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.
