Nanotechnology-Based Targeting of Breast Cancer Liver Metastases
Abstract
This project implements a new approach to quickly help patients with metastatic breast cancer. It is well recognized by doctors and scientists that the organ where cancer spreads and its microenvironment are important in determining if treatments will work. Although personalization of therapies based on molecular signatures is an acceptable clinical practice in breast oncology, distant metastases are usually treated in similar ways, regardless of the organ they have gone to. We believe that it is important to change this therapeutic approach by considering tumors metastasized in different organs as different diseases, which require personalized therapy that accounts for the location of the tumors. In this proposal, we focus on liver metastasis, one of the most challenging metastases, as it is generally considered a death sentence for breast cancer patients. Our approach could also be used to treat metastasis in other organs. Liver metastases occur in more than 30% of patients with metastatic breast cancer. Although some breast cancer patients respond to current treatments, the typical survival is only 1–14 months, which is incredibly poor compared to survival from metastases at other distant sites (e.g., isolated soft tissue metastases have a median survival of > 50 months and bone 33–48 months). Thus, new therapeutic approaches for liver metastases are urgently needed. One of the factors that dooms treatment for breast cancer liver metastasis is lack of efficient blood vessels. While the liver is an organ enriched with blood vessels, normally showing with a pronounced red color, breast cancer metastases appear as white spots, which means that they are poor in blood vessels. This situation is specific for breast cancer lesions in the liver. The consequence is that chemotherapies do not reach all of the tumor cells. This is a main reason for treatment failure. Many breast tumors in the liver are surrounded by immune cells, called macrophages. The function of these cells in the body is to engulf “foreign” objects. We have designed a therapy that uses macrophages to deliver therapeutic nanovectors to target liver tumors. These cells are like “Trojan horses,” retaining drugs in the proximity of tumors in the liver and, consequently, increasing local concentrations of therapeutics even when the tissue is poorly vascularized. This approach significantly prolongs survival from breast cancer liver metastasis in vivo. In this proposal, we develop a system to quickly determine which patients will likely benefit from the proposed approach and, in particular, to predict the effect of macrophage-delivered therapy on liver lesions based on tissue samples or histological slides taken from patient-resected tumors. This will help to efficiently personalize this nanomedicine-based therapy. We propose to: (1) evaluate ability of different breast cancers (including commercially available human cell lines and clinically derived tumors from patients) to recruit macrophages in vitro in three-dimensional breast tumor spheres, which resemble poorly vascularized liver tumors; (2) test the correlation between the number of macrophages in primary tumors and in distant tumors in the liver in vivo and in clinical samples from patients, and the ability to take up and slowly release nanotherapeutics; (3) apply sophisticated computational modeling to fine-tune therapy schedules and quickly predict response based on patient tumor-specific analysis of macrophages and other markers in the tumor microenvironment. Lastly, we will assess toxicity to ensure clinical utility. We strongly believe that the proposed approach, in combination with existing therapies targeting the primary site as well as bone, lung, and other organ metastases, will provide a much needed personalization of therapy for patients with breast cancer liver metastases. We are excited that the outcome of this project represents a dramatic paradigm shift in the way that metastases ar
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110012
Entities
People
- Hermann B Frieboes
Organizations
- United States Army
- University of Louisville