A new route to blocking children's bone cancer

October 02, 2019

wing sarcoma is a bone cancer that appears mainly in teenagers. Due to a single defective gene, once it spreads to distant organs it is hard to treat. 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. These findings were published recently in Cell Reports.

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. 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 suitable for living cells revealed previously unknown interactions: Once activated by hormones, glucocorticoid receptors were found to be binding in the cell nucleus to transcription factors of the E-twenty-six, or 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: 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 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, a drug that is approved for the treatment of adrenal insufficiency and works by reducing 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.

"Our findings provide the basis for a personalized approach to the treatment of Ewing sarcoma," 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.
-end-
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 Biological Regulation Department; Dr. Chamutal Bornstein-Ovits and Prof. Ido Amit of the Immunology Department; Prof. Adi Kimchi and Drs. Lee Roth and Yuval Gilad of the Molecular Genetics Department; Dr. Mattia Lauriola of the University of Bologna; 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.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.

Weizmann Institute of Science

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.