Cancer Stem Cells and Targeting Embryonic Signaling Pathways

Abstract

The treatment of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) has reached a plateau of effectiveness with doublet chemotherapy. Profound responses are observed with anti-epidermal growth factor receptor (EGFR) tyrosine kinase and anaplastic lymphoma kinase inhibitors in patients with EGFR-activating mutations and EML-4-anaplastic lymphoma kinase gene fusion, respectively. Patients eventually will develop disease progression. With an increased understanding of the biology of lung cancer, its molecular complexity has become very apparent, and curing this disease with current conventional treatments is highly unlikely. One hypothesis, discussed in an introductory talk by Dr. Rudin, is that this is due to the existence of cancer stem cells (CSCs) within a tumor population. 1 Putative CSCs have been described in a variety of hematologic and solid tumors including lung cancer. 2 Many questions are still unresolved in this challenging field. Extensive characterization of murine CSC models have not yet found their human counterpart for all tumor types. CSC markers still need to be properly defined and validated. The true origin of CSC is still unclear, and the ability to define a CSC niche and how it is regulated is very complex. More than one CSC type with different phenotypes per tumor type is likely. Murine models of lung adenocarcinomas have shown the importance of the tumor genotype in defining the type of lung cancer propagating cell and the implications of CSC heterogeneity for cancer treatment. 3 Embryonic signaling pathways (ESPs) such as Hedgehog (Hh), Notch, Wnt, and Bmi-1 are fundamental in normal stem-cell development and organogenesis. These same pathways are also involved in driving CSC activity. 4 The first presentation of this session by Dr. Rudin focused on the CSC model and the role of some of the ESP in lung cancer. Subsequent presentations by Dr. Rudin, Dr. Weiss, and Dr. van Tournout focused on the development of novel agents that target the Hh pathway, and Dr. Camidge and Dr. Stewart discussed novel agents targeting the Notch pathway, to possibly eliminate lung CSC. SUMMARY OF PRESENTATIONS