Recent research by Tavazoie, Hani Goodarzi GS and Olivier Elemento, a former Princeton postdoctoral fellow who has since joined the faculty at Cornell Weill Medical College, has produced an extensive listing of pathways followed by a cancerous cell, along with the set of gene expressions that activate or suppress the pathway. The research also identified the sequences in the DNA that regulate the expression of the genes and launch the pathway.
The team’s work, Tavazoie said, will help other researchers to “minimize the side effects and maximize the efficacy of drugs.”
“Cancer therapy as it exists now has been largely developed by a trial-and-error process,” Tavazoie explained. “In the process of killing cancer cells, [it] ended up killing a lot of normal cells. So cancer therapies have a lot of horrible side effects.”
The researchers developed a “powerful” approach, Tavazoie said. They generated computational tools that enabled them to look at the “levels of more than 20,000 different genes in tumor samples versus normal samples and from that information identify which pathways were perturbed in cancer.”
The researchers were able to confirm associations that had been discovered earlier, and, “using traditional methods, they identified a lot of new stuff as well,” Tavazoie added.
The team discovered that “there was a lot of heterogeneity in the pathways perturbed by mutation,” he noted. “Identifying those heterogeneities, classifying them into groups and treating groups specifically is likely to be a very effective way of dealing with the cancer in the future.”
The researchers gathered significant information about the regulatory context of the pathways. The activation of a pathway depends on the expressions of the genes that are part of it, Goodarzi explained. The expression of the genes is in turn regulated by how certain proteins or transcription factors bind to sequences of the DNA in their neighborhood, also called motifs. The Princeton researchers have developed computational methods to find pathways and identify the motifs that launch the expression of genes responsible for the pathway.
“Once you have a much better scientific foundation for understanding what actually went wrong, you can be much more precise in how you can treat it,” Tavazoie noted. “In terms of basic sciences, we now have a much better understanding of what actually happens.”
The researchers have made the tools they developed available to the public through an interactive web interface developed by Bambi Tsui ’09.
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