Photoacoustic molecular imaging for planning of neoadjuvant antibody-drug-conjugate treatment of triple negative breast cancer - PROJECT SUMMARY Advances in omics has shifted the treatment of triple negative breast cancer (TNBC) from systemic chemoimmunotherapy to strategies based on patient-specific molecular profiles. One such promising molecular target for TNBC is trophoblast cell-surface antigen 2 (Trop-2), the target for sacituzumab govitecan (SG), a recently approved antibody-drug conjugate (ADC) treatment for TNBC. In the neoadjuvant (NA) setting, early results of SG treatment of TNBC have been promising, with highest survival and response observed in patients with medium/high Trop-2-expressing tumors. Current receptor-assessment methods are based on biopsies, which are prone to spatial sampling errors, cannot assess expression heterogeneity, and are not amenable to longitudinal sampling. Thus, there exists a critical clinical need for a diagnostic platform capable of non-invasive, comprehensive, longitudinal, and quantitative assessment of Trop-2 expression in TNBC to effectively plan and personalize ADC therapies such as SG. The goal of our research is to develop molecular photoacoustic imaging (PAI) to predict and monitor the early response of a TNBC tumor to ADC treatement (i.e., SG) and provide actionable feedback for “right-sizing” of therapy. No other currently available imaging system offers simultaneously excellent molecular contrast at clinical depth with spatiotemporal resolution. PAI can address this need as an emerging clinical modality that is non-ionizing, low-cost, and offers high-contrast and highspatiotemporal- resolution imaging for breast imaging, which was recently FDA approved. However, clinical use of molecular PAI has previously been limited by current contrast agents that are hampered by regulatory/safety concerns, suboptimal signal generation, lack of adequate photostability, or absorption spectrum overlapping with endogenous blood, making quantification through spectral unmixing difficult. We propose an innovative imaging probe based on antibody-targeted polymersomes loaded with J-aggregates of indocyanine green (ICG) dye (Ps- ICGJ). Our preliminary data show that antibody-targeted Ps-ICGJ provides impressive stability, PA signal intensity and linearity, and PAI detection limit of ~100 total labeled TNBC cells. Further, all components comprising the Ps-ICGJ contrast agent are non-toxic and made with FDA-approved materials providing a path towards future clinical translation. Our hypothesis is that non-invasive PAI using Trop-2-targeted Ps-ICGJ (aTrop-2-Ps-ICGJ) will provide quantitative, longitudinal, and point-of-care planning and monitoring of SGtherapy response for TNBC, which will be tested through the following aims: develop molecular Ps-ICGJ PAI contrast agent (SA1); optimize PAI of Ps-ICGJs in labeling of Trop-2+ in TNBC in vitro (SA2); validate Ps-ICGJbased PAI of Trop-2 expression in vivo (SA3). This study requires animal use because validating Ps-ICGJ-based PAI of Trop-2 expression in a living tumor microenvironment (SA3) – including vascular delivery, tumor uptake kinetics, and monitoring of SG therapy response – cannot be replicated in vitro and requires an intact, physiologically relevant in vivo system to validate the agent's preclinical diagnostic and monitoring capability. This project will deliver a new capability for quantitative molecular imaging that will combine high sensitivity with greatly improved spatial resolution for ADC therapy planning/monitoring that can be easily adapted to multiple cancer biomarkers in translational studies that are focused on ADC treatment planning and guidance.
