Drug helps target attack on tumors

Researchers at Penn's Cancer Center have developed a drug that will help doctors fine-tune cancer treatments to patients.

The drug, EF5, allows doctors to effectively determine the oxygen content of a tumor, which subsequently dictates the appropriate course of treatment to be followed.

Cancer clinicians have long known that hypoxic tumors -- which thrive in oxygen-starved environments -- are much more resistant to radiation and chemotherapy than their non-hypoxic cousins. But, until now, physicians have had difficulty assessing hypoxicity.

"In the old days, it was pretty clear that hypoxia had an impact in animal tumor models," said Cameron J. Koch, Ph.D., a Penn professor of radiation oncology who developed EF5. "Theoretically, it should have been important in humans, as well."

Sydney Evans, V.M.D., and Cameron J. Koch, Ph.D., are hopeful EF5 will enable doctors to target treatments of cancerous tumors.

Koch began developing EF5 in the late 1980s when he came to Penn. The drug, recently approved by the FDA for a Phase I clinical trial at the University of Pennsylvania Medical Center, will assist researchers in "finding out about the biology of hypoxia in human tumors at both the microscopic and macroscopic levels," Koch said.

"It will be very important in determining a treatment response, predicting which tumors will do well and which won't do well," Koch added.

No toxicity has been shown in animal studies of EF5, according to Sydney Evans, V.M.D., an assistant professor of veterinary medicine at Penn, who has spent the last several years demonstrating EF5's safety and efficacy in animal tumor models.

Measuring human tumors for hypoxia was a source of controversy in the medical community for years, Evans said. "It was well-accepted that hypoxic tumors in rodents made them more resistant to therapy," Evans said. "But nobody was sure about hypoxic tumors in humans. It was problematic because there was no way of measuring if a tumor was hypoxic."

Over the last few years, another method, using a thin needle electrode, was developed and has been reasonably effective. However, EF5 answered concerns that the method be simpler and more generally applicable, Evans said.

An example of how it works: Patients with soft tissue sarcomas, and with early-stage cervix tumors, located at the neck of the uterus, are given EF5 intravenously (researchers are hoping to develop an oral method) two days before their tumors are surgically removed or biopsied.

During that time, EF5 attaches, or "binds" to hypoxic tumor cells, but washes out of tumor regions that are oxygen-rich. A small portion of the tumor, removed at surgery, is then exposed to fluorescent monoclonal antibodies (developed by researchers at the University of Rochester Cancer Center).

The antibodies fasten to the hypoxic regions in the tumor and highlight its oxygen content.

Also in the trial, the needle electrode method is being employed to measure the oxygen content. "Using the needle electrode is currently considered the standard method for measuring the tumor's oxygen content," Koch said. "However, by using EF5 with the needle electrode, we will have more precise information as to the amount and location of the oxygen within the entire tumor. Hopefully, it will increase the accuracy of tumor hypoxia diagnosis."

"When we know which tumors are hypoxic, we'll be able to custom-tailor a patient's cancer treatment," said Gillies McKenna, M.D., chair of radiation oncology at Penn's Cancer Center. "This may mean prescribing a more aggressive form of therapy, such as modifying the way radiation is delivered, or giving radiation in combination with drugs designed to exploit the hypoxic nature of the tumor."

Both Evans and Koch praised McKenna for his support in the development of EF5 and expressed pride that it is a "homegrown" find in the Penn research community. With FDA-approval granted in February, the Phase I trial has already seen EF5 administered to one human patient with no problems, and more patients will soon be treated, Evans said.

"This could have a major impact on cancer therapy," Evans said. "It's so exciting that it's homegrown, and the fact that it went from a chemical in a bottle to humans in a five-or-six-year period, that's just astonishing. It just

doesn't happen."

In the future, Penn researchers hope to adapt the EF5 technique for use with the Positron Emission Tomography (PET) imaging, which basically will allow for a non-invasive procedure of identifying the oxygen content with the patient's tumor.

"Applications of this drug are far-reaching," Evans said. "We'll be able to non-invasively examine the binding of EF5 for other diseases in which hypoxia occurs, such as heart attacks and strokes, in addition to the use in cancer."

Originally published on April 16, 1998