Photon-counting X-ray and Optical Tomography for Preclinical Cancer Research

Preclinical imaging is a critical tool in cancer research. Since cancer exhibits very complex spatiotemporal features, there is a strong need for the development of novel imaging technologies to characterize cancerous tissues and their microenvironments. For this purpose, multimodal imaging has the best potential to provide anatomical, functional and molecular information concurrently in live and intact animals. Of our primary interest, human epidermal growth factor receptor 2 (HER2) expression has prognostic and predictive values in breast cancer. Currently, therapeutic monoclonal anti-HER2 antibodies that inhibit receptor dimerization are FDA- approved. However, an increasingly more complex view of the role of HER2 in breast cancer has emerged from genome sequencing that highlights the importance of inter- and intra-tumor heterogeneity in therapy resistance. Thus, there is a clear need for a non-invasive preclinical imaging modality that is capable of monitoring the interplay between HER2 receptor expression level, targeted drug delivery, and tumor response.

The overall goal of this project is to develop a hybrid x-ray and optical prototype for High-dimensional Optical Tomography (HOT) Guided-by Energy-resolved Micro-CT (GEM), visualize and quantitate breast tumor heterogeneity, HER2 expression and dimerization, and therapeutic response in preclinical models. The specific aims are to (1) prototype a hybrid HOTGEM system for comprehensive and synergistic x-ray and optical imaging, (2) develop joint methods for image reconstruction from datasets in multi-contrasts collected with the HOTGEM system, and (3) characterize breast cancer in xenograft systems with varying levels of HER2 and HER2-activating mutations using the HOTGEM system. Upon completion, the proposed HOTGEM system will have been validated to offer 50μm x-ray resolution for material decomposition and 100μm optical resolution for target localization in co-registration within 30 minutes for each hybrid in vivo scan, demonstrated to be a breakthrough for tomographic HER2 imaging, and ready for technology transfer and commercial translation.