The idea that prostate cancer can be treated successfully just by blocking the activity of a protein called insulin-like growth factor (IGF-1) has been undermined by two new studies.
IGF-1 blockage is a goal being pursed by a number of drug companies and academic researchers, stimulated by studies showing an association between high levels of the protein and prostate cancer risk. Many efforts are aimed at blocking the receptors for IGF-1 in prostate cancer cells.
IGF-1 is a polypeptide hormone that can influence growth, differentiation and survival of cells expressing the type 1 receptor (IGF-1R). Previous clinical, epidemiological and experimental studies have strongly implicated IGF-1 as a contributing factor in the natural history of prostate cancer. There is, however, very little evidence to prove that the expression or activation of the IGF-1 signaling pathway at physiologically relevant levels is sufficient to cause a healthy prostate cell to become a cancer cell.
Without a proof of concept, therapies under development to treat prostate cancer by inhibiting the ability of insulin-like growth factor (IGF-1) to activate its target receptor could have unexpected results especially if a major tumour suppressor gene (p53) is already compromised.
At the Fred Hutchinson Cancer Centre in Seattle, Greenberg et al., conducted a pair of experiments by manipulating gene expression directly in the epithelial compartment of the mouse prostate gland to better understand the role of IGF-1R. Compared to studies that correlated elevated levels of IGF-1 with the risk of developing prostate cancer, Greenberg’s research showed that eliminating IGF-1R expression in an otherwise normal mouse prostate caused the cells to proliferate and become hyperplastic. Persistent loss of IGF-1R expression ultimately induced cell stasis and death. Both of these processes are regulated by the tumour suppressor gene p53 that is commonly mutated in human prostate cancers. It was, therefore, hypothesized that tumours with compromised p53 might not respond predictably to therapies targeting IGF1 signaling.
To test their reasoning they conducted a second experiment by crossing mice carrying the prostate-specific IGF-1R knockout alleles with transgenic mice that develop spontaneous prostate cancer when p53 and select other genes are compromised. The results were as expected: prostate epithelial-specific deletion of IGF-1R facilitated the emergence of aggressive prostate cancer in the genetically engineered tumour prone mice.
The study was published in the May 1 edition of Cancer Research, and supports a critical role for IGF-1R signaling in prostate tumour development. It identifies an important IGF-1R-dependent growth control mechanism, according to the authors.
If the predictions hold true, then tumour cells with intact p53 may show the best response to therapy targeting the IGF-1R signal, however when p53 is not functioning normally, response to this therapy may not be as expected and the cancer may proliferate aggressively.
A search of the database for clinical trials registered with the National Cancer Institute found 18 trials in process that use therapies to inhibit IGF-R1. None of them, however, include the tumour’s p53 status as a criterion for recruiting research participants. These data suggest that it might be an idea to get data on a patient’s tumour before treatment and after treatment, and see if the status of p53 shows whether it would respond more or less to IGF-1 treatment.
The other study, led by Cohen et al. at UCLA, also used mice bred to develop prostate cancer, with some also bred to lack IGF-1 receptors. The research was based on the idea that conventional wisdom suggests that without the IGF receptors, the tumours would fail to develop or be much smaller.
What actually happened was that they were not reduced in size; in fact, they were exactly the same size. Low IGF-1 levels in the mice were accompanied by higher levels of growth hormone and insulin, which stimulated growth of the cancer cells.
Ultimately, these studies do not suggest that IGF-1 blockage is doomed as a treatment, but rather it shows the need for targeting multiple pathways. As the cancers find ways to overcome IGF-1 blockage, it could be used in conjunction with other therapies.