Investigational cancer compound receives FDA approval to begin human trials

UNIVERSITY PARK, Pa. -- An investigational compound developed by Penn State researchers that targets and destroys cancer cells while leaving healthy cells unharmed has been approved for phase one clinical human trials by the U.S. Food and Drug Administration (FDA).

Keystone Nano, a biopharmaceutical company cofounded by James Adair, professor of materials science and engineering, biomedical engineering, and pharmacology, recently was approved to begin clinical trials to assess ceramide nanoliposome for possible use in treating cancer. The trials will seek to establish safe dosing levels and examine the compound’s efficacy as an anticancer therapy. Keystone Nano was founded in 2005 with Mark Kester, former professor of pharmacology at Penn State College of Medicine in Hershey, with the goal of gaining FDA approval for nanoscale biomedical products.

The compound works by weaving ceramide – a known anticancer therapeutic agent that’s never been used in clinical testing to treat cancer – with other fatty lipids that dramatically increase its delicate stability in the body. Upon reaching the tumor, it penetrates the cellular lining before depositing its chemotherapeutic cargo. The coating has resulted in a much greater window of effectiveness over current chemotherapy treatment because ceramide has been found harmless to noncancerous cells in dozens of preclinical animal tests.

A cancer drug’s window of treatment is determined by the gap between the point in which a drug becomes an effective treatment and when it becomes harmful to the patient. Drugs with a larger window of treatment generally pose fewer risks to the patient.

“There’s a whole litany of side effects that cancer patients put up with. About three percent of all patients die from the side effects of the chemotherapy,” said Adair. “We’re very encouraged by ceramide nanoliposomes because the study findings suggest that they could kill cancer while doing little or no harm to the patient.”

Phase one of the trial will recruit patients with solid tumors for testing. If the trial reaches Phase two, it is expected to focus on liver cancer.

Delivering the dose

Kester resolved ceramide’s instability obstacle by protecting the compound in a proprietary fatty coating. Ceramide is then able to freely flow through the body, before eventually being sucked in by the tumor as it funnels metabolic resources from the host.

In dozens of animal tests, the researchers found that the compound remained in the body attacking cancer tumors for more than a day.

“Ceramide is a bioactive lipid that selectively kills cancer cells. At equal dosing, normal cells go to sleep, cancer cells die,” said Kester, now director of NanoStar Institute at the University of Virginia. “The problem is it precipitates. It falls out of solution. The only way to deliver it is to turn it into a nanoformulation, which is our intellectual property. Think of it as a very small FedEX truck that delivers on time, all the time but only to the cancer cells.”

The targeted delivery system if approved, may offers positive benefits over current chemotherapy, which tends to target the human body like a hatchet, delivering a few percent of the dose to the tumor, said Adair. The dose that doesn’t reach the tumor causes harm to the immune system and the body. That means that the therapeutic window of treatment is narrow and rife with side effects.

According to researchers, because ceramide nanoliposome works like a more like a scalpel, it leaves healthy cells unharmed at effective dosing, the therapeutic window of treatment is much greater and potential harm to the body is much lower.

The nano formulation has been shown to preserve the body’s ability to rebuild rapidly regenerating cells found in areas such as the digestive system and scalp, which means patients likely won’t experience digestive problems or hair loss from the treatment. Also, the patient’s immune system isn’t attacked like it is with chemotherapy.

Clinical trials

Phase one of the clinical trials, a goal of Penn State nanomedical researchers since 2003, will begin by testing patients who haven’t responded to treatment methods and will focus on proper dosing levels and  efficacy. Phase two is anticipated to focus on liver cancer, which annually kills about 27,000 people in the United States and 700,000 worldwide. There is currently no known cure for the disease and the lone existing treatment method extends life, on average, between six to eight weeks. Testing will take place at three sites: the University of Maryland, the University of Virginia and the Medical University of South Carolina.

The compound will be given to 30 patients, increasing dosage until side effects are noticed. Adair and Kester said ceramide nanoliposome could become an FDA-approved drug within a few years if it shows promise in clinical testing.

New formulations of targeted treatment

Other formulations developed by Adair use nanojackets — formed from calcium phosphate — that are formulated to seek out cancer cells to deliver a chemotherapeutic agent or imaging cargo. In animal tests, that’s led to similar results as ceramide nanoliposome, where chemotherapy delivers only to the cancer, ignoring healthy cells.

It’s also produced another benefit: early detection. In other studies, researchers have combined nanojackets with fluorophores, which emit light, to detect cancer tumors using near infrared light. Early detection alone would dramatically increase survivor rates, which could diminish as the cancer progresses.

The targeted compound has also shown promise in treating non-tumor cancers. In lab tests, it eliminated 30 percent of chronic myeloid leukemia, a nonsolid cancer of the blood stream. Adair said he expects these technologies, now in preclinical trial phase, to reach the clinical trial stage within a few years.

“With targeting, our research has shown you can have your particles hunt down and kill single cell cancers of the blood,” said Adair. “The particles that don’t find their way to the cancer remain intact. They never deliver their cargo unless they get absorbed by the cancer’s cell membrane. It’s a trigger that no other formulations really have.”