Part two of my interview with Dr Eva Schmelz (Virginia Tech) regarding her ovarian cancer research. You may find part one here.
4. Other research you are doing involves synthetic sphingolipid metabolites. What are they?
Sphingolipids are a large, very diverse group of membrane-bound lipids, containing a sphingoid backbone, a fatty acid and a more or less complex headgroup. This individual components vary among species (plants and bacteria contain different sphingolipids than mammals) and several hundreds of different sphingolipids have been identified. They are structural components of the cell membranes, affect the membrane fluidity, can mediate cell-cell or cell-matrix interactions and have many more functions depending of the types of sphingolipids present, their concentrations and where in the cell and in which cell they are located. Most interestingly for our research is their function as second lipid messengers, mediating the response of cells to growth factors, stress, inflammatory compounds etc., and regulate cell growth and cell death, motility and many other functions that are also important for cancer cells. Most of our daily foods contain sphingolipids, the highest amounts are found in soybeans and dairy products. In the intestinal tract, they are digested to the same bioactive molecules that are generated in the cells to regulate cell growth and death. By feeding sphingolipids in the diet, we can expose the cancer cells in mice to these bioactive molecules and suppress their growth and reduce tumor formation while not affecting normal cells. Natural sphingolipid metabolites are very quickly cleared from the circulation and from cells; we have used synthetic sphingolipids developed in Dr. Merrill’s lab that avoid clearance and stay active in the cells for longer. They have therefore a higher toxicity towards cancer cells but also a higher toxicity towards normal cells, causing more side effects than natural sphingolipids. The correct dosing is therefore very important in order not to cause severe side effects of the treatment.
5. What role does synthetic sphingolipid metabolites play in ovarian cancer prevention?
We have used synthetic sphingolipids administered directly into the peritoneal cavity to eradicate metastatic cells but have not yet found a formulation that guarantees a slow release that kills cancer cells but only minimally affects the normal cells lining the organs and the peritoneal cavity. Orally adnminitstered synthetic sphingolipids have been used in other rodent cancer models but they seem to cause more side effects than the natural compounds.
6. How will this research be translated to prevent ovarian cancer or treat it?
We have used dietary sphingolipids to suppress metastatic ovarian cancer in mice (manuscript in preparation) – similar to many other natural compounds, the success of this way of administration is restricted to the less aggressive cancer or earlier stages. We have not been able to stop fast-growing tumors of any kind (breast, ovarian) that develop lethal disease in 3 weeks. However, less aggressive disease can be reduced in mice, significantly enhancing the lifespan of these mice. Other groups have also shown that non-toxic doses of sphingolipids can enhance the effect of conventional drugs, thus reducing the side effects. We have not yet had an opportunity to test this in women but this is an exciting possibility.
I think immunotherapy for ovarian cancer is very promising since it utilizes the specific gene changes in the tumor of an individual woman to train the immune system to detect these cancer cells- even the dormant ones- rather than trying to kill cancer cells with highly toxic compounds that by themselves can cause severe DNA damage in normal cells. The same would be true for targeted therapies if we can get the information of the response of the individual cancer. Especially ovarian cancer has such diverse and individual genetic changes and redundant pathways to bypass targeted signaling pathways that make it more difficult to suppress cancer growth by specifically inhibiting one target. I believe that taking a step back, looking at the tumor microenvironment rather than only the tumor cells alone and identify the factors that are important for ovarian cancer cell implantation at the omentum and other metastatic sites independent of the specific genotype of the cancer cell is a novel avenue to deal with this heterogeneity. We then can develop drugs that prevent the interaction of the supporting factors with the cancer cells and thereby suppressing the deadly metastatic outgrowth irrespective of the individual genetic changes. This is a more preventive approach against metastasis compared to the immune or chemotherapeutic approaches.
Novel treatment approaches that also do not rely on the individual genetic changes in the cancer cells have also been subject to investigation here at Virginia Tech. Dr. Rafael Davalos, also featured in the VT magazine article, uses the bioelectrical fingerprint of cancer cells to either selectively eradicate cancer cells or enrich for cell populations of interest- tumor cells, stem-like cells, tumor associated cells- for diagnostic purposes or treatment decision making and efficacy control. To this end, we have published the first reports that indicate we can identify ovarian cancer cells by their unique bioelectrical fingerprint which are different in benign and aggressive cells. I believe that in addition to individualized medicine that specifically utilizes the individual genetic makeup of a cancer cell for treatment decisions, the methods that utilize biophysical or bioelectrical properties that are altered in cancer cells independent of their specific mutations, epigenetic changes or changes in non-coding DNA are a promising way to detect and treat many cancers including ovarian in the future.
Thank you Dr. Schmelz for your responses and your continued research to better understand what causes metastasis and how to treat and prevent ovarian cancer.
Every Day is a Blessing!