Warning: Ignoring the insulin receptor may bring lackluster results for IGF-1R inhibitors

September 1, 2010

Drugs that target the insulin-like growth factor receptor may be backfiring because another receptor steps up to take over

Hope springs eternal in cancer research, and some of the most remarkably aspirational activity surrounds IGF-1R (the insulin-like growth factor-1 receptor). So many people have imagined ways to disable the oncogenic effects of IGF-1R simply by blocking its action. But how could anything about this receptor be simple?

Yes, it is a major signal transduction factor in the process of malignant transformation. And it is expressed in nearly all malignancies, solid and hematologic. But it is also a key player in normal physiology, including energy systems, glucose and insulin regulation, bone health, and the maintenance of neurons. It's part of a complex system of individual and hybrid receptors that includes none other than the insulin receptor itself. Knocking it out won't kill cells adjacent to a tumor, necessarily, but the systemic effects are difficult to predict.

IGF-1R trials: Modest results so far

For the dozen-odd agents with alphanumeric names that target IGF-1R, progress has not been straightforward over the past two decades. Adverse effects have been relatively mild, but every trial includes a few subjects who develop hyperglycemia or insulin resistance. In trials using IGF-1R inhibitors as monotherapy, response rates have have been nearly nil. As a combination agent (especially used with therapies targeted at other growth factors), the results have been modest at best. Two phase II trials of an anti-IGF-1R monoclonal antibody in combination with other drugs have been discontinued for lack of efficacy.

For obvious reasons, drug developers have chosen to target IGF-1R, sparing the insulin receptor itself. Inhibiting IGF-1R would be less likely to wreak direct havoc on glucose metabolism. But two studies now suggest that this may not be a workable strategy.

At least in breast cancer (where IGF-1R is overexpressed and contributes to tumor growth and chemotherapy resistance), the insulin receptor proves integral to the pathway by which IGF-1R promotes malignancy. Disabling IGF-1R may simply enhance the insulin receptor's effect on the growth of tumors.

Insulin receptor activity crucial to IGF-1R's oncogenic function

In cell culture, using short interfering RNAs to knock down the expression of the insulin receptor reversed the resistance of breast cancer cells to the IGF-1R inhibitor A12, according to a study headed by researchers at the University of California-San Francisco. It also enhanced the ability of A12 to slow the growth of breast cancer cells. The UCSF team also demonstrated that suppressing the function of the insulin receptor is essential to the anti-tumor activity of the IGF-1R inhibitor A12 in a mouse model of a neuroendocrine tumor.

This study echoes one by University of Minnesota researchers, who also down-regulated the insulin receptor in breast cancer cell lines and found that this inhibited their ability to proliferate and metastasize. This all fits in neatly with epidemiologic studies that show higher cancer rates among people who are obese or have diabetes.

The insulin receptor, "may afford mechanisms of adaptive resistance to anti-IGF-1R therapeutics in tumors that initially respond and then relapse," the UCSF-based team suggest in Proceedings of the National Academy of Sciences. Measures of insulin receptor expression may also prove useful to predict which patients are likely to respond to therapies based on IGF-1R, they add. (Given the tantalizing history of drug trials in this area, it's not surprising that nearly every review about the potential of these inhibitors calls for such predictors of response.)

Gene PTK6 found to regulate this activity

Another such biomarker could be PTK6, the gene recently found to regulate IGF-1R's ability to stimulate the growth of cancer cells that are unmoored from their anchorage to tissue or a vessel wall. A team from MD Anderson, Harvard-affiliated institutions in Boston, and Sanofi Aventis found that reduced levels of PTK6 in breast tumors correlate with long-term recurrence-free survival.

As the growth of some cancer cells in an anchorage-free environment is critically dependent on IGF-1R, the discovery of this gene's effects could offer more than just prognostic potential.