Two 'Hot' New Targets in Colorectal Cancer

CRYSTAL CITY, Virginia—Two of the hottest targets in colorectal cancer are spurring "lots of enthusiasm," Lee M. Ellis, MD, professor of surgical oncology and cancer biology, The University of Texas M.D. Anderson Cancer Center, said at the 2006 Gastrointestinal Oncology Conference, sponsored by the International Society of Gastrointestinal Oncology. The two targets, c-Src and urokinase plasminogen activator receptor (uPAR), both play key roles in tumor metastases and migration.

Src, a Tyrosine Kinase Protein

Src is a "prototypical member" of the tyrosine kinase family of proteins, Dr. Ellis said. "Although there are a number of members of the family, Src itself is the most important in colorectal cancer," he said. The other family members are expressed "at much lower levels" in colorectal tumors, he added. Dr. Ellis called Src "a central mediator of a number of cellular functions," the most important being cell survival. "This is where it may play a role in tumor resistance to chemotherapy," he said.

Early work on the protein in the 1990s found high levels of Src activity during metastasis. A German team also reported that colorectal cancer patients with high levels of Src have worse prognosis than patients with lower levels of the protein, he said.

In work performed by Duxbury and Whang (Clin Cancer Res 10:2307-2318, 2004), Src inhibitors were shown to resensitize chemotherapy-resistant pancreatic adenocarcinoma cells. "We see this in cells resistant to gemcitabine [Gemzar]," Dr. Ellis said. "Once given the Src inhibitor, the cells became resensitized to the chemotherapy drug, and show a marked reduction in tumor growth. This is important when you consider the number of patients who become resistant to our current therapies."

One Src inhibitor is already on the market. Dasatinib (Sprycel), a small molecule, was approved in June 2006 by the FDA for the treatment of resistant chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) (see ONI July 2006, page 1). It inhibits several tyrosine kinases, including Src, and should be tested in colorectal cancer patients, Dr. Ellis said.

Several other Src inhibitors are nearing human trials, he said.

uPAR May Trigger Cross-Talk

The second "hot target," uPAR, is a cell-surface receptor that plays a key role in angiogenesis and tumor migration. Dr. Ellis said there is good evidence of "cross-talk" between cellular pathways triggered by uPAR and another important cell-surface receptor, endothelial growth factor receptor (EGFR). "It's a very complex system that we're still figuring out," he commented.

Preliminary results from Dr. Ellis' laboratory suggest that inhibiting uPAR improves survival in animal models of colorectal cancer. And, as with Src, drugs targeting uPAR look strongest when combined with traditional chemotherapy, he said. "The anti-uPAR monoclonal antibody had some positive effects on its own, while combining it with chemotherapy had an even better, synergistic effect," he said. "There was a marked decrease in tumor proliferation."

Targeted Therapy in Combination

Dr. Ellis also said that researchers have begun preclinical experiments that deploy two or more targeted therapies simultaneously. "Even though this approach is attractive, we have to keep in mind that all of these molecules play a role in normal cell function and in targeting several of them at once, we may encounter some unknown toxicities."