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

2/19/14Follow @tanseyverse

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 it does have its challenges.”

What Lowe sees as a challenge for Polaris is that its drug, ADI-PEG 20, is an enzyme, arginine deiminase, derived from a microbe, as in the asparaginase drugs. Polaris has chemically modified the enzyme, using a common strategy to minimize immune system reactions. But Lowe speculates that Aeglea’s lead drug candidate, AERase, may turn out to be better tolerated than the Polaris drug. (They also say they’ve tinkered with their human enzyme to improve its performance, engineering natural arginase enzyme to break down arginine more efficiently, and to last longer in the bloodstream.) Comparisons will have to wait, however, until Aeglea has conducted clinical trials of AERase.

In addition to the arginine-crunching enzyme developed in Georgiou’s lab, Aeglea has acquired the rights to two other enzymes developed by the team to attack tumor cells with abnormal appetites. The first, AECase, degrades the related amino acids cystine and cysteine. Aeglea sees this as a drug candidate for certain solid tumors and hematological malignancies such as leukemia that are dependent on those amino acids, Lowe says. The second enzyme, AEMase, breaks down methionine, which is gobbled up avidly by certain tumor cells. Aeglea plans more work to identify the cancer types that would be most vulnerable to methionine starvation, Lowe says.

Such enzyme therapies could have advantages compared to antibodies, a growing class of biologic drugs for cancer, Lowe says. Antibody drugs must penetrate into the tumor to bind directly to molecules that promote cancerous growth, he says. Getting the molecules into tumor cells can be tricky in diseases such as brain cancer and pancreatic cancer. By contrast, enzymes that split apart amino acids only need to spread through the bloodstream, Lowe says.

“We manipulate the macro-environment of the tumor to achieve nutritional deprivation of what is otherwise essential to (tumor) survival,” Lowe says.

To lay the scientific groundwork for its potential therapies, Aeglea will be studying further which tumor cell types lose their ability to make arginine, and how, Lowe says. This alone could have value as a diagnostic tool to identify tumors that would be vulnerable to arginine starvation drugs, he says.

Understanding what silenced the gene for the arginine-manufacturing enzyme could also reveal whether that process could be easily reversed. For example, could the tumor cell recover its ability to make arginine, and therefore become resistant to Aeglea’s arginine-depleting enzyme?

Lowe says tumor cells could lose their ability to make arginine in one of three ways. First, the gene that codes for the arginine-manufacturing enzyme may have been deleted, in whole or in part. Second, that gene may have been chemically modified, through natural processes known as epigenetics, to silence its activity. And third, the gene may be inactive because it no longer can send out messenger molecules (mRNA) that are needed to produce the enzyme.

Some of these gene-silencing mechanisms may be less durable, and more reversible, than others.

“It could vary from tumor type to tumor type,” Lowe says

Work on the arginine-depleting enzyme is the company’s top priority. Aeglea’s goal is to take each of its enzymes through early stage clinical trials and then sell them to larger drug companies, or partner up on their development, Lowe says. Each of its three enzymes is held in a separate subsidiary of an Aeglea holding company to allow for flexibility in its transactions, he says.

By compiling its grant proposal for CPRIT, the three-employee company got a jumpstart on the process of preparing to seek FDA approval for the first phase of clinical trials on its arginase enzyme, AERase, Lowe says. The company isn’t disclosing how much money it sought from CPRIT, but Lowe says the amount would fund Phase I testing and preparations for a Phase II trial. Aeglea expects to hear in March whether it passed CPRIT’s first cut and will be invited to make a presentation to the state cancer funding agency in April, he says.

Aeglea hopes that its arginine-destroying enzyme drug will kill enough tumor cells to help give patients a significant increase in survival time. But that may depend on the answer to another question about tumors that are vulnerable to amino acid starvation. Because genes mutate and consequently vary among the fast-growing cells within a tumor, do some tumor cells retain their ability to make arginine even if many others cannot? And once the arginine-dependent tumor cells have died for lack of the amino acid during AERase treatment, how long would it take for the arginine-making cells to grow in numbers and worsen the disease? The answer could be years, which might extend the lives of patients. But it could be a matter of weeks, Lowe says.

Tumor cell populations often pull such end-runs around individual drug therapies—which is why cancer drugs often work well in combinations that hit the disease hard from multiple directions, Lowe says.

Aeglea expects that AERase will also work best as part of a drug combination that could defeat the flexibility of tumor cells with a “one-two punch,” Lowe says.

“That’s what it’s going to take,” he says.

Bernadette Tansey is a freelance journalist based in Berkeley, CA. Follow @tanseyverse

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