New therapeutic strategies for refractory ovarian cancer with molecular targeted drugs targeting EpCAM-positive cancer stem cells

Associate Professor Takeshi Motohara, a cancer research scientist based at the Department of Obstetrics and Gynecology, Kumamoto University in Japan, explains that cancers arise from genetic mutations that accumulate in certain cells. 'These mutations change the fundamental biology of the cell, allowing it to break free from the cell cycle and grow rampantly. To understand cancer, it is necessary to understand the underlying molecular mechanisms that derive from these genetic mutations.' Typically, these are large changes in particular protein pathways that alter the cell's behaviour. The changes in the molecular biology of the cell also change what proteins the cell expresses on its surface. This is important as proteins in the cell membrane modulate the cell's interaction and response to its surrounding microenvironment. They are also responsible for how the cell responds to various cancer treatments. This makes them an excellent target for anti-cancer therapeutics. Additionally, as they are present on the cell surface, they can also be used as biomarkers to identify the presence and type of cancer. 'This is important for cancer diagnostics and also as a means to check whether a treatment has been effective in eliminating the cancer,' Motohara notes. 'Further changes in the cell's molecular biology allow it act as cancer stem cells.' Normal stem cells are capable of dividing and producing a wide variety of cell types. It is thought these cancer stem cells provide the same function within a tumour. In addition to this ability to provide different cell types, cancer stem cells appear to be the cells that survive cancer treatments. Most cancer treatments target the rapidly dividing cells that form the majority of the tumour, however the cancer stem cells do not divide rapidly and are thus missed. This allows the cancer to recover after treatment. Identifying and targeting these cells is of vital importance to cancer treatment.

The molecular biology behind ovarian cancer remains lacking. Currently, there are few reliable treatments and biomarkers. This cancer is particularly lethal as there are few symptoms when the cancer starts to metastasise. At this point, treatment effectiveness is dramatically reduced and survival rates are low. Motohara and a team of researchers at the Department of Obstetrics and Gynecology are working to identify the molecular mechanisms behind ovarian cancer. 'Our research is focused on understanding the molecular mechanisms of evolution of ovarian cancer, especially the biology of ovarian cancer stem cells regarding metastasis and chemoresistance, and on the development of novel therapeutic strategies for ovarian cancer,' he says. 'Ultimately, we hope that ovarian cancer treatments directed toward the eradication of the subpopulation of ovarian cancer stem cells will lead to higher survival rates and brighter prognoses for patients.'

The focus of Motohara and his colleagues' work are two prominent cell surface markers epithelial cell adhesion molecule (EpCAM) and CD44v6. EpCAM is normally involved in cell adhesion in epithelial tissues but a simple cleavage of the protein can cause part of it to remain inside the cell and cause havoc with gene expression, promoting tumour growth. CD44 is an important protein for fundamental cell functions such as cell-cell interactions, migration and adhesion. However, a variant known as CD44v6 can be produced through RNA splicing that allows the protein's properties to be harnessed by the cancer stem cell. This greatly aids the cancer's ability to migrate and establish growth on different tissues and is therefore a key part of the metastatic events that are the primary cause of lethality.