Neal Rosen Seminar Recap

Neal Rosen, Enid A. Haupt Chair in Medical Oncology at the Memorial Sloan–Kettering Cancer Center, visited Minnesota on May 18 to present the keynote lecture at the Masonic Cancer Center Research Symposium in the Great Hall of Coffman Memorial Union. Due to conflicting meetings, I could not attend the rest of the Symposium, so my comments are limited to Dr. Rosen's talk. Doug Yee, Director of the Masonic Cancer Center and a former postdoc in Neal's lab, gave him a warm introduction to the assembled crowd.


The title of Neal's presentation was "Feedback Regulation of PI3K-Signaling Pathways–Biologic and Therapeutic Implications." The main theme of the talk was what he calls adaptive resistance of cancers to oncoprotein inhibition by small molecule drugs. He presented data with MAPK and AKT kinase inhibitors to show that inhibition of these oncoproteins relieves upstream feedback inhibition and can attenuate the effects of therapy resulting in oncogene addition - sustained negative feedback throughout the signaling network.

Dr. Rosen takes a question from the crowd

A couple points about the choice of drugs to study were made. First, Neal made the point that drugs are the best way to understand adaption to pathways since this can't be done with siRNA. Second, allosteric kinase inhibitors are preferred, presumably due to issues related to target selectivity. He also related key reasons why effects of a drug can be limited in humans: poor patient selection, suboptimal drug, inadequate pathway inhibition, and adaptive resistance.


Neal closed the talk with a proposal for the design of clinical experiments with oncoprotein inhibitors. A four-step treatment process was proposed with the goal of maximizing tumor cell death:
1. Biopsy the patient's tumor and determine the driver mutation.
2. Treat the patient with an inhibitor of the driver protein at the maximal tolerated dose for x hours.
3. Re-biopsy the tumor and determine its mechanism of adaptation
4. Treat the patient with the driver inhibitor and an inhibitor of the putative dominant driver of the adaption.


This was an informative presentation that captured the interest of both basic and clinical scientists in the audience. Although most of the data was published, Neal put forth some provocative ideas that are sure to spark discussion within the oncology community.