Thursday, June 8, 2023
6/8/2023
PROJECT ABSTRACT Breast cancer (BC) is the most prevalent cancer and the second-leading cause of cancer-related death for women in the USA. For moderate-risk and, especially, low-risk women with a 1-in-8 lifelong chance of developing BC, there are very few options available to reduce their risk. For high-risk women, prophylactic mastectomy is currently the most effective procedure for preventing BC. This aggressive surgical procedure affects women physically, emotionally, psychologically, aesthetically, and socially. Therefore, there is a need to develop new strategies for primary prevention that focus on high-risk women, but that could also be applied to moderate- and low-risk women. Our overall hypothesis is that the local killing of mammary epithelial cells will be as effective as prophylactic mastectomy in preventing BC, but with minimal side effects. Our preliminary and published data demonstrate that intraductal (ID) injection of a 70% ethanol (EtOH) solution is effective at locally ablating mammary epithelial cells in rodent models and at preventing tumor formation in an aggressive mouse model of BC. The scientific rigor of prior preclinical and clinical research studies as well as clinical use of ID procedures strongly support the translational feasibility of our approach. We have developed a refined EtOH-based solution that contains: tantalum oxide (TaOx) nanoparticles as a high-resolution contrast agent to monitor in vivo filling of ductal trees by CT/X-ray imaging; and ethyl cellulose as gelling agent to further minimize collateral tissue damage. The research objectives of this study are: a) to optimize methods for achieving and in vivo visualizing maximal epithelial ablation; b) to determine the protective benefit and safety concerns of incomplete epithelial ablation; c) to understand the interactions of the components of the ablative solution with the tissue (e.g., fibrosis) and their potential interference with imaging findings (e.g., contrast clearance); and d) To apply this knowledge to establish a clinically compatible procedure for image-guided ablative therapy. To accomplish these, we propose the following two specific aims: Aim 1) To evaluate therapeutic efficacy and safety profile of the ID ablative procedure in rat models of breast cancer; Aim 2) To assess scalability of this image-guided ID ablative procedure in the multi-ductal tree system of a rabbit model. Given the clinical uses of EtOH, diagnostic ID procedures, and clinically compatible imaging protocols, positive results of this study could rapidly lead to the evaluation of image-guided EtOH-based ablation procedure in first-in-human clinical trials for high-risk women. If successful in a high-risk setting, this ID procedure could be offered to moderate- and low-risk women who want to decrease their chance of developing BC and the cancer-associated anxiety that affects their quality of life.
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