Targeting Increased Polyamine Transport of Resistant Melanomas
Abstract
Fiscal Year 2015 (FY15) Peer Reviewed Cancer Research Program (PRCRP) Topic Area: Melanoma and other skin cancers. FY15 PRCRP Military Relevance Focus Area: Gaps in cancer treatment that may affect the general population but have a particularly profound impact on military health. In recent years, the treatment of metastatic melanoma has progressed dramatically due to the development of targeted therapies that specifically inhibit proteins that are found in higher levels or that are activated in melanoma. The discovery that many melanoma tumors are driven by a mutant BRAF protein precipitated the development of specific inhibitors of the mutant BRAF (vemurafenib and dabrafenib). Although BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with mutant BRAF melanoma, the tumors inevitably relapse after a short time and are resistant to further treatment with these drugs. Thus, new therapeutic strategies are urgently needed to overcome the acquired resistance to BRAF inhibitors in order to increase survival in melanoma patients. The scientific objective of this proposal is to test whether melanomas that are insensitive to current BRAF inhibitors can be successfully treated using a novel drug called AP, which we predict will selectively enter and kill BRAF inhibitor-resistant cells with high polyamine transport activity. Whereas treatment with a BRAF inhibitor quickly kills rapidly growing tumor cells that make up the bulk of the melanoma tumor, a very small subpopulation of slow-growing cancer stem cell (CSC)-like cells are not killed. These chemoresistant-CSCs have the ability to survive in relatively harsh, low-oxygen conditions in the melanoma tumor, and they can also transform themselves into melanoma cells that can grow into a more aggressive tumor that can metastasize to other parts of the body, resulting in the patient s death. Thus, the ideal treatment approach is to co-treat with a BRAF inhibitor and a compound that can target these chemoresistant CSCs. All cells need polyamines in order to grow and survive; however, melanoma tumor cells are especially addicted to these growth factors and scavenge them from their surroundings via their polyamine transport system. The rationale for our drug design is that both natural polyamines and polyamine-based drugs are imported into cells via a specific polyamine transport system. We propose that polyamines are critical for CSC survival and their development of resistance to BRAF inhibitor drugs. Because of this need for polyamines for survival, CSC that are resistant to BRAF inhibitors dramatically increase their import of polyamines via their polyamine transport system. Using a Trojan Horse approach, AP, which is disguised as a polyamine, will enter the CSC tumor cells but, unlike normal polyamines, it will kill the chemoresistant CSC subpopulation of cells in the melanoma tumor. In contrast, normal cells have limited polyamine transport activity and will remain unharmed at the low doses needed to kill the tumor cells. Not only can AP target the polyamine transport system of melanoma cells, but it can also block CXCR4, a protein that plays an important role in tumor metastasis and recruitment of tumor-promoting immune cells (such as macrophages) from the bone marrow to the tumor. We will test to what extent AP can also block metastasis and the action of tumor-infiltrating macrophages that also contribute to the development of resistance to BRAF inhibitors. Over the next 2 years, this project will test the ability of a novel compound (AP) to enter and selectively kill melanoma tumor cells that are resistant to BRAF inhibitors using both cultured cells and in animal models of melanoma. A success here will provide a new medicine to be used in tandem with existing BRAF inhibitors to increase their effectiveness that can be tested in clinical trials in the next 5 years. The ultimate applicability of the project will be a new therapy for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610370
Entities
People
- Susan Gilmour
Organizations
- Lankenau Institute for Medical Research
- United States Army