a potent anti-tumor effect in multiple solid tumor models, including prostate and breast cancer, and it was well tolerated for more than five months,” says Georgiou. “This suggests that AEB3103 could be a safe and effective alternative to experimental drugs targeting oxidative stress that are currently under clinical evaluation.”

“This is an excellent example of how interdisciplinary, collaborative research can lead to more rapid development of novel therapeutic strategies in the fight against cancer,” says DiGiovanni.

Additional authors were Shira Cramer, Achinto Saha, Surendar Tadi, Stefano Tiziani, Wupeng Yan, Kendra Triplett, Candice Lamb and Yan Jessie Zhang all of UT Austin; Susan Alters and Scott Rowlinson of Aeglea Biotherapeutics; and Michael Keating and Jinyun Liu of MD Anderson Cancer Center.

The research was funded by the National Cancer Institute and Aeglea Biotherapeutics Inc.

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