Researchers Developing Technology To Outsmart Metastasized Cancers

Many types of cancer cells have a great affinity for folate — a form of water-soluble B vitamin — because they need the nutrient in order to grow and divide. In fact, cancer cells have evolved a mechanism to capture folate more effectively than normal cells. Making use of this selectivity, researchers have developed a way to trick cancer cells into attracting and even ingesting anticancer agents that are attached to folate molecules. As a result, these chemotherapeutic agents can be delivered more specifically to cancer cells while leaving the surrounding normal tissue unharmed.

One form of this "Trojan Horse" therapeutic approach (folate-targeted immunotherapy) was used by a joint Purdue-Endocyte research team to successfully treat more than 200 mice with late-stage metastatic disease. The results of these studies were published in the May Journal of Cancer Immunology and Immunotherapy.

"It's using cancer's nutritional needs against itself," said Philip Low, Purdue's Joseph F. Foster Distinguished Professor of Chemistry who led the research team that discovered this diagnostic and treatment method. "We are essentially slipping medicine in with cancer's favorite food."

The discovery has thus far yielded two different but complementary treatment methods that involve attaching various markers (folate-targeted immunotherapy) or anticancer agents (folate-targeted chemotherapy) to the vitamin.

The treatment method that "marks" cancer will be tested in Phase I Food and Drug Administration-regulated human clinical trials beginning in November. The objective of this method is to force the body's immune system to fight the disease, said Christopher Leamon, Endocyte's vice president of research.

"There's no better drug than your own immune system, which consequently is capable of getting rid of every last bacterium, every last virus or every last fungus in the body. Today's drugs can't do that," Leamon said. "Unfortunately, many cancers develop ways to evade immune surveillance. But we've found a way to redirect a patient's immune system to kill those resistant cancer cells by using our folate-targeted approach."

Researchers have found that certain cancers — among them ovarian cancer and renal cell carcinoma — have high levels of folate receptors. These receptors are located on the surfaces of cancer cells and are responsible for binding folate in a very specific manner, similar to the way a key is inserted into a lock. Cancer cells that are receptive to folate often express more folate receptors in secondary (metastasized) sites formed once the cancer becomes widely disseminated throughout the body.

Researchers hoped to bypass normal, healthy cells by delivering folate linked to an anticancer agent directly into the cancer. They discovered, though, that cancer cells don't take in all of the folate at once, but rather wear the excess folate on their cell surfaces,storing it for future use. Some of the drugs they attach tofolate, consequently, also are stored on the cancer cell surfaces.

Taking advantage of this discovery, Purdue researchers and Endocyte scientists devised an alternative way to fight the cancer cells. One of their strategies involves priming the body's immune system to fight a certain substance or "beacon," and then attaching that beacon to the cancer using folate. The beacon would enable the immune system to "see" the cancer and begin to remove it.

"We essentially decorated the cancer with an inert chemical the body was programmed by our vaccine to fight," Leamon said. "By retargeting the immune system, its natural killer (NK) cells and macrophages were alerted to intruders and eliminated the cancer along with them."

To retarget the immune system, scientists first inoculated mice to raise antibodies against a hapten (a small, inert organic chemical) called fluorescein. Once high levels of the antibodies were circulating throughout the rodents' systems, cultured cancer cells were injected. Tumors were allowed to establish themselves and spread throughout their hosts. Normally this would cause death in 21 days, however, the mice that were injected with the folate-fluorescein conjugate eight days after the injection of cancer cells lived well beyond 120 days (a point at which the animals were considered to be cured).

Another part of Endocyte's technology stems first from its ability to diagnose cancer. In order to determine which cancers have folate receptors and, therefore, are receptive to a folate-related treatment, cancer must be detected by using a folate-related diagnostic procedure Endocyte developed called FolateScan. This diagnostic method now is being tested in Phase I/II FDA-regulated human clinical trials.

To diagnose cancer, another type of "beacon" — this time a radioactive imaging agent — is attached to the folate. FolateScan is administered intravenously to patients. When nuclear imaging of the patient shows that the radio-labeled folate conjugate has concentrated in an unknown mass, it tells researchers that the mass has folate receptors and that the tissue is malignant. More importantly, it means that the cancer detected is the type that may be receptive to a folate-related therapy.

Researchers initially used the radioactive agent indium to detect folate-receiving cancers, but then developed a new diagnostic approach with technetium. Technetium decays more rapidly and decreases the patient's exposure time to the radioactive agent from one month to two days. The shorter half-life of technetium also allows researchers to more safely inject patients with larger quantities of radioactive agents in order to improve the quality of the scanned image. Preclinical results of this research are expected to be published this fall.

Founded in 1996, Endocyte is located in the Purdue Research Park. Purdue has licensed the drug delivery technology to Endocyte under an exclusive commercial arrangement. The company employs 24 people.