Precision lung cancer therapy design through multiplexed adapter measurement
- Precision lung cancer therapy design through multiplexed adapter measurement
List of Collaborating Institutions
- University of California, Los Angeles
Massachusetts Institute of Technology
Moffitt Cancer Center
Combination therapy holds considerable promise for overcoming intrinsic and acquired resistance to targeted therapies but will rely on our ability to precisely identify the best drug combination for particular tumors. While immense focus exists on using genomic information to direct therapeutic strategies, many resistance mechanisms do not rely on genetic changes and, in fact, can arise from entirely tumor-extrinsic factors within the microenvironment. For example, although the receptor tyrosine kinase (RTK) AXL is widely implicated in resistance to targeted therapies such as those directed against EGFR, its regulation by phosphatidylserine, as opposed to mutation, amplification or autocrine ligand, make identifying the tumors that will respond to AXL-targeted therapy especially challenging.
We propose to study both downstream and receptor-proximal signaling during bypass resistance mediated by AXL, and then across a wider panel of RTKs. Integrating these measurements with quantitative modeling will identify the connectivity between receptors, interacting adapters, and downstream signaling events, thereby defining the essential set of signaling network changes required for tumor cell survival in response to targeted therapeutics. We will then apply this understanding by measuring RTK-adapter interaction using proximity ligation to predict the RTKs driving bypass resistance and test these predictions in a panel of patient-derived xenograft tumors.
This work will considerably improve our ability to identify effective drug combinations by (a) developing a mechanism-based assay for identifying which among many RTKs tumor cells are relying upon for survival, (b) improving our basic understanding of exactly how network-level bypass resistance arises due to activation of non-targeted RTKs both at the receptor-proximal and downstream signaling layer, and (c) expanding our understanding of the RTK AXL with links to resistance, tumor spread, and immune avoidance.
Aaron Meyer is an Assistant Professor in the Bioengineering Department at the University of California, Los Angeles. Dr. Meyer received his Ph.D. in Biological Engineering from MIT in 2014 under the mentorship of Drs. Douglas Lauffenburger and Frank Gertler then was an independent Research Fellow at the Koch Institute for Integrative Cancer Research at MIT from 2014–2017. His lab combines computational modeling with quantitative experiments to study cancer and innate immune signaling. These efforts are generally applied on two scales, with mechanistic receptor activation models to understand the pleiotropic effects of therapeutic interventions, and data-driven approaches to study bypass resistance mechanisms in cancer.
Dr. Eric Haura is a Senior Member in the Department of Thoracic Oncology at the H. Lee Moffitt Cancer Center in Tampa, Florida. He received his BS in biomedical engineering from Johns Hopkins University, completed medical school at Duke University School of Medicine, completed a residency program in internal medicine at Johns Hopkins, and then returned to Duke to pursue a clinical fellowship in hematology and oncology. He is co-leader of the Chemical Biology and Molecular Medicine Program and directs the Lung Cancer Center of Excellence at Moffitt. He is a board certified medical oncologist specialized in the treatment of all types of lung cancers and thoracic cancers. His research interests include assessment of signaling pathways using proteomic technology, chemical biology tools to study drug mechanisms of action, and proteomic technologies to enable precision medicine.
Forest White is a Professor in the Department of Biological Engineering at MIT, where he serves as co-Chair of the Biological Engineering Graduate Program. He is a member of the Koch Institute for Integrative Cancer Research and the Center for Environmental Health Sciences at MIT. Prof. White received his Ph.D. from Florida State University in 1997 and was a post-doctoral associate at the University of Virginia from 1997-1999. After completion of his post-doc, he joined MDS Proteomics as a Senior Research Scientist and developed phosphoproteomics capabilities for the company. In July 2003 he joined the Department of Biological Engineering at MIT as an Assistant Professor; in 2007 he was promoted to Associate Professor, and in 2014 he was promoted to Full Professor. Prof. White’s laboratory investigates cellular signaling mechanisms in cancer, metabolic diseases, and immunology.