Validation of MECP2 as a New Therapeutic Target in TNBC
Abstract
The goal of this study is to investigate whether the overexpression of a newly discovered oncogene, MECP2, defines a subset of triple-negative breast cancers (TNBCs) that has unique molecular characteristics that make it susceptible to less toxic therapies than those currently used. Traditionally, TNBC has been characterized by what it is not, that is, not hormone receptor positive, and not HER2/Neu amplified. This classification does not distinguish among subtypes of TNBC with clinically important characteristics. Our prior work has focused on defining a subset of TNBC that is vulnerable to the platinum chemotherapy agents, and others have developed various molecular profiles with the goal of dividing TNBC into subtypes that predict susceptibility to various therapies. The ultimate clinical goal is to be able to treat a patient with TNBC with the therapies most likely to benefit her, and to move away from the one-size-fits-all model with very toxic chemotherapies that currently results in a high rate of recurrence in the adjuvant setting, and poor survival in the metastatic setting. We recently conducted a screen of all genes, looking for genes that when overexpressed could substitute for a mutated gene commonly active in human malignancy, activated Ras. Our motivation was that though activated Ras is present frequently in a number of human cancer types, it is rare in breast cancer, raising the possibility that there are a variety of undiscovered genes that could take its place in breast cancer. Further, there are a large number of contiguous groups of genes present in TNBC and other cancer genomes at higher than normal number (amplified DNA segments) that are often shared by many cancers, and since there are extra copies, these genes are often expressed at higher than normal levels. The specific genes on these segments whose overexpression confers an advantage for these cancers are often unknown. Our screen found 15 genes that could substitute for activated Ras, and we examined this list for those potentially important in human cancers. The Methyl CpG Binding Protein 2 gene (MECP2) is amplified in a very striking manner across approximately 20% of all of human malignancies, and its rate of 30% amplification in TNBC strongly implies clinical importance. We have strong preliminary data supporting the importance of MECP2 in a subset of TNBCs, and these data set the stage for this Breakthrough Level II application. We have shown that several cell lines that grow readily in tissue culture derived from TNBC tumors have amplified, overexpressed MECP2 and that reducing their MECP2 expression results in very significantly decreased growth. This result strongly suggests that therapy to inhibit MECP2 activity may have an antitumor effect. Further, we have begun to define those aspects of MECP2 action necessary for its role in cancer promotion and growth. MECP2 requires both DNA methylation and the activity of an HDAC complex that modifies chromatin for its cancer-promoting activities. There are Food and Drug Administration (FDA)-approved drugs for other cancers that either inhibit DNA methylation or HDAC function; therefore, there is an urgent need to define the subset of TNBC dependent on MECP2 and to characterize the effect of these FDA approved drugs in this subset of TNBC. These drugs, 5-azacytidine and HDAC inhibitors, have many fewer side effects than currently used chemotherapy, so their use in this subset of TNBC might mean not only a clinically meaningful benefit, but a better quality of life for patients. Lastly, because these drugs are already FDA-approved, success in this proposal will result in unusually rapid translation into clinical trials. The first specific aim will investigate the MECP2 dependence and the response to MECP2-directed drug therapy of additional TNBC cell lines and a new TNBC model, patient-derived xenografts (PDXs). PDXs are a model of TNBC, in which a patient s tumor is directly
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510016
Entities
People
- Daniel Silver
Organizations
- Dana–Farber Cancer Institute
- United States Army