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Keck Seminar: Delivering on the Promise of Personalized Medicine
Gordon Mills, MD, PhD, Chair of Systems Biology, UT MD Anderson Cancer Center
 
date:4:00PM   US Central (GMT −0500)
Friday, April 20, 2012
 
location:BRC Auditorium, BioScience Research Collaborative Building, Rice University
 
sponsor:Gulf Coast Consortia
 
summary:

Gordon B. Mills, MD, PhD, joined The University of Texas M. D. Anderson Cancer Center in 1994, and hold the rank of Professor with joint appointments in Systems Biology, Breast Medical Oncology and Immunology; he serves as chairman of the Department of Systems Biology; head of the section of Molecular Therapeutics, and holds the Wiess Distinguished University Chair in Cancer Medicine. Dr. Mills is co-Director of the Kleberg Center for Molecular Markers and Director for the South Campus Research Building II. He is also co Director of the Sheikh Zayed bin Sultan Al Nahyan Institute for Personalized Cancer Therapy. The Center and the Institute are responsible for developing and implementing personalized molecular medicine at MDACC. Dr. Mills has published extensively on the molecular analysis of cancer and currently serves as principal investigator or project investigator on many national peer review grants including Stand Up To Cancer, NIH/NCI SPOREs RO1s, and PPGs, Department of Defense, and Komen Foundation grants, and is a collaborator on multiple other national grants. Dr. Mills published more than 500 papers; holds more than 20 patents related to novel technologies and molecular markers, and has co-founded an early diagnostics company. He currently sits on the scientific advisory boards of multiple companies and venture capital groups. Based on his expertise in technology development, he was the founding head of the M. D. Anderson Cancer Center Technology Review Committee.

ABSTRACT
The realization of the promise of personalized molecular medicine will require the efficient development and implementation of novel targeted therapeutics. The goal will be to deliver the right drug to the right patient at the right time at the right dose. This effort will require a integration of information from the DNA, RNA and protein level into predictors of which patients are likely to respond to particular therapies. The overall likelihood of response to particular drugs represents the interaction between predictors of sensitivity with predictors of resistance. Efficient clinical trials testing these precepts will require the development and implementation of novel trial designs. It is likely that we will need to increase the size of phase I and II trials to allow the identification and validation of molecular markers at the same time as the initial evaluation the toxicity and efficacy of targeted therapeutics. This will come with the advantage of being able to deliver targeted therapeutics to enroll a much smaller population of patients selected for the likelihood to respond in phase III trials accelerating the approval of effective targeted therapeutics.

The phosphatidylinositol 3’kinase (PI3K) pathway is aberrant at multiple levels across a wide variety of tumors making it the most common activating aberration in cancer. This has led to the development and now early clinical testing of drugs targeting multiple components of the pathway. The efficient utilization of these drugs will require the ability to accurately determine mutation and activation status in tumors as well as determining the interaction between the PI3K pathway and other pathways in driving tumor pathophysiology. Using a novel accurate and sensitive mass spectroscopy based sequencing approach, we have evaluated mutations in the PI3K pathway across more than 500 breast cancer samples. We have also implemented a high throughput functional proteomics approach designated reverse phase protein arrays to characterize the level and activity of multiple signaling pathways. We demonstrate than an integrated analysis of mutation, proteins levels and protein activity is able to predict lack of response to trastuzumab in patients and to novel drugs targeting the PI3K pathway in vitro. This demonstrates that the response to targeted therapeutics is due to an interaction of markers of sensitivity and markers of resistance and provides important approaches for patient selection.

The PI3K pathway is critically important to cellular function and is thus under exquisite homeostatic control. The feedforward and feedback loops in the pathway determine the response to perturbation of the pathway by mutation or therapeutic intervention. Strikingly inhibition of the pathway at the level of mTOR or AKT results in the activation of potent feedback loops resulting in activation of multiple cell surface tyrosine kinases, PI3K itself and in the case of mTOR inhibitors, AKT. This may contribute to the observation that mTOR inhibitors appear to make some patient tumors grow more rapidly an unexpected and disappointing consequence of targeted therapeutics. Our preliminary systems biology- based mathematical and experimental models of the PI3K signaling network accurately predict these consequences as well as the biochemical processes involved. Further, the models suggest combinations of targeted therapeutics likely to reverse the negative effects of the mTOR inhibitors converting the outcome from negative to positive in terms of tumor growth.

 
more info:Gulf Coast Consortia
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