Tumor Cells’ Weird Appetites for Amino Acids Are Aeglea’s Targets

Xconomy Texas — 

Researchers are always looking for the Achilles’ heel of cancer—some weakness in tumor cells that can be attacked by drugs while leaving normal cells unharmed.

Austin, TX-based Aeglea BioTherapeutics is trying to exploit a vulnerability that might make it possible to starve certain cancers to death.

In some tumors, the cells can no longer make one of the building blocks of proteins, an amino acid called arginine. That’s usually no problem—the tumor can import arginine from the bloodstream and continue growing. But Aeglea is developing a drug designed to dry up the blood’s supply of arginine long enough to kill the cancer cells.

“The tumor’s getting a free lunch and it can’t survive without it,” says Aeglea CEO David Lowe.

By contrast, normal cells may be able to make the amino acid themselves or ride out the shortage.

Aeglea’s lead drug candidate is an engineered human enzyme that breaks up molecules of arginine, making the amino acid unavailable as a nutrient in the bloodstream. That enzyme, arginase (AERase), and two others acquired by Aeglea, were created in the lab of University of Texas at Austin professor George Georgiou. Georgiou and his collaborator Everett Stone are scientific founders of Aeglea, which was formed last year to develop the engineered enzymes as drugs.

Aeglea recently submitted a grant proposal to the Cancer Prevention and Research Institute of Texas (CPRIT), a $3 billion state fund that resumed operations in December after a suspension while state authorities investigated its methods of awarding grants. The possibility of winning CPRIT money was part of the draw that had led Aeglea to locate in Texas, Lowe says.

The chance of gaining non-dilutive capital also helped the company close a $12 million Series A fundraising round in December co-led by Lilly Ventures and Novartis Bioventures, he says. A maker of biologic drugs, KBI Biopharma, is providing manufacturing support as Aeglea’s strategic partner. The CPRIT money would also come in handy, Lowe says. But Aeglea will do fine even if it doesn’t win a grant, he says.

Aeglea CEO David Lowe

Aeglea CEO David Lowe

“CPRIT is icing on the cake for us,” Lowe says. “The company isn’t going away without it.”

Aeglea’s drug development program builds on scientific insights that go back decades. Researchers had noted that some tumors developed malfunctioning pathways for the creation of certain amino acids, making them dependent on outside supplies. One drug class that takes advantage of such a weakness began gaining approvals back in the mid-1990s. Those drugs attack a cancer cell type that needs to import the amino acid asparagine.

Enzymes called asparaginases, which break down asparagine, are now used in combination therapy regimens to treat acute lymphoblastic leukemia by depriving the cancer cells of the molecule. Drugs currently sold in the United States include pegaspargase (Oncaspar) from Sigma-Tau Pharmaceuticals of Gaithersburg, MD, and Dublin, Ireland-based Jazz Pharmaceuticals’ asparaginase Erwinia chrysanthemi (Erwinaze.) Although such asparaginase drugs, derived from microbial enzymes, have been used for 20 years, patients must sometimes switch from one to the other if they develop hypersensitivity to one of the drugs. For example, one of the most common side effects of Oncaspar is allergic reactions.

Aeglea is trying to starve tumors that are dependent on a different amino acid, arginine. In these tumors, the gene for an enzyme needed to produce arginine, argininosuccinate synthetase, has lost its activity. The inability to make arginine is seen in a wide range of cancer types, including melanoma and liver, kidney, and prostate cancer, according to a 2012 paper by Georgiou and Stone.

The company hopes to avoid the kind of immune system reactions seen with the microbe-derived asparaginase by making its drug from human enzymes.

Lowe says Aeglea is now learning from the findings of a potential competitor, San Diego, CA-based Polaris Pharmaceuticals, which is also developing an enzyme designed to deplete the blood supply of arginine. The lead drug candidate from Polaris, ADI-PEG 20, is in a late stage trial for the most common form of liver cancer, hepatocellular carcinoma.

“That enzyme is really paving the way for us,” Lowe says. “But … Next Page »

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