Therapeutic target discovery and drug development in cancer stem cells for leukemia and lymphoma: from bench to the clinic.

INTRODUCTION: Cancer stem cells (CSCs), also known as tumor initialing cells, have self-renewal capacity and are believed to play an important role in residual disease or tumor relapse. CSCs exhibit characteristic slow growth rate and are resistant to conventional chemotherapy/radiotherapy in experimental models. The type of cells commonly employs aberrant activity of the embryonic signal transduction pathways - Notch, Hedgehog (Hh), and Wnt - for uncontrolled proliferation and survival. Areas covered: The following article discusses key genetic and molecular alterations in Notch, Hh and Wnt pathways and drugs targeting the alterations for the treatment of leukemia and lymphoma. Expert opinion: Early signs of signal agent activity have been observed in certain types of leukemia and lymphoma with experimental therapeutics targeting the embryonic pathways in the CSC signaling network. However, clinical development of agents that inhibit the Wnt/β-catenin, Notch and Hh signaling appear to be more complex in relapsed or refractory malignancies. A strategy to effectively target signaling may rely on early application of biomarkers representative of the active signaling nodes companion to the molecularly targeted agents. Biomarkers for efficacy could potentially guide selective treatment of hematological malignancies or cancer with drugs that target the embryonic pathways.