Currently funded NIH projects are listed below. ISP Investigators are also involved in several collaborations with industry partners including Boehringer-Ingelheim, Novartis, Roche, and Vertex that focus on the use of multiplex measurement and computational modeling to understand mechanisms of drug action.
Pharmaco Response Signatures and Disease Mechanism (NIH LINCS Program)
Investigators: Peter Sorger, Tim Mitchison, Nathanael Gray, Caroline Shamu, Cyril Benes (MGH) and Josh Stuart (UCSC)
The Harvard Medical School (HMS) Library of Integrated Network-based Cellular Signatures (LINCS) Center was established in October 2010 as one of two research centers in the US creating libraries of signatures that describe how cells respond to perturbation. As of October 2011, a total of 10 centers from across the U.S. are participating in the NIH LINCS program. The aim of the HMS LINCS Center is to create signatures that measure responses to therapeutic drugs of cells derived from different human tissues. Much of our work is on tumor cells (from breast, liver and colon), but we also study primary human cells from normal and diseased patients. As perturbing agents, our focus is on small molecule kinase inhibitors, which are a leading class of therapeutic agents for treatment of cancer, autoimmune and other diseases.
Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
Investigators: Tim Mitchison, Peter Sorger, Caroline Shamu, Ralph Weissleder (MGH), Anthony Letai (DFCI), and Suzanne Gaudet (DFCI)
The long-term goal of this Program Project is to understand, in precise quantitative terms, how individual cancer cells and tumors respond to drug treatment, from target engagement to induction of apoptosis to eventual tumor regression. We are addressing this goal in the context of two drug classes that trigger apoptosis in cancer cells, anti-mitotic drugs, and targeted apoptosis inducers, including TRAIL and ABT737. Experiments are performed in cell culture and mouse tumors. We aim for an understanding of the cellular response to these drugs that is (i) mechanistic in explaining cellular phenotypes in terms of interactions among specific proteins and other bio-molecules, (ii) quantitative in applying mass-action kinetics and other mathematical formalisms to predicting the behavior of ensembles of interacting proteins from knowledge of their individual biochemistry, (iii) probabilistic in accounting for the variability from one cell to the next in responses to drugs with the attendant likelihood that only a fraction of tumor cells will arrest or die in response to treatment with a chemotherapeutic drug, (iv) post-genomic in analyzing diverse cell lines (and ultimately patient samples) with knowledge of their genetic differences and with the possibility of applying powerful knock-out/in and RNAi strategies to alter genotype, and (v) integrative in assuming that determinants of drug response are multi-factorial and that multiple interacting pathways rather than single genes or proteins must be studied.
Quantitative Analysis of Pharmacological Mechanism by Intravital Imaging
Investigators: Ralph Weissleder (MGH), Gaudenz Danuser, Tim Mitchison, and Peter Sorger
NIH/NIGMS R01 RFA-CA-11-005
The goal of this multi-investigator project is to analyze the responses of tumors in the mouse to anti-cancer drugs individually and in combination using subcellular resolution intravital microscopy, advanced image analysis and mathematical modeling.
Quantifying post-translational modifications and protein expression by HTP-MS
Investigators: Marc Kirschner, Michael Springer, and Hanno Steen (Children’s Hospital Boston)
We are using a newly-developed mass spectroscopy technique, FLEXIQuant, to provide absolute quantitation of the levels of 1,000 proteins in several different cell lines. At the same time as providing quantitation, FLEXIQuant provides information on which peptides in a protein are modified, and to what extent. Our ultimate deliverables from this project will be as follows: (1) A set of 1,000 clones in FLEXIQuant vectors, deposited with a non-profit plasmid repository and freely available to the community; (2) for the proteins corresponding to these clones, a comprehensive database of peptides detectable in mass spectroscopy experiments after digestion with 4 different proteases; (3) for the mRNAs corresponding to these clones, a comprehensive database quantitating the levels of mRNAs in 6 cell lines under different conditions; and (4) a database comparing mRNA levels, protein levels, and post- translational modifications for these clones in the same cell lines, under the same conditions. This work will for the first time open up the study of post-translational modifications on the genomic level, and will provide a range of important data for analysis by the community.