Selective inhibitors of tumor-initiating cells
Described herein are novel malignancy associated gene signature biomarkers, and assays and methods thereof, to classify prognosis or malignant potential of a cancer and identify cancer-initiating cells. The malignancy associated gene signature biomarkers, assays and methods described herein provide, in part, new methodologies to screen for novel drugs for treating cancers and tumors, such as, for example, triple-negative breast tumors. Using the assays and methods described herein proteasome inhibitors, histone deacetylase inhibitors, and glycolysis inhibitors, were identified as being highly effective in altering gene expression signatures specifically in malignant or cancer-initiating cells.
1. A method of identifying a candidate therapeutic agent against a cancer initiating cell comprising the step of
a. exposing a human breast primary epithelial cell transformed derivative (BPLER) cell culture to a test agent, wherein said BPLER cell culture comprises human breast primary epithelial cells (BPE) transformed with at least one genetic element selected from hTERT, SV40 early region and h-RAS V12 ;
b. measuring expression of at least ten malignancy associated response signature biomarkers wherein the at least 10 biomarkers are selected from the expression signature biomarker set consisting of SEQ ID NOs:1-154 in the BPLER cell culture to obtain a measured expression level,
c. comparing the measured expression level from step (b) to an expression signature reference from a BPLER cell culture that has not been exposed to the test agent, wherein a decrease of expression of at least 5 of the at least 10 biomarkers in the test culture compared to the expression signature reference indicates that the test agent is a candidate therapeutic agent against a cancer initiating cell.
2. The method of claim 1 , wherein the cancer initiating cell is a basal-like breast tumor-initiating cell.