Wnt inhibitors also are being investigated in phase I clinical trials. Oral LGK974[80] is a potent and specific inhibitor of O-acyltransferase Porcupine (Porcn) that acetylates Wnt proteins required for their biological activities is being investigated in a phase I clinical trial in patients with malignancies dependent screening library on Wnt ligands. This trial is enrolling patients with pancreatic and colon adenocarcinoma. Targeting ATP-driven efflux transporters has been explored in preclinical and early phase clinical trials. The first drug efflux pump inhibitor is verapamil.

Simultaneous treatment with verapamil and chemotherapy resulted in promising antitumor activity. Other agents such as Dofequidar Fumarate (MS-209), Biricolar (VX-710), and tariquidar are in various stages of clinical development[81-83]. Most of the experience with these agents is derived from lung and breast cancer trials but these agents, to our knowledge, have not been investigated in gastrointestinal cancers. CONCLUSION Identification and targeting CSC is an intriguing area and may provide a new therapeutic option for patients with cancer including gastrointestinal malignancies. It is a rapidly evolving area in the treatment of gastrointestinal and other tumors. Although great progress has been

made, many issues need to be addressed. The CSC model does not fully explain the observed genetic heterogeneity of many tumors. This criticism may however be explained by the fact that even CSC may evolve over time

and give rise to cells that are both genetically and functionally heterogeneous[1]. Furthermore, accurate targeting of CSC will require precise isolation and characterization of those cells. This field is also evolving but further research is needed to identify markers that are specific for CSC. Nevertheless, there continues to be significant excitement about this field and hope that it may represent a new treatment modality in patients with cancer. Footnotes P- Reviewer: AV-951 Han X, Kamer E, Pan WS S- Editor: Song XX L- Editor: A E- Editor: Lu YJ
Core tip: MiR-140 is an important tumor suppressor. By inhibiting stem cell growth through interaction with the Wnt, SOX2 and SOX9 pathways, breast cancer initiation, progression and growth are reduced. miR-140 is progressively downregulated as breast cancer grade decreases, through both estrogen binding and differential methylation in the miR-140 promoter region. By targeting these mechanisms using epigenetic therapy miR-140 tumor suppressor signaling can be reactivated. INTRODUCTION Breast cancer is a heterogeneous disease comprised of several histologic and molecular subtypes. Transformation from normal mammalian epithelial cells to aggressive malignancy is due to the accumulation of numerous genetic and epigenetic changes.