Hacking the programs of Cancer Stem Cells

Liang Fang and his colleagues in Walter Birchmeier's group, working with the Screening Unit and Medicinal Chemistry Group of the FMP and the campus company EPO, have now discovered a molecule that interrupts biochemical signals essential for the survival of tumor cells called Wnt-addicted cancer stem cells. The discovery is the product of an approach known as "rational drug design," targeting specific molecules based on a thorough understanding of the biology of a disease and the biochemical signals that support it. The work appeared ahead of print in the online edition of Cancer Research. Liang Fang and his colleagues took advantage of years of research carried out by Birchmeier's lab on the biochemistry of cancer-related signaling within cells. Much of their work has been devoted to unraveling a molecular network called the Wnt signaling pathway, which plays an essential role in healthy embryonic development. In adults the system helps maintain the structure and integrity of tissues. Its activity must be carefully controlled, but in many cancers the system is switched on inappropriately. Tumor cells hijack it to promote their uncontrolled growth and survival and the migrations seen in metastases. In the current study Liang Fang and his colleagues focused on a component of the Wnt pathway called beta-catenin. "In the absence of an environmental signal, beta-catenin is locked out of the cell nucleus," Birchmeier says. "It is linked to a complex of proteins that ultimately break it down. External signals can release it from this 'destruction complex,' and it travels to the cell nucleus." "We observed a strong reduction of tumor growth," Walter Birchmeier says. "What remained of the tumors seemed to be devoid of cancer stem cells, LF3 seemed to be powerfully triggering these cells to differentiate into benign tissue. At the same time, no signaling systems other than Wnt were disturbed. All of these factors make LF3 very promising to further develop as a lead compound, aiming for therapies that target human tumors whose growth and survival depend on Wnt signaling."