Targeting cancer stem cell efficient DNA repair pathways: Screening for new therapeutics

Abstract

The existence of 'cancer stem cells (CSCs)' has been a topic of vigorous discussion for the last few years within the field of cancer biology. Continuous characterization of tumor cells has lead to an abundance of data supporting the existence of cell populations with stem cell characteristics, including self-renewal and expression of stem cell markers. There is also evidence suggesting that these cells are responsible for chemo- and radio-resistance and are the initiation point for metastasis, cancer recurrence, and ultimately patient demise. Therefore, finding new drugs that induce cancer stem cell death are of high interest as new therapies for cancer. Gene expression arrays, functional genomics screens with siRNA, as well as screening of small molecule libraries are approaches being used to better understand the cellular pathways that are critical for cancer stem cell survival. Finding drugs that target these pathways in cancer stem cells could represent novel therapies for cancer, in particular for the prevention of metastasis and recurrence. Recent data shows that DNA repair genes are upregulated in pancreatic cancer stem cells, thus providing increased genomic stability and resistance to cell death upon treatment with DNA damaging agents such as gemcitibine. Here we review how a higher efficiency of DNA repair in cancer stem cells can be leveraged therapeutically, and discuss how small molecule screening approaches using stem cells are being used to find new potential therapies that result in terminal differentiation or cell death of cancer stem cells, both as single agents or in combination with other chemotherapeutics.