A team at the Ludwig-Maximilians University (Munich, Germany) has shown that Ewing's sarcoma interferes with a special signaling pathway in bone development - making itself vulnerable to attack. This could open up new therapeutic options, especially for highly aggressive tumors.
Ewing's sarcoma is the second most common malignant bone tumor in children and adolescents. The disease starts with a single spontaneous mutation that results in a fusion oncogene. This fusion oncogene activates further genes and initiates a process that can trigger cancer. Ludwig-Maximilians University (LMU, Munich, Germany) scientists led by Dr. Thomas Grünewald, head of the Max Eder Junior Research Group for Pediatric Sarcombiology at the Institute of Pathology at the LMU and head of department at the German Cancer Research Center (German acronym: DKFZ) in Heidelberg, have now been able to show that one of the genes activated by the fusion oncogene is involved in bone development and that the overactivation of this gene is a promising starting point for new therapies. The scientists’ have reported their latest project findings, in the journal "Nature Communications".
Current treatment strategies cannot prevent relapses with often fatal outcomes in about one-third of patients with Ewing's sarcoma. Dr. Grünewald is, therefore, looking for new therapeutic options. "The fusion oncogene itself is not a suitable target structure for various reasons. Therefore, we are trying to find so-called surrogate targets. For example, these are genes that are activated by the fusion oncogene," said Dr. Grünewald. "We have focused on genes that play a role in natural bone development and found that the SOX6 gene is upregulated in Ewing's sarcoma," added Dr. Grünewald. This gene is normally only active for a short period of time during bone growth and then causes massive cell division. "When we switched off the gene in Ewing’s sarcoma cell lines, tumor growth in our model systems decreased significantly. We assume that SOX6 is permanently activated by the fusion oncogene so that the Ewing cells proliferate strongly," he explained.
However, the fact that the tumor uses the SOX6 signaling pathway for its own purposes also opens an opportunity for the patients: The gene also intervenes in the cells’ stress balance, so that cells with highly regulated SOX6 have higher levels of reactive oxygen species (ROS) than other cells. This, in turn, makes the cells particularly sensitive to the active substance elesclomol. The substance was originally developed to treat malignant melanomas and also induces increased ROS levels. "If the already elevated ROS level in cells with highly regulated SOX6 is further increased by elesclomol, a threshold value is exceeded above which the cells die," said Grünewald. "In cells without increased SOX6 activity, however, this threshold is hardly ever reached." Extensive cell culture investigations and 3D bone models confirmed that elesclomol actually significantly reduces the viability of Ewing’s sarcoma cells with high SOX6 activity compared to cells with low activity. Mice treated with elesclomol also showed reduced tumor growth.
Therefore, the research team believes that elesclomol could be a promising option in the future for the selective treatment of Ewing sarcoma patients in whom SOX6 is particularly highly upregulated. "There are patients with higher and lower SOX6 expression. It is particularly high when the patients are carriers of a genetic variant which, in interaction with the fusion oncogene, ensures that the tumor proliferates particularly strongly - in other words, they have a poorer chance of cure," concluded Dr. Grünewald.
Source: Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability toward oxidative stress in Ewing sarcoma Aruna Marchetto, Shunya Ohmura, Martin F. Orth, Maximilian M. L. Knott, Maria V. Colombo, Chiara Arrigoni, Victor Bardinet, David Saucier, Fabienne S. Wehweck, Jing Li, Stefanie Stein, Julia S. Gerke, Michaela C. Baldauf, Julian Musa, Marlene Dallmayer, Laura Romero-Pérez, Tilman L. B. Hölting, James F. Amatruda, Andrea Cossarizza, Anton G. Henssen, Thomas Kirchner, Matteo Moretti, Florencia Cidre-Aranaz, Giuseppina Sannino, Thomas G. P. Grünewald Nature Communications 2020 https://www.nature.com/articles/s41467-020-16244-2