This proposal is from an inter-disciplinary team with expertise in imaging, systems biology and clinical research (Weissleder, Sorger, Mitchison and Danuser). It responds to RFA-CA-11-005, and proposes to create and validate a platform for quantitative cancer pharmacology in mice using live imaging at the single-cell level. The immediate goal is to determine how individual cancer cells in tumors respond to single and dual-agent 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). Our focus will be on the use of navitoclax (ABT263;an investigational antagonist of Bcl-2 and Bcl-Xl) and gemcitabine (a well established, S-phase-specific cytotoxic drug), both individually and in combination.
Aim 1 will develop and validate live-cell biosensors for measuring pre-drug tumor states and drug responses in mouse xenograft tumors by sub-cellular resolution intravital imaging.
Aim 2 will develop injectable imaging agents based on novel bioorthogonal chemistries that will be used to label drugs fluorescently or with 18F. These agents will then be validated using the biosensors from aim 1.
Aim 3 will focus on the development of computational methods for extracting quantitative data from intravital images, and on the creation of data- driven, multi-scale (PK/PD;single cell kinetics and mechanistic/molecular) mathematical models that elucidate therapeutically relevant differences between mono and combination therapy. Overall, our goal is to gain an understanding of drug action that is: a) quantitative (in the treatment of data that may vary in time and space);b) probabilistic (accounting for cell-to-cell and tumor-to-tumor variability);c) mechanistic at the molecular level;d) post-genomic (analyzing diverse cell lines and patient samples with known genetic differences);e) integrative (assuming that determinants of drug response are multi-factorial);f) mathematically sophisticated (with respect to mass-action, lumped parameter and stochastic modeling);and g) medically relevant (by analyzing a combination therapy currently under clinical investigation and by developing translatable measurement methods). Success of the project will result in an integrated platform for single-cell cancer pharmacology. This platform will not only serve to overcome prevailing impediments to the translation of preclinical results into a clinical setting, but will provide the knowledge base for rational and predictive combination therapy. Likewise, it will improve our ability to develop effective drugs capable of inhibiting new and existing targets, and could also be more broadly used in the development of other emerging anti-cancer drugs.
The central goal of this multi-investigator application is to develop novel theoretical concepts, approaches and advanced imaging technologies to gain in-depth, systems level knowledge of how biological molecules, proteins and cells interact during cancer treatment. The proposed studies will continue to push the research frontier and will lead to new clinical strategies to combat cancer.
|Mikula, Hannes; Stapleton, Shawn; Kohler, Rainer H et al. (2017) Design and Development of Fluorescent Vemurafenib Analogs for In Vivo Imaging. Theranostics 7:1257-1265|
|Dubach, J Matthew; Kim, Eunha; Yang, Katherine et al. (2017) Quantitating drug-target engagement in single cells in vitro and in vivo. Nat Chem Biol 13:168-173|
|Arlauckas, Sean P; Garris, Christopher S; Kohler, Rainer H et al. (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9:|
|Miller, Miles A; Askevold, Bjorn; Mikula, Hannes et al. (2017) Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 8:15906|
|Pucci, Ferdinando; Garris, Christopher; Lai, Charles P et al. (2016) SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352:242-6|
|Vinegoni, Claudio; Dubach, John M; Feruglio, Paolo Fumene et al. (2016) Two-photon Fluorescence Anisotropy Microscopy for Imaging and Direct Measurement of Intracellular Drug Target Engagement. IEEE J Sel Top Quantum Electron 22:|
|Giedt, Randy J; Fumene Feruglio, Paolo; Pathania, Divya et al. (2016) Computational imaging reveals mitochondrial morphology as a biomarker of cancer phenotype and drug response. Sci Rep 6:32985|
|Miller, Miles A; Gadde, Suresh; Pfirschke, Christina et al. (2015) Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. Sci Transl Med 7:314ra183|
|Yang, Katherine S; Kohler, Rainer H; Landon, Matthieu et al. (2015) Single cell resolution in vivo imaging of DNA damage following PARP inhibition. Sci Rep 5:10129|
|Chittajallu, Deepak R; Florian, Stefan; Kohler, Rainer H et al. (2015) In vivo cell-cycle profiling in xenograft tumors by quantitative intravital microscopy. Nat Methods 12:577-85|
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