Targeted Drug Nanocarriers for Inhibiting Bone Metastatic Breast Cancer
Abstract
Breast cancer frequently spreads (metastasizes) to distant sites, where it can disrupt normal biological function. Most patients who die or experience serious pain and loss of quality of life due to breast cancer do so because of these distant metastases. In breast cancer patients, the primary tumor has less of an impact, since it is normally removed by mastectomy. Unfortunately, once tumors have metastasized, they are often resistant to currently available therapies and therefore are very challenging to treat. Additionally, the available treatments often have serious side effects and cause significant reductions in patient quality of life even if they improve survival. Therefore, drugs with fewer side effects and better ability to specifically and potently attack the metastatic tumor cells are needed for breast cancer patients. Breast cancer cells can spread to many different organs with the most common being the brain and bone. Approximately 70% of breast cancer patients that die from disease will have bone metastases, and these incurable metastases are a significant cause of patient pain and loss in quality of life due to increased risk for fracture and the toxic nature of the drugs used to treat them. In order to solve this problem, we combined expertise of a cancer expert (Sterling) whose research has focused on breast cancer metastasis to bone and a biomedical engineer (Duvall) whose research focuses on targeted nanoparticle delivery of therapeutics. We have previously shown that the protein GLI2 drives production of the tumor-derived factor know as parathyroid hormone related protein (PTHrP), which directly contributes to breast tumor establishment and bone destruction. Genetic inhibition of GLI2 expression in breast cancer cells dramatically reduces breast cancer growth in bone and bone destruction in a mouse model, suggesting that GLI2 will make an ideal target for new therapeutics designed to block breast cancer skeletal metastases. We have tested multiple GLI2 and pan-GLI inhibitors and consequently identified GANT58 as a promising drug for inhibiting tumor-induced bone disease through reducing GLI2 function. However, therapeutic use of GANT58 and other GLI2 inhibitors has been challenging due to poor solubility and delivery to bone, indicating a need for new delivery technologies that enable the application of these drugs for treating and/or blocking breast cancer metastasis to bone. Therefore, we hypothesize that bone-targeted nanoparticle delivery of GLI2 inhibitors will significantly reduce breast cancer metastasis to bone, block growth of existing bone metastases, and inhibit tumor-induced bone disease. Unlike standard chemotherapeutics that indiscriminately kill dividing cells, GLI2 inhibition is not anticipated to have significant negative side effects in adult breast cancer patients because GLI2 expression is not required in most adult tissues. Dr. Duvall s group has recently developed safe and efficient nanoparticles for targeted delivery of small molecules to tumor cells in vivo. These nanoparticles have been designed to maximize drug delivery to and retention in bone in order to improve efficacy and avoid any potential negative effects on normal tissue. We will test the performance of these nanoparticles loaded with the GLI2 inhibitor in preclinical models for toxicity, localization in bone and pre-existing bone tumors, and the ability to stop occurrence and growth of breast tumor metastases in bone. We anticipate that these studies will yield new therapeutic options reducing tumor-induced bone disease and mortality associated with bone metastatic disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510622
Entities
People
- Julie Sterling
Organizations
- United States Army
- Vanderbilt University