To William Gerald, a pathologist and researcher at Memorial Sloan-Kettering Cancer Center in New York, it’s clear that any effort to understand and defeat cancer will involve more than just analyzing gene expression data derived from microarray experiments. In fact, the 13-year veteran of Sloan-Kettering is already making forays into what he describes as comprehensive molecular analysis by integrating his microarray results with data from gene copy number and protein expression studies.
Nevertheless, microarray analysis is the technique Gerald has relied on for the past few years to advance understanding of prostate cancer — and to collect data for his most well-known findings to date. Last year, Gerald’s group published a paper in the American Journal of Pathology that looked at a particular subtype of prostate cancer involving androgen-independent tumors. Patients with these types of tumors eventually do not respond to androgen deprivation therapy, and Gerald wanted to know why.
Gerald’s approach was to use microarray analysis to compare the gene expression profiles of various types of prostate tumors: those that were still susceptible to androgen deprivation therapy, tumors responding to androgen deprivation, and tumors that had become resistant to androgen deprivation therapy. Using a threshold for top-ranked, differentially expressed genes on a 60,000-probe-set Affymetrix array, Gerald’s group found more than 100 genes potentially involved in the tumor’s mechanism for androgen resistance.
Beyond that, Gerald and his colleagues wanted to understand how the tumor cells were becoming resistant to androgen deprivation therapy, and the exact role androgen receptors played in this process. To do this, Gerald’s lab developed a model for the pathways involved in the growth of androgen-resistant prostate tumors based on the microarray gene expression data. Ultimately, the model will allow Gerald’s group to analyze how the androgen receptor is reactivated and the mechanisms for reactivating androgen-responsive genes.
“The concept was that since these were androgen independent [tumors] the androgen receptor was no longer important,” says Gerald. “But that is not true. In fact it’s this dramatic overexpression of the receptor that helps to drive resistance. So [these results have] maintained the androgen receptor as a legitimate therapeutic target. Even though these tumors seem to be independent of that pathway, they’re not, really.”
And Gerald is optimistic that integrating data from gene expression experiments with gene copy, protein expression, and metabolite expression data will only lead to greater insights into tumor behavior. Comprehensive molecular analysis should provide a better reflection of the underlying biology, he says, and lead to additional markers useful as diagnostic tools, and taken a step further, to improving the ability to predict tumor behavior. “With the technology that’s available these days things are moving quickly, and each additional bit of information helps,” Gerald says.
— John S. MacNeil