Why targeted cancer therapies have not hit the ‘bull’s-eye’  pg. 2

“I think the mistake has been in assuming that these results will accurately predict clinical effect. They do not.”

In the 1990s, researchers optimistically predicted that targeted therapies—drugs designed to act only on a single cellular component—would be more effective and would eventually replace conventional cytotoxic therapies. Since targeted therapies would only affect cells that harbored the specific target, the drugs also would be safer and cause less damage to normal tissues.

This hypothesis was based largely on trials of Herceptin, the first growth factor-targeted monoclonal antibody approved to treat breast cancer. It prevents epidermal growth factor (EGF) from binding to a receptor known as Her2.

“At a very crucial time in its development, it was recognized that only those tumors that had significantly high levels of expression of the receptor Her2 would likely respond,” Rothenberg says. Because of this, the clinical trials were limited to patients whose tumors overexpressed Her2, and quickly showed that it was a beneficial agent to incorporate into therapy.

However, when the same strategy was tried with another receptor that binds EGF, Her1, “Lo and behold, this didn’t carry over,” he says.

Her1-targeted drugs such as Iressa, Tarceva, and Erbitux showed a similar activity in all patients, whether their tumors expressed low, intermediate or high levels of the receptor. Even patients whose tumors didn’t express Her1 benefited from Erbitux.

Then in 2004 scientists discovered that patients were more likely to respond to Iressa or Tarceva if they had a mutation in the Her1 receptor.

“So that taught us an important lesson,” Rothenberg says. “Even though we talk about targeted therapies, different targets may have different rules of engagement. We can’t make a sweeping assumption that what is true in one is true in all.”

Underlying the unpredictability is a significant amount of crosstalk between numerous cell-signaling pathways.

“Shutting down one pathway doesn’t necessarily lead to death of the cancer,” he says. “Other regulatory pathways may be abnormally functioning in these cells. Therefore, our approach currently is to target complementary pathways, so that we can more completely shut down those growth factor signaling pathways that are driving the cancer cell.”

Rothenberg and his colleagues also are using pharmacogenomic profiling to define the biology that drives the clinical activity of drugs, both the anti-tumor activity and toxicity.

“To relate this information about drug response to genomic or proteomic profile of the tumor will give us hopefully more useful and predictive information about what drugs might be useful in what doses and in what setting,” he says.

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