Dr. Pilar Blancafort, an Assistant Professor in the Department of Pharmacology, has received a Department of Defense Breast Cancer IDEA Award to study breast cancer stem cells. The title of her proposal is "Re-writing the histone code of breast cancer stem cells." Her award is $407,000 for 2 years. Dr. B. Strahl, an Associate Professor in the UNC Biochemistry Department who studies histone modification and gene regulation is a collaborator on the project.
Women with basal or triple negative breast cancer typically develop aggressive tumors which are able to metastasize quickly. This subtype of breast cancer is not very responsive to chemotherapy; current anti-hormonal treatments such as tamoxifen are not very effective and tumors relapse after chemotherapy. Breast cancer stem cells (CSC), which can be likened to “corrupted” stem cells, populate these tumors. Given that cancer stem cells are resistant to drugs, have the ability to self renew, migrate and differentiate in all cell types in the mammary gland, these kinds of cancers have the poorest prognosis. Thus, there is a need for a novel approach to targeting the genes that are responsible for self renewal and tumor generation that have become dysregulated in these cells.
The goal of this study is to develop a novel specific method to kill CSC cells by editing the chromatin at specific gene promoters to generate an epigenetic “off switch” in self-renewal gene promoters. These switches will generate persistent chromatin silencing markers leading to inhibition of self-renewal in cancer stem cells. The tool being developed to do this is a novel molecule named Design Epigenetic Remodeling Factors (DERFs). DERFs are designed with a portion developed in the Blancafort lab called a Zinc Finger (ZF), that can bind to specific sequences in a gene. These ZFs will be engineered with chromatin remodeling domains to target genes specifically damaged in CSCs, to kill CSCs and not normal cells.
Another potential outcome will be the sensitization of the CSCs to chemotherapy; which will allow a smaller dose of a therapeutic agent to be required to destroy the tumor. This can potentially help patients by preventing the relapse of the tumor/metastasis upon chemotherapeutic treatments, and also to help relieve the suffering and side effects associated with chemotherapy.
Drs. Blancafort and Strahl first plan to develop the proof of concept by expressing these novel tools in basal cancer models of tumors in animals, then working with researchers at UNC-CH to encapsulate these new tools in artificial particles (nanoparticles) that will be specifically delivered into the tumors and metastasis.
This project proposes a novel approach to suppress what might be the root of the basal breast cancer, with direct applications in the clinic for treatment of basal breast cancer.
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