Systems approaches to understanding the relationships between genotype, signaling, and therapeutic efficacy
- Systems approaches to understanding the relationships between genotype, signaling, and therapeutic efficacy
- Douglas A Lauffenburger
Kevin M Haigis
The promise of precision medicine for cancer is a personalized therapeutic strategy based on the molecular features of an individual’s tumor. This concept is most effectively demonstrated by the successes in targeting oncogenic kinases with small molecules or antibody inhibitors. But while successes have garnered significant attention in recent years, precision medicine has not made an impact for the vast majority of cancer patients. The high profile successes associated with inhibitors of kinases such as ABL, EGFR, ALK, and B-RAF bring to the forefront the major disappointment associated with efforts to establish precision medicine for cancers expressing mutant K-RAS. K-RAS mutations occur in 15% of all cancers, but are significantly enriched in three of the four most deadly forms: lung, colorectal, and pancreatic. Importantly, KRAS mutations are associated with resistance to conventional and targeted therapies, most notably therapies targeting the epidermal growth factor receptor. As such, three decades after the initial identification of KRAS mutations in human cancers, prospective knowledge of K-RAS mutation state in a given cancer is useful largely only for its ability to predict negative response to therapy. The major shortfall of the precision medicine movement is the lack of direct inhibitors for specific oncogenic events, such as K-RAS mutation. The alternative to direct inhibition of an activated oncoprotein is to target downstream pathways, but this requires an absolute understanding of contextual cues that influence oncogenic effector signaling. Lack of depth in our understanding of the relationship between genotype, network signaling state, and therapeutic response leads to ineffective precision medicine. With its focus on network-level biology and its ability to uncover molecular mechanisms through computational analysis, systems biology provides a means to overcome this lack of understanding. This project is designed to take advantage of the broad array of expertise within our research community in order to make precision medicine a realistic goal for patients with K-RAS mutant cancer.
Douglas A Lauffenburger is Ford Professor of Bioengineering and (founding) Head of the Department of Biological Engineering at MIT. A central focus of his research program is in cell-cell communication and intra-cellular signal transduction important in pathophysiology with application to drug discovery and development, with emphasis on development of predictive computational models derived from quantitative experimental studies. More than 100 doctoral students and postdoctoral associates have undertaken research education under his supervision, and he has served as a consultant or scientific advisory board member for a number of bio/pharma companies.
Kevin M Haigis is Associate Professor of Medicine at Harvard Medical School, and Director of Cancer Genetics at Beth Israel Deaconess Medical Center. During his graduate training at the University of Wisconsin-Madison, Dr. Haigis studied the somatic genetics of intestinal tumor initiation under the guidance of Dr. William Dove. In his post-doctoral work, Dr. Haigis studied the oncogenic properties of the RAS GTPases in the laboratory of Dr. Tyler Jacks in the Massachusetts Institute of Technology Center for Cancer Research (now the David H. Koch Institute for Integrative Cancer Research).
Wilhelm Haas is Assistant Professor of Medicine at Harvard Medical School. The Haas laboratory uses quantitative mass spectrometry-based proteomics to study the cellular pathways that characterize cancer cells in a comprehensive proteome-wide manner. This is fueled by recent discoveries that have enhanced the depth and throughput of proteomics in quantifying proteins and their post-translational modiﬁcation.
Ken Lau is Assistant Professor of Cell & Developmental Biology at Vanderbilt University School of Medicine. His background is in combining experimentation and modeling to study complex biological phenomena. Dr. Lau completed his PhD (bioinformatics and proteomics) in 2008 at the University of Toronto, Canada. After postdoctoral work at Harvard/MIT under the tutelage of Drs. Kevin Haigis and Douglas Lauffenburger, he started his own lab at Vanderbilt in the spring of 2013. The Lau laboratory uses quantitative single-cell analysis to dissect complex epithelial systems in vertebrates, investigating signaling networks that allow cells to compute and arrive at fate decisions within multicellular architectures.
Kimmie Ng is Assistant Professor of Medicine at Harvard Medical School, and Director of Clinical Research for the Center for Gastrointestinal Oncology at Dana Farber Cancer Institute. Dr. Ng received her BS in Molecular Biophysics & Biochemistry at Yale University and her MD at University of Pennsylvania, and worked as a Clinical Scientist at Genentech before joining the Dana Farber Cancer Institute.