Targeted treatment reduces deadly brain tumors in children

LA JOLLA, CALIF. – January 23, 2019 – Chemotherapy and radiation therapy are effective treatments for cancer because they destroy rapidly dividing cells, including tumor cells. But for children – whose tiny bodies are still growing – these treatments can cause permanent damage. This is especially true for children with brain cancer, and researchers are working hard to find treatments that reduce side effects while remaining effective.

Scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) announced that a targeted therapy blocking a protein called LSD1 was able to reduce tumors in mice with a form of brain cancer in the US. child called medulloblastoma. Inhibitors of LSD1 are being evaluated in clinical trials on other cancers, which could accelerate their potential pathway to children with medulloblastoma. The study was published in Nature Communications January 18, 2019.

"Submitting a developing child to chemotherapy and radiation from the head and spine can be devastating in the long run, some children even become intellectually handicapped as a result of treatment and can not go to college, live alone or Robert Wechsler-Reya, Ph.D., lead author of the journal, professor and director of the Tumor Initiation and Maintenance Program at SBP and director of the Neuro-Oncology Research Program Joseph Clayes III Genomics at The Rady Children's Institute of Genomic Medicine. "Our lab seeks to understand the genetic pathways behind medulloblastoma in order to find better ways to intervene and treat tumors. This study shows that a personalized treatment based on the type of tumor specific to a patient could be within our reach. "

Medulloblastoma is the most common malignant tumor of the pediatric brain. Cancer is diagnosed every year in more than 350 children in the United States. The treatment consists of a surgical procedure to remove the tumor, followed by chemotherapy and radiation therapy. One third of children succumb to cancer. For two-thirds of the children who have survived, many have serious life-long side effects of treatment, including cognitive impairment and increased risk of other cancers due to the damage done to them. ; DNA.

In recent years, scientists have learned that medulloblastoma is not a disease, but four distinct subtypes that differ by the mutations that cause them, the cells at the origin of the cancer and the probability of survival long-term. A subtype called group 3 medulloblastoma is the most lethal form of the disease.

This article builds on the earlier work of scientists studying group 3 medulloblastoma, in which they demonstrated that a transcription factor (a protein that binds to DNA and activates genes) , called GFI1, is activated in about one-third of group 3 tumors. In the previous study, scientists used genetic badysis approaches and the unique method of SBP to create murine models of medulloblastoma to confirm that GFI1 was essential for these tumors – a key indicator of the interest of a targeted drug.

However, transcription factors are intrinsically difficult to target therapeutically, which has earned them the nickname "unbearable". The scientists have therefore looked for an accomplice of GFI1, a protein that interacts with him and can be targeted more easily. Their quest revealed an epigenetic modifier called lysine demethylase 1 (LSD1).

"LSD1 seems to be the Achilles' heel of this cancer," says Wechsler-Reya. "And we were even luckier: an LSD1 inhibitor already existed and was undergoing clinical trials for the treatment of other cancers."

Scientists obtained an inhibitor of LSD1 and tested it in their murine model of GFI1-activated group 3 medulloblastoma. Their studies showed that the drug significantly reduced the size of tumors developed under the skin of the mouse, reducing cancer by more than 80%. This suggested that it could also be effective against patients' tumors if it could be administered to the brain.

"Our lab is currently working on drug delivery technologies that could carry this drug beyond the tumor's blood-brain barrier. It could be a "Trojan Horse" nanoparticle that would infiltrate the drug in the brain or could involve pumping the drug. directly into the tumor, "says Wechsler-Reya." If these approaches succeed, an LSD1 inhibitor could be a promising targeted treatment for children with GFI1-mediated GOL1 medulloblastoma. "

Wechsler-Reya adds: "These studies would not have been possible without the extraordinary efforts of Catherine Lee, a former postdoctoral researcher in my lab and first author of the study.This project was extremely ambitious and Catherine worked without "We have also been fortunate to be able to work with Paul Northcott in St. Jude and Stefan Pfister at the German Cancer Research Center, whose generosity and dedication have made this important breakthrough possible."

###

The first author of the study is Catherine Lee, Ph.D., a former postdoctoral fellow at the Weschler-Reya Laboratory and a senior senior scientist at Pfizer.

Other authors of the study include Vasilisa A. Rudneva, Ph.D., and Paul A. Northcott, Ph.D., of the St. Jude Children's Research Hospital; Serap Erkek from NCT Heidelberg, European Molecular Biology Laboratory (EMBL) and German Center for Cancer Research; Marc Zapatka from the German Center for Cancer Research; Lianne Q. Chau, Silvia K. Tacheva-Grigorova, Alexandra Garancher and Jessica M. Rusert, Ph.D., SBP; Ozlem Aksoy, Ph.D., Robin Lea and William A. Weiss, M.D., Ph.D., from the University of California at San Francisco; Helai P. Mohammad, Ph.D., of GlaxoSmithKline; Jianxun Wang, Chinese Medicine University of Beijing; and H. Leighton Grimes, Ph.D., Cincinnati Children's Hospital Medical Center. The DOI of the study is 10.1038 / s41467-018-08269-5.

The research reported in this press release was funded by the National Institutes of Health (NIH) (R01CA159859, F31NS086367), NINDS, Alex Foundation's Lemonade Stand, CureSearch for Childhood Cancer Cancer, Human Frontiers Science Program (LT00432 / 2014), California Institute for Regenerative Medicine. (LA1-01747), American Association for Cancer Research, The Brain Tumor Charity, Syrian Associated Syrian-Syrian Associations (ALSAC), St. Jude Children's Research Hospital, German Cancer Research Center and BMBF (# 01KU1505G). The content engages only the responsibility of the authors and does not necessarily represent the official opinion of the NIH.

About the Sanford Burnham Prebys Medical Discovery Institute

Sanford Burnham Prebys Medical Institute (SBP) is an independent, non-profit medical research organization that conducts world-clbad collaborative biological research that translates its discoveries to benefit patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare diseases in children. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its NCI-designated cancer center and Conrad Prebys Chemical Genome Center, SBP employs nearly 900 scientists and staff in San Diego, La Jolla, California. For more information, visit SBPdiscovery.org or Facebook on Facebook. com / SBPdiscovery and on Twitter @SBPdiscovery.