Using Function to Inform Genomics
June 1, 2011 Leave a comment
Recently, I was asked to evaluate a charming young woman with an unusual gynecologic primary. She had received numerous forms of therapy and surgery for her low-grade carcinoma. Her most recent surgery provided tissue to our laboratory for analysis. The results were consistent with the clinical presentation, revealing relative resistance to virtually all conventional chemotherapeutic drugs, but a very striking pattern of sensitivity to three compounds associated with the insulin like growth factor signaling pathway.
As all three compounds pointed to activity in this pathway, I reasoned that the patient had a mutation upstream, as I wrote in my report to her physician. I suggested that they should investigate this pathway.
I was subsequently apprised that, upon my recommendation and at the request of patient’s husband, an analysis had been submitted to a laboratory that identified a mutation in PI3K, the very pathway that I had identified in our functional analysis. Thus, this patient’s resistance to chemotherapeutics and sensitivity to PI3K inhibitors reflected the profound survival signal provided by this mutation. Of interest, when the family originally requested a molecular profile be conducted in parallel with our functional profile, the commercial lab in Arizona did not include PI3K mutational studies. It wasn’t until the functional results pointed to the PI3K pathway that the specific mutational analysis was undertaken and found positive.
This experience is very similar to our original work with the EGFR inhibitors gefitinib and erlotinib. Several years before the EGFR mutation was identified and long before the mutational analysis was commercially available we identified activity in patients using the functional platform. Patients were then treated based upon the EVA-PCD results under protocol with every one of these patients responding, as we reported (Nagourney Proc ASCO, 2007). This speaks to the robustness of the functional platform and to its capacity to guide drug development.