Science Editor

The epidermal growth factor receptor family is a cancer targeting mainstay, with multiple approved therapeutics targeting either the receptor itself or the kinase it activates.

Some, such as trastuzumab (Herceptin, Genentech Inc.) and cetuximab (Erbitux, ImClone Systems Inc.), target the receptors, to prevent them from activating the kinase that is attached to them. Others, such as erlotinib (Tarceva, OSI Pharmaceuticals Inc., Genentech Inc.) and gefitinib (Iressa, Astrazeneca plc) jam the active site of the kinase itself.

But while both approaches have proved successful in the short term, resistance tends to rear its ugly head over longer periods of time; and so, researchers still are looking for additional ways to foil the receptor-kinase complex, making resistance that much more difficult.

A paper in the July 17, 2006, issue of Cancer Cell reported on moving further upstream to obstruct yet another step in the pathway: by inhibiting the enzyme that releases heregulin, which binds to epidermal growth factor receptors HER-3 and HER-4.

Epidermal growth factor receptors are activated by a so-called autocrine loop, that is, cells secrete the growth factors that then bind to receptors on themselves. After binding, two receptors will bind to each other, and that doubling activates the kinase, which then goes on to activate cell growth pathways.

To start the loop, the secreted growth factors need to be released from the cell membrane, and the job of freeing them falls to so-called sheddases. Sheddases are similar to matrix metalloproteases, which cut up the extacellular matrix and play a role in cancer metastasis. (See BioWorld Today, May 11, 2005.)

Clinical success in targeting matrix metalloproteases has proved elusive to date, but the sheddase inhibitor described in the Cancer Cell paper, which was co-authored by researchers from Wilmington, Del.-Based Incyte Corp., the University of Texas Southwestern Medical Center at Dallas and the University of California at San Francisco, is more selective than the broad-spectrum inhibitors that currently are available for metalloproteases, and "has a far superior safety profile in preclinical models, including the lack of musculoskeletal side effects," the authors wrote.

The paper described the effects of inhibiting ADAMs in lung cancer, but Incyte is furthest along in testing sheddase inhibitors for breast cancer:

The company is in Phase Ib/II dose escalation trials with INCB7839, a sheddase inhibitor related to the one described in Cancer Cell.

"The strongest rationale is in breast cancer," Richard Levy, senior vice president of development at Incyte, told BioWorld Today. That is because in the case of Her-2, sheddases are active via two mechanisms: They prevent the release of the ligands that activate HER-1 and HER-3 and allow them to form complexes with HER-2, but they also prevent cleavage of HER-2 itself. Such cleavage of HER-2 activates the receptor, and breast cancer patients with high levels of cleaved HER-2 receptor have a poor clinical prognosis.

Another reason Incyte's clinical development is focused initially in breast cancer is that the cleaved HER-2 receptor can be measured in plasma just by taking a blood sample. "Other cancer types need surrogate markers, which tend to be more complex and take longer to obtain," Levy explained.

Incyte's Cancer Cell paper first demonstrated the existence of a heregulin-HER-3 stimulatory loop in lung cancer tumor cells. That loop was related to whether cells are sensitive to gefitinib: Heregulin up-regulation correlated with the cell's sensitivity to gefitinib, while the correlation between receptor up-regulation and gefitinib sensitivity was only weak.

In the Cancer Cell paper, the scientists then tested whether inhibiting the sheddases ADAM17 and ADAM10, which free heregulin from the cell membrane, would restore the sensitivity of cells with up-regulated heregulin to gefitinib.

They found that an inhibitor of ADAM17, but not ADAM10 and other control ADAMs, blocked the release of heregulin from the cell membrane and increased gefitinib sensitivity in cell culture. In a xenograft model, the compound also showed antitumor activity, both when given alone and in combination with paclitaxel.

Levy said that the company expects sheddase inhibitors would be used as part of combination therapy. A sheddase inhibitor "might be effective by itself, but it is likely to have the greatest clinical utility when used in combination with other therapies," he said.

In the same issue of Cancer Cell, a paper by researchers from Vanderbilt University in Nashville, Tenn.; the Cold Spring Harbor Laboratories in Cold Spring Harbor, N.Y.; and the University of Texas Southwestern Medical Center at Dallas described a mutation in HER-2 in certain lung cancer cells.

The mutated receptor activated kinases more strongly than wild-type; in culture, cells with that mutation were insensitive to kinase inhibitors but remained sensitive to therapies aimed at the receptor.