Epigenetic Targeting of the Cancer Stem Cell Hierarchy in Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (lacking estrogen and progesterone receptors and HER2 amplification; hereafter TNBC) is the most deadly form of breast cancer and often affects young women. It cannot be treated with hormonal therapy or Herceptin, and resistance to chemotherapy and radiation invariably emerges rapidly; thus, novel, more effective therapies are urgently needed. Many cancers appear to be driven by stem-like cells that fuel the growth of the cancer and give rise to daughter cells that differ from their parents. The stem cells are the cancer drivers, and while most of the tumor cells are killed by chemo and radiation, these driver cells are treatment resistant and survive chemo- and radiation therapy to allow the tumor to regrow and show up later as metastatic disease. Other groups have shown that these stem-like cancer cells can be identified by certain proteins or markers on their cell surface and by their ability to form tumors when very few cells are injected into a mouse host. Our group recently showed that targeting the breast cancer stem cells may be more complicated than previously anticipated. It seems that within cancer stem cell populations there exists a hierarchy in which parent stem cells are more aggressive, more highly metastatic, and driven by different molecular pathways compared to daughter stem cells. Both the parent and daughter subsets of stem cells can form tumors and may differ in how they respond to chemo and radiation, with the parent stem cells being more resistant. We carried out a drug screen using a new family of drugs that alter the shape of packaged DNA or chromatin. These drugs modify cell behavior by turning on and off master regulators that govern stem cell behavior and differentiation processes in normal and cancer. The exciting thing here is that these epigenetic drugs are already in clinical trials in leukemia and lymphoma, and we can test their potential for use in this most deadly form of TNBC. Our grant proposes to investigate whether our preliminary findings are applicable to a larger number of TNBC models and verify their action in tissue culture. We will then investigate further how these chromatin modulating enzymes (targeted by the epigenetic drugs) work to drive the genes that dictate stem cell action. Finally, the grant will test these new drug compounds in human breast cancer tumors grown in mice to see if they actually target breast cancer stem cell activity and test if they can prevent metastasis and cause metastasis to regress. We will also test if these drugs that target different breast cancer stem cell subpopulation act synergistically when used together to downregulate tumor growth and metastasis in these animal models of breast cancer. The ability of these drugs to complement taxane chemotherapy will also be tested since the chemo hits the non-stem cell population, while these drugs appear to target the stem cells. This work is innovative since no one to date has reported stem cell subsets that have a parent daughter relationship in breast cancer. Furthermore, it is innovative because we apply drugs with emerging efficacy in leukemia to the most aggressive form of breast cancer. This grant tests for the first time if novel combinations and sequencing of EZH2 and DOT1L inhibitor drugs will eliminate two different TNBC stem cell populations and tests their potential to abolish the stem-like cell subsets that initiate tumor formation and metastasis. We will also test for the first time whether combinations of epigenetic drugs (EZH2 and DOT1L inhibitors) may augment the efficacy of chemotherapy for breast cancer, since they would kill the most chemoresistant cancer stem cells, while chemotherapy would eliminate the non-stem bulk tumor population. This work has the potential to provide a new form of therapy that effectively cuts TNBC off at the roots.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510581
Entities
People
- Joyce M Slingerland
Organizations
- United States Army
- University of Miami