BioWorld International Correspondent

TORONTO - Understanding of the molecular mechanisms that control the growth and survival of tumor cells has generated a broad range of novel targets, and after many years of research the first generation of so-called "molecular therapeutics" aimed at these targets have recently reached the clinic.

This is a significant step in the evolution of cancer drugs, and has the potential to provide a powerful new armamentarium for clinical oncologists, Tilman Oltersdorf, director of molecular biology at Idun Pharmaceuticals Inc., told attendees of the Biotechnology Industry Organization's International Biotechnology Convention & Exhibition during a session on "Molecular Therapeutics: A New Generation of Cancer Drugs."

An example of the length of time it has taken to translate understanding of molecular pathways into therapies is the epidermal growth factor receptor, which has been studied for more than 20 years, said Gisela Schwab, vice president of clinical development at Abgenix Inc., of Fremont, Calif.

"This is an important pathway in proliferation, angiogenesis and resistance to chemotherapy," Schwab said, noting that various strategies have been invoked to inhibit EGFr and there are now a number of products in the clinic. Six of these are tyrosine kinase inhibitors, of which two are in advanced clinical development. Four are anti-EGFr antibodies, two of which are mouse antibodies, one is a chimeric antibody, and the fourth, ABX-EGF, a fully human antibody that Abgenix is developing in collaboration with Immunex Corp., of Seattle.

ABX-EGF is has just entered an extended Phase II trial and Schwab outlined clinical and preclinical findings to date. In preclinical trials, ABX-EGF down-regulated expression of EGFr, inhibited EGFr tyrosine kinase phosphorylation, angiogenesis and tumor growth, worked in concert with chemotherapeutic agents, and eradicated established tumors in mice, with no recurrence up to one year later, she said.

In Phase I and Phase IIa trials there were safety issues and no immunological response to the antibody. A number of patients, suffering from a broad range of tumors, showed complete or partial responses. All patients had a dose-related skin rash, a factor that has been reported to correlate with anti-tumor activity.

"On the basis of these results we launched a comprehensive Phase II study using ABX-EGF as a monotherapy, and in combination with chemotherapy," Schwab concluded.

David Lynch, senior staff scientist at Immunex, discussed the development of the membrane protein TRAIL/Apo2L (TNF-related apoptosis inducing ligand) and antibodies targeted at one of its four receptors, as molecular therapeutics.

Lynch noted that TRAIL/Apo2L has at least two receptors and two of these, R1 and R2, have intracellular death domains and can cause apoptopic cell death. "The question is, can TRAIL/Apo2L kill tumor cells?" he said.

Studies by Immunex showed that TRAIL/Apo2L is toxic to a wide variety of tumors. Of 77 tumor types tested, 74 percent were susceptible, with TRAIL/Apo2L inducing apoptosis. "Not only this, but it is nontoxic to normal cells," said Lynch.

In mouse models of colon cancer, most mice treated with TRAIL/Apo2L had a complete elimination of the tumor, and the protein has also been shown to work in combination with chemotherapy.

Immunex is also investigating the use of antibodies that bind one of TRAIL/Apo2L's receptors, TR2, to induce apoptosis. Lynch said TR2 is expressed in "virtually every one" of 100 tumor types studied. Three TR2 monoclonal antibodies developed by Immunex have each mediated complete remission of tumors in animal models.

Antibodies may have an advantage over the TRAIL/Apo2L protein in a therapeutic context because they have a far longer half-life, concluded Lynch.

Lee Rubin, chief scientific officer at Curis Inc., of Cambridge, Mass., discussed the inhibition of Hedgehog, a pathway that is involved in cell proliferation during embryonic development and also has a role in the formation of certain tumors, including basal cell carcinoma, medulloblastoma (childhood brain cancer) and colon cancer.

Curis has focused on basal cell carcinoma and has demonstrated that these sun-induced skin lesions are initiated when the Hedgehog pathway is mutated. The company has developed a small-molecule inhibitor of the pathway, Cur 61414, which Rubin said has not only been shown to block the appearance of basal cell carinoma by blocking the Hedgehog pathway in mice, but also causes the regression of established tumors.

"Furthermore, normal cells are unaffected," he said.

Curis has now extended the research to find out whether Cur 61414 is effective in other tumors where the Hedgehog pathway is implicated, and has shown it is effective in preclinical models of medulloblastoma.