Using Sphingolipids to Target Metabolism and Metastasis in Breast Cancer
Abstract
Cancer cells take up nutrients from the environment faster than normal cells and assemble these nutrients into new cells with incredible efficiency. When plenty of raw materials are available, no normal cell can out-proliferate a cancer cell. However, when raw materials are limited and the production of new cells should slow, cancer cells continue to try to grow at full throttle. This makes them vulnerable; cancer cells that aren t able to rest or hibernate when nutrients are limiting will eventually starve to death. Our plan is to develop drugs that create nutrient limitation to induce a hibernation-like state in normal cells while eliminating the cancer cells that can t go to sleep. There is a strong precedent for this idea as people who eat less are protected from cancer while people who are overweight are more prone to cancer and have worse outcomes. By reducing how much cells can eat, we hope to produce similar benefits without forcing patients to actually starve. For nutrients to enter a cell, they must cross the membrane barrier that separates a cell from its environment. Nutrient transporter proteins in this membrane function like doors that let sugars and amino acids into the cell interior where they can be used to make the bricks necessary to build new cells. Cells go hungry when there are no nutrients knocking at the door, but they also go hungry if there are plenty of nutrients and no doors. We have identified compounds that remove these nutrient transporter doors from the membrane. These compounds starve cells as effectively as actually taking the nutrients away. To the best of my knowledge, no one has ever tried this approach of targeting the nutrient transporters in order to starve cancer cells to death. The overarching challenge we are addressing is to revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. As outlined above, the normal cells should hibernate and wake up ready for spring once the treatment is suspended. This work is also responsive to the challenge of eliminating the mortality associated with metastatic breast cancer. Disseminated tumor cells will be just as susceptible to these circulating drugs as the original tumor mass. In fact, the more advanced the disease is, the more mutations the tumor cells will have that sensitize them to starvation. Even the stem cells that likely drive tumor recurrence have metabolic changes that should make them susceptible to these drugs. In addition to targeting existing metastases, these drugs may actually stop metastasis from occurring. A protein targeted by our drugs allows cancer cells to crawl in and out of the blood stream. This protein is known to be activated in breast cancers, and thus our therapeutic approach is particularly well-suited to breast cancer. The era of "personalized" medicine is here, and everyone is focused on identifying precisely what is wrong in an individual patient s tumor. Our starvation strategy is a good one precisely because the drugs that we are developing will kill almost every kind of cancer cell, whether it overexpresses HER2 or EGFR, lacks BRCA1/2, or has a mutation not common in breast cancer. We have piloted much of our work in leukemia systems because the cells are easy to isolate from mice and study in the lab. However, we want to move this work into a solid tumor system and breast cancer is ideal because (1) there are well-developed animal models for metastasis, (2) in screening a panel of cancer cell lines, one of the most sensitive cells to our drug is a highly aggressive, triple-negative breast cancer cell line with high metastatic potential, and (3) a protein that our drugs target is already known to be hyperactivated in human breast cancers and required for metastasis. The compounds we have developed have properties that should make them excellent drugs. They are derived from a Food and Drug Adminis
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510010
Entities
People
- Aimee L Edinger
Organizations
- Naval Information Warfare Center Pacific
- United States Army