Cancer Stem Cells
Conference speakers in the cancer drug development track offered some frustrated commentary about progress in cancer drug development, emphasizing the need to consider completely new drug targets. Several speakers pointed out that most oncology drugs that fail do so late in the drug development cycle, typically in Phase III trials, and that few cancers are cured or have been transformed by drug therapy, despite decades of research. One reason put forth for this is that current chemotherapeutic drugs target the wrong cancer cells.
OncoMed Pharmaceuticals’ (www.oncomed.com) vp of cancer biology, Timothy Hoey, Ph.D., described his company’s isolation, characterization, and validation of cancer stem cells (CSCs) as potential therapeutic targets. Oncomed’s scientific founders, Michael Clarke, M.D., and Max Wicha, M.D., originally demonstrated the presence of these cells in solid tumors of epithelial origin in a 2003 study of breast cancer. Since then, CSCs have been identified in other solid tumors including prostate, brain, colon, and pancreatic cancers.
While normal human embryonic stem cells are healthy cells found in fetal embryos that give rise to normal body tissues and organs, CSCs comprise a small fraction of tumor cells and, among tumor cells, uniquely have the capacity for self-renewal.
“A limited subpopulation of tumor cells can drive tumor growth and generate tumor heterogeneity and have the ability to regenerate a tumor when transferred to mice,” Dr. Hoey noted. “We now have evidence that these CSCs preferentially survive chemotherapy.”
According to Dr. Hoey, OncoMed has isolated and characterized CSCs from a variety of tumors and is developing novel therapeutics targeting these cells. In collaboration with Dr. Clarke’s lab, they also developed an invasiveness gene signature from CSCs that provides prognostic insight into patient outcome.
In his presentation Dr. Hoey described techniques for manipulation and quantitation of the tumorigenic potential of these cells. In order to validate CSC targets, he and his colleagues had to overcome several technical hurdles including the ability to culture them while retaining their tumorigenicity; manipulating them, for example by introducing exogenous genes and shRNAs; and the ability to study single CSCs to monitor their fate and potential.
OncoMed isolates CSC populations in sufficient numbers for study by FACS (fluorescence activated cell sorting) and then infects isolated CSCs in vitro with lentiviral vectors encoding a reporter gene that would allow identification of CSC-dependent tumor growth in vivo.
Tumors produced in mice by the labeled CSCs allowed scientists to distinguish among tumors that were responsive or unresponsive to various shRNAs, overexpressed proteins, or drug candidates.
“We have tested about 150 antibodies in xenograft models derived from CSC-driven human tumors and identified a number of antibodies with reproducible antitumor activity,” Dr. Hoey reported. “In our most advanced project, we have discovered an antibody that binds with high affinity and selectivity to its target and functions to completely block ligand-receptor binding and subsequent signaling in CSCs. This antibody has shown activity in a variety of tumor models both as a single agent and in combination with approved cancer treatments.”