The lungs of a mouse with untreated Ewing sarcoma (left) contain numerous tumor cells (shown by luminescent colors) that have spread from the bone; the lungs of a mouse treated with a drug reducing the synthesis of glucocorticoids are almost free from the sarcoma (right)
REHOVOT, ISRAEL—October 2, 2019—Ewing sarcoma is a bone cancer that appears mainly in teenagers. Caused by a single defective gene, once it spreads to distant organs it is hard to treat. Researchers at the Weizmann Institute of Science have now discovered molecular interactions underlying Ewing sarcomas and proposed a potential treatment that has shown promise in a study in mice. These findings were published in Cell Reports.
Dr. Swati Srivastava, a postdoctoral fellow in the laboratory of Prof. Yosef Yarden in the Department of Biological Regulation, conducted research together with colleagues that focused on glucocorticoids: receptors for steroid hormones. These receptors are present in virtually all human cells, conveying hormonal messages related to stress, wakefulness, and a host of other important functions. But sometimes glucocorticoid receptors stimulate malignant growth by moving to the cell nucleus, where they physically interact and bind with transcription factors – molecules that turn genes on or off. The researchers wanted to learn more about the role of these interactions in malignancy.
A highly sensitive protein interaction analysis that can be used on living cells revealed previously unknown interactions: once activated by hormones, glucocorticoid receptors were found to be binding, within the cell nucleus, to transcription factors of the E-twenty-six (ETS) family, together forming a physical complex. One of the transcription factors in the ETS family is known to drive the development of Ewing sarcoma; its gene fuses abnormally with another gene, creating an oncogene: a cancer-causing gene.
When the study turned up this link between the Ewing sarcoma oncogene and glucocorticoid receptors, the researchers set out to test a hypothesis: that these receptors boost the growth of the sarcoma. Indeed, a series of studies supplied evidence that this is indeed the case. Physical binding between glucocorticoid receptors and the protein made by this oncogene increased the growth and migration of Ewing sarcoma cells in a laboratory dish and gave an even stronger boost to the growth and spread of the sarcoma in mice.
The major medical significance of these findings is that they open the door to a new treatment option for Ewing sarcoma. When the researchers implanted human Ewing sarcoma cells into mice, the tumors grew much more slowly when the mice were treated with metyrapone, a drug that is approved for treating adrenal insufficiency and works by reducing glucocorticoid synthesis. In other experiments, also in mice, the drug mifepristone – which blocks the glucocorticoid receptor and is approved for other clinical applications – prevented the metastasis of Ewing sarcoma via a major cancer cell dissemination route: from bone to lungs. In contrast, when the researchers increased the activity of glucocorticoid receptors, the sarcomas grew and spread much faster.
Prof. Yosef Yarden and Dr. Swati Srivastava propose a new treatment for Ewing sarcoma
Furthermore, the team performed a genetic analysis of tumor samples from patients with Ewing sarcoma and identified seven genes regulated by the glucocorticoid receptors that were expressed in higher-than-normal levels in patients with particularly lethal tumors. These genes might serve as a genetic signature enabling a selection of patients for treatment: those with upregulated “signature” genes are especially likely to benefit from treatment aimed at neutralizing glucocorticoid receptors. The signature genes may also help predict the course of the disease, as their increased expression could signal a poor prognosis; reduced expression, on the other hand, may signal better chances for survival.
If research in human patients confirms the study’s findings, they offer new hope to youngsters with this malignancy, especially in cases when the sarcoma has metastasized beyond the bone.
“Our findings provide the basis for a personalized approach to the treatment of Ewing sarcoma,” Dr. Srivastava says. The fact that the study made use of drugs that have already been approved for other uses should facilitate the implementation of this approach.
Study participants also included Dr. Nishanth Belugali Nataraj, Arunachalam Sekar, Dr. Soma Ghosh, Diana Drago-Garcia, Dr. Donatella Romaniello, and Dr. Ilaria Marrocco of the Department of Biological Regulation; Dr. Chamutal Bornstein-Ovits and Prof. Ido Amit of the Department of Immunology; Prof. Adi Kimchi and Drs. Lee Roth and Yuval Gilad of the Department of Molecular Genetics; Dr. Mattia Lauriola of the University of Bologna, Italy; Dr. Ron Rotkopf of Weizmann’s Life Sciences Core Facilities Department; Profs. Olivier Dellattre and Andrei Zinovyev, and Drs. Olivier Mirabeau and Didier Surdez of Institut Curie in Paris; and Prof. Heinrich Kovar of the Children’s Cancer Research Institute of the Medical University of Vienna.
Prof. Yosef Yarden’s research is supported by the Dwek Institute for Cancer Therapy Research; the David and Fela Shapell Family Foundation INCPM Fund for Preclinical Studies; the Moross Integrated Cancer Center; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Willner Family Center for Vascular Biology; the Rising Tide Foundation; the Marvin Tanner Laboratory for Research on Cancer; the Comisaroff Family Trust; and the European Research Council. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.
