Alam M.,Dana-Farber Cancer Institute |
Rajabi H.,Dana-Farber Cancer Institute |
Ahmad R.,Dana-Farber Cancer Institute |
Ahmad R.,King Saud University |
And 2 more authors.
Oncotarget | Year: 2014
The capacity of breast cancer cells to form mammospheres in non-adherent serum-free culture is used as a functional characteristic of the self-renewing stem-like cell population. The present studies demonstrate that silencing expression of the MUC1-C oncoprotein inhibits growth of luminal MCF-7 and HER2-overexpressing SKBR3 breast cancer cells as mammospheres. We also show that triple-negative MDA-MB-468 breast cancer cells are dependent on MUC1-C for growth as mammospheres and tumor xenografts. Similar results were obtained when MUC1-C function was inhibited by expression of a MUC1-C(CQC→AQA) mutant. Moreover, treatment with the MUC1-C inhibitor GO-203, a cell penetrating peptide that binds to the MUC1-C cytoplasmic domain and blocks MUC1-C function, confirmed the importance of this target for self-renewal. The mechanistic basis for these findings is supported by the demonstration that MUC1-C activates NF-κB, occupies the IL-8 promoter with NF-κB, and induces IL-8 transcription. MUC1-C also induces NF-κB-dependent expression of the IL-8 receptor, CXCR1. In concert with these results, targeting MUC1-C with GO-203 suppresses IL-8/CXCR1 expression and disrupts the formation of established mammospheres. Our findings indicate that MUC1-C contributes to the self-renewal of breast cancer cells by activating the NF-κB→IL-8/CXCR1 pathway and that targeting MUC1-C represents a potential approach for the treatment of this population.
Genus Oncology and Dana-Farber Cancer Institute | Date: 2015-02-12
Peptides from the Mucin 1 (MUC1) cytoplasmic domain and methods of use therefor are described. These peptides can inhibit MUC1 oligomerization, thereby preventing tumor cell growth, inducing tumor cell apoptosis and necrosis of tumor tissue in vivo.
Dana-Farber Cancer Institute and Genus Oncology | Date: 2013-03-28
The invention provides method of treating cancers that express MUC1 by the administration of PI3-K inhibitors in combination with MUC1-directed cancer therapies. The PI3-K inhibition may advantageously be combined with peptides that inhibit MUC1 oligomerization, or further with other standard anticancer therapies such as chemo-, radio- and surgical therapies.
Genus Oncology and Dana-Farber Cancer Institute | Date: 2014-03-10
The invention provides for treatment of HER2+ cancers using a combination of anti-MUC1 therapy and anti-HER2 therapy. In particular, the invention addresses the treatment of trastuzamab-resistant cancers, both primary and acquired, using the same combination of agents.
Genus Oncology and Dana-Farber Cancer Institute | Date: 2014-04-01
The present invention is directed to improved compositions for cellular delivery of peptides. Using segments of only 3-5 positively-charged residues, one can effectively transfer peptides, including therapeutic peptides, into cells. Also provided are modified peptides such as those include stapled and cyclized peptide technology, as well as peptoids/peptidomimetics.