Development of a Novel Separase Inhibitor, Sepin-1, for Breast Cancer Therapy
Abstract
Our goal in this project is to develop a new class of drugs that are safe and effective with the least side effects for the treatment of advanced, metastatic, highly heterogeneous, and refractory breast cancer (BC) tumors, for which current treatment options are limited. A great majority of the highly aggressive breast tumor cells have abnormal chromosome numbers (more or less than 46), a phenotype called aneuploidy. Aneuploidy is associated with not only an aggressive disease phenotype but also lower overall survival. Aneuploid tumors that are classified into the same clinical subtypes can be genetically varied (heterogeneous), and they are thought to contribute to metastasis and acquired resistance to therapy. Although aneuploidy is a well-established feature of advanced BC, surprisingly the aneuploidy status and its underlying mechanisms have not been well exploited for BC therapy and as a means to circumvent tumor heterogeneity. Separase, an enzyme important for cell division, is overexpressed in more than 60% of breast tumor specimens, 50% of triple-negative (ER/PR/HER2-) BC (TNBC) tumors, and 65% of Luminal-B BC tumors. Separase overexpression strongly correlates with aneuploidy, high incidence of relapse, metastasis, and a lower 5-year overall survival rate. In mouse models, Separase overexpression has been shown to induce aneuploidy, genomic instability, mammary tumorigenesis, and intratumoral heterogeneity. We propose here that modulation of Separase enzymatic activity constitutes a new therapeutic strategy for targeting Separase-overexpressing aneuploid tumors to circumvent heterogeneity, particularly the hard-to-treat BC tumors that often develop resistance to conventional chemotherapy. In our laboratory, we have identified five novel small molecular inhibitors of Separase enzymatic activity, which we named Sepin 1-5. Our studies indicate that Sepin-1, one of the lead compounds, is not only well-tolerated by the animals, with the least toxicity, but also is highly effective in inhibiting the growth of Separase-overexpressing human TNBC tumor xenografts in mice. In this same assay, however, Sepin-1 has very little activity in inhibiting the growth of tumors with low-Separase activity. Encouraged by these preliminary studies, we propose here: (1) to examine phramocokinetics, pharmacodynamics, and the efficacy of Sepin-1 in animal models by implementing an innovative mouse clinical trial, and (2) to characterize the mechanisms of Sepin action at the molecular level. Blocking the overexpressed Separase activity as a strategy to eliminate and/or sensitize resistant cancer cells to chemotherapy and to circumvent tumor heterogeneity is a new therapeutic approach that, if successful, will significantly impact cancer treatment. To implement this project, we have assembled a team of collaborators with expertise in cancer biology (Dr. D. Pati), clinical pharmacology (Dr. Stacey Berg), histopathology (Dr. Roger Price), and mouse clinical trials (Dr. Michael Lewis), and last but not least, a patient advocate for BC research (Mrs. Anne Meyn, a projectLEAD graduate with 7 years of experience as an active BC research advocate). At the end of this project (i.e., within 3 years), we hope to develop druggable agents to inhibit Separase activity that can be used in Phase I clinical trials to treat patients with Separase overexpressing primary and/or refractory breast cancer. We also anticipate that the status of Separase expression of the human breast tumors can be used as a new classification for personalized therapeutic intervention.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510122
Entities
People
- Debananda Pati
Organizations
- Baylor College of Medicine
- United States Army