Glutamine Metabolic Reprogramming in Breast Cancer Metastasis to Bone
Abstract
Rationale: Most deaths related to breast cancer occur in patients that endure advanced disease resulting from breast cancer cells that escape to form tumors in distant organs throughout the body. These metastatic tumors most frequently occur in the bone and result in intense pain and a reduced quality of life for patients. Many patients do not develop these tumors in their bones until up to a decade later due to disseminated breast cancer cells lying dormant within the bone environment. However, the understanding of how cells metastasize only to remain inactive or dormant within the bone is limited. One clue is derived from the amino acid glutamine. The most aggressive and difficult to treat forms of breast cancer often use more glutamine to create energy and materials needed for cell division and other processes. However, glutamine is more rapidly consumed by bone metastasis compared to the original breast tumor. Glutamine is also important for the function of bone-forming osteoblasts, and dysregulation of glutamine metabolism within osteoblasts by tumor cells may contribute to metastasis development and progression within the bone. Therefore, enhanced glutamine utilization or metabolism may enhance the development of breast cancer metastases and/or dormancy escape of breast cancer cells within the bone. Objective: The objective of this proposal is to determine how glutamine metabolism within breast cancer cells and bone-forming osteoblasts regulates metastatic spread and dormancy escape within the bone. We will expand this knowledge to examine a new therapeutic strategy to treat patients with existing bone metastatic breast cancer. Aims: To accomplish the objective, we proposed two specific aims. In Aim 1, we will seek to determine how glutamine metabolism within breast cancer cells promotes metastasis and dormancy escape. Here, we will also evaluate whether an existing glutaminase inhibitor can sensitize bone-residing breast cancer cells to an existing class of non-chemotherapy drugs called senolytics. This novel therapy will be tested on a patient-derived breast cancer tissues that will provide valuable preclinical information in treating bone metastatic breast cancer in patients. In Aim 2, we will use a novel mouse model to evaluate how glutamine metabolism within the bone environment, specifically from bone-forming osteoblasts, prepares the bone to support recruitment and growth of breast cancer cells at this distant site. Significance: Metastatic breast cancer patients often face a poor overall outcome due in part to the complexity of the advanced state and limited therapeutic options. Better understanding of how breast cancer metastases develop and progress within the bone will aid in the development of better therapies for patients enduring bone metastatic breast cancer. If successful, this work will identify how breast cancer cells and bone-residing osteoblasts use glutamine to support breast-to-bone metastasis and dormancy escape. We will also exploit this knowledge to define a novel and innovative strategy to treat bone metastatic disease. These outcomes will (1) provide a better understanding of how dormant breast cancer cells within the bone may later awaken to form painful bone tumors by increasing glutamine usage and (2) revolutionize treatment regimens by identifying a new therapeutic strategy combining glutaminase inhibition and senolytics that is anticipated to be more effective and less toxic than current chemotherapies used to treat metastatic breast cancer. We propose the use of drugs that are either approved by the Food and Drug Administration, undergoing clinical trials, or natural products to expedite a clinical outcome in five years or less. Therefore, these preclinical findings have the potential to positively impact the more than 50% of metastatic breast cancer patients that develop bone metastatic disease in the near future. Metastatic breast cancer is currently
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210109
Entities
People
- Deanna N. Edwards
Organizations
- United States Army
- Vanderbilt University