Ewing sarcoma: steroids may enhance the growth, but therapy is meant to “bite to the bone”

Ewing’s sarcoma is a malignant tumor of the bone, with small round cells, with a strong metastatic potential. It starts between 5 and 30 years and has a peak incidence between 12 and 18 years. The annual incidence is estimated at 1 / 312.500 children before the age of 15. The most frequent symptom is pain. Other symptoms depend on the contiguity of the tumor with the different organs: pelvic tumors are associated with sphincter and motor disorders, nervous compression or mechanical disorders; rib tumors are associated with breathing disorders or pleural effusion; vertebral tumors are associated with spinal or radicular compression. In the early stages, the tumor often develops in the bones, particularly in the pelvis (30%), in the thorax (20%), in the femur (16%), in the fibula (9%), in the vertebrae (8%) and in the humerus (5%). The disease has a high metastatic potential (bones, lungs, bone marrow). Neuroepithelioma represents a highly differentiated neurological variant. Although no specific cause has been identified, in 90% of tumors of this type there is a characteristic translocation involving the EWSR1 gene (22q12.2), often a translocation t(11;22) (q24;q29). Many variants of this translocation have been described  involving genes FLI1, ERG, ETV1 and NR4A3.

Researchers at the Weizmann Institute of Science have discovered molecular interactions underlying Ewing sarcomas and proposed a potential treatment, which has shown promise in a study in mice. Postdoctoral fellow Dr. Swati Srivastava in the laboratory of Prof. Yosef Yarden in the Biological Regulation Department, together with colleagues, conducted research focusing on receptors for steroid hormones called glucocorticoids. These receptors are present in virtually all human cells, conveying hormonal messages related to stress, wakefulness and a host of other important functions. Usually, cell stimulation with glucocorticoids lead to suppression of cell replication, either in normal or malignant tissues and in immune cells. This is the rationale for their emploiment in leukemia, limphomas and bone marrow cancers. But sometimes glucocorticoid receptors stimulate malignant growth. They do this 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 conducted by the team revealed previously unknown interactions.

Hormone-bound glucocorticoid receptors were found to be binding in the cell nucleus to a transcription factor family called ETS family, forming together 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. 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 Ewing sarcoma. 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 laboratory 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, an approved drug for the treatment of adrenal insufficiency that inhibits the synthesis of glucocorticoids.

In other experiments, also in mice, another 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 the lungs. In contrast, when the researchers increased the activity of glucocorticoid receptors, the sarcomas grew and spread much faster. Furthermore, the researchers 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: Their increased expression may 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 may offer new hope to youngsters with this malignancy, especially in cases when the sarcoma has metastasized beyond the bone.

Radiotherapy, indeed, is the leading support therapy for this cancer. Survival without recurrence, in localized forms, is 70%. For forms with lung metastases, the survival rate is about 50%. The forms with bone or bone marrow metastases have a much more poor prognosis. Some other research is focused on drugs blocking the receptor for insulin-like growth factor (IGF-1) but it will take time for these to be officially approved. Same goes for another attempt with exeprimental molecules like the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509, which together seem to show enhanced efffect on the growth of Ewing sarcoma cells in culture and ex-vivo. Research on this topic is being conducted by researchers at the Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Though epigenetic therapy may be similar to that induced by molecules that regulate transcription factors, also most of these epigenetic drugs are in experimental phases. Some of them are in phase I and II. Very few are in being tested in phase III clinical trial. Steroid antagonsits, instead, are already available, some others approved by FDA and it will be fra easier for scientists to address them for the cure of this cancer.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Srivastava S et al. Cell Rep. 2019 Oct 1; 29(1):104-117.

Welch D et al. PLoS One. 2019 Sep 24; 14(9):e0222228.

Gallegos ZR, Taus P et al. Mol Cell Biol. 2019 Jun; 39(14).

Informazioni su Dott. Gianfrancesco Cormaci 1714 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it

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