We study human biology. Specifically, our current research is focused on the imaging and quantitative measurement of cancer treatments. My laboratory employs a variety of techniques including whole body and intravital microscopic imaging, novel chemical approaches for perturbing systems, and innovative sensing strategies including nanotechnology approaches. Our goals are to obtain quantitative and systems-wide global measurements, to perform dynamic serial measurements, and to integrate multiple and various data sets into models. Increasingly, our work has been focused in reconciling the gap that exists between imaging and traditional cell biology research, but in an in vivo setting. Our work on nanomaterials and the development of novel miniaturized next-gen chips has led to advanced clinical trials. While our research is often basic in nature, much of our work has a translational focus, with in vivo imaging playing a major role. Some specific research projects include:
Intracellular In-Vivo Imaging
New ultra-resolution microscopic imaging technologies are being used to understand the complexity, heterogeneity and in vivo behavior of cancers. During cancer development we are interested in understanding the spatiotemporal activity of specific proteins (certain kinases and receptors), biological processes (apoptosis, proliferation) and cell-cell interactions ￼in vivo.
Equally important, we are also interested in trying to understand why so many cancer drugs fail. Using companion imaging drugs (see next section), we determine how individual cancer cells in tumors respond to therapy in vivo by measuring both the uptake and distribution of drugs in tumor cells (pharmaco-kinetics, PK), as well as the multiple downstream responses that play out over different time-scales (pharmaco-dynamics, PD). These single cell “systems pharmacology” ￼experiments invariably use engineered cell lines, mouse models using a panoply of fluorescent reporter proteins and fluorescently labeled drugs. Results from ongoing projects will likely have an impact on our understanding of tumor biology at the systems level, promote earlier clinical diagnosis and accelerate drug development.
Small molecule in vivo imaging agents
By harnessing a recently developed bioorthogonal in vivo detection (BIND) chemistry, which involves the highly specific and fast reaction between strained trans-cyclooctene and tetrazine derivatized imaging reporters, we are developing cell permeable small molecule affinity ligand-based imaging probes as companions to therapeutic drugs. In parallel we are developing BODIPY derived drug conjugates which are both fluorescent and can be labeled with 18F. ￼Both approaches are used to modify small molecule drugs to image EGFR, VEGFR, HER2, C-MET, MEK, PI3K/mTOR, PARP1, PLK1, AKA, BCL-2, among others. We typically first develop and test library of compounds and validate key hits by imaging by intravital microscopy. We also focus on the protein-wide identification and validation of binding partners of lead compounds, for which we will use in vitro and in vivo proteomic approaches. These experiments are critical since a comprehensive understanding of the interacting proteins and their associated protein complexes is important for the development of imaging agents and the interpretation of imaging studies. Finally, we explore the translational potential of these companion imaging drugs in therapeutic trials.
Nanoscale real-time sensing using next-gen chip technology
There is a need for better detection platforms for specific mammalian cells, bacteria and viruses implicated in human disease. Traditional tools such as culture and biochemical analysis are often slow, rely on fixed (i.e. dead) tissue and require skilled personnel or specialized facilities. Recently, several rapid testing platforms based on nanotechnology and microfluidics ￼have been developed in our lab (see figure). For example, we have developed a miniaturized nuclear magnetic resonance system (µNMR), Hall sensor based chips and single cell analysis systems. These devices are designed to be simple and sensitive enough so that they can be used in a clinical point-of-care device. Several clinical trials are ongoing including: 1) detection of circulating cancer cells in peripheral blood; 2) exosome profiling in cancer patients undergoing treatment; 3) profiling of freshly harvested human cancer cells to measure treatment response to drugs and 4) detection of pathogens in clinical samples.