Targeting the Bone Stromal Compartment to Enhance Tumor Cell Killing and Protect Against Chemotherapy-Induced Bone Loss
Abstract
Despite the fact that the majority of breast cancer cases are diagnosed early, approximately 10%-20% of patients recur with metastatic disease within 10 years. Significantly, these cases arise in patients previously "cured," demonstrating that primary tumor cells can metastasize early and remain dormant in distant sites only to awaken years later. Given the large percentage of patients that return to the clinic years after their initial "cure," and the sad fact that treatment options are limited and in many cases only palliative, uncovering the mechanisms that protect dormant metastatic cells and allow their eventual outgrowth will have a profound impact on the development of novel therapies and patient outcome. Using a novel mouse model, we find that age-related changes in the bone drives bone turnover that we suggest can create a safe haven that allows the emergence of metastatic bone lesions. Our data suggest that these changes are due to the secretion of tumorigenic factors referred to as the senescence-associated secretory phenotype (SASP). Intriguingly, SASP expression also occurs in response chemotherapeutic agents. This finding raises the possibility that the very agents we employ to destroy cancer cells also drive bone loss and create safe havens that allow cancer cells to lay dormant and emerge months to years later to grow into life-threatening lesions. This proposal will determine how SASP factors contribute to bone loss following chemotherapy. Further, we will determine how SASP factors create a protective niche within the bone. Data obtained from this study will set the stage for us to develop strategies that preserve the cytotoxic effects of chemotherapy on tumor cells, while at the same time mitigating chemotherapies detrimental impact on the bone microenvironment. Because nearly all breast cancer patients, regardless of subtype are treated with chemotherapeutic agents, our work holds the potential to not only positively impact the day-to-day lives of breast cancer patients but also to identify new therapeutic options that limit the outgrowth of life-threatening metastatic lesions in the bone.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610728
Entities
People
- Sheila Stewart
Organizations
- United States Army
- Washington University in St. Louis