Studies reveal new therapeutic targets for aggressive types of rhabdomyosarcoma

Scientists at St. Jude Children’s Research Hospital have delved into the biology of the disease to find new treatments for childhood cancer, targeting processes that were long thought to be “out of control.” I am. This approach reveals new strategies for treating aggressive forms of rhabdomyosarcoma.Survey results released today Scientific translation medicine..

This strategy involves targeting a class of protein called KDM4 for the treatment of alveolar rhabdomyomyoma caused by PAX3-FOXO1 gene fusion. Rhabdomyosarcoma is a type of cancerous tumor that develops in soft tissues such as muscle. Soft tissue sarcoma accounts for 7-8% of all childhood cancers. There are two types of rhabdomyosarcoma, embryonic and alveoli. The alveolar form occurs in children of all ages and often affects the large muscles of the arms, legs, and trunk.

When a part of one gene attaches abnormally to another gene, Gene fusion Occurs.Together, these gene fragments encode fusion neoplastic proteins, which are proteins that play a role in driving. cancer.. Alveolar rhabdomidoma with PAX3-FOXO1 fusion is more aggressive, has a higher metastatic rate, and has a poorer prognosis than cancer without fusion.

“Rhabdomyosarcoma caused by this fusion is a dangerous disease that is very difficult to cure,” said the corresponding author, Dr. Junyang, MD of St. Jude Surgery. “It’s almost never Genetic mutation Promote it with a limited treatment option in the fusion positive version. By examining the class of proteins that remove methylation marks from histones, we were able to identify promising targets that had not been previously evaluated. When combined with standard of care, the model showed a complete response and was often very resistant to chemotherapy alone. “

Target transcription

Transcription factors are proteins involved in the process of “transcription” or conversion of DNA information into RNA. Transcription is an essential biological process because the RNA copy of a gene’s DNA sequence is used to make the protein. Transcription is usually a highly regulated process, cancer cell, May become dysregulated. This dysregulation makes cancer cells dependent on abnormal proteins or factors involved in the process.

The Core Regulatory Circuit (CRC) is Transcription factor Establish and maintain cell identity (cell type and function). PAX3-FOXO1 fusion is a genetic abnormality that affects transcription factors that play an important role in building the CRC network of rhabdomyosarcoma.

“These transcription factors are so difficult to target because they don’t have binding pockets, so it’s difficult to develop drugs that can bind them,” said co-lead author Dr. Sivendrasin (St. Jude Surgery). I am. .. “Cancer cells rely on these transcription factors and their CRC regulatory network. Targeting the CRC protein partner (KDM4B in this case) has been shown to disrupt the network and effectively treat cancer. I did. “

To study PAX3-FOXO1 fusion and elicit the role of different parts of the network, researchers have performed advanced analyzes of RNA-seq, CUT & TAG, ATAC-seq and more. Through these efforts, they narrowed down to KDM4B and revealed that KDM4B is an important node of CRC caused by alveolar rhabdomyomyoma. fusion Oncogene.

“This study has come a long way to understand the mechanism behind why KDM4 inhibition appears so successful in this subtype of rhabdomyosarcoma,” co-leader. Authors Hongjian Jin, Ph.D., St. Jude Center for Applied Bioinformatics said. “We were able to track an important relationship between KDM4 and the major regulatory circuits of this cancer.”

New treatment strategy

Transcription factors have historically been difficult to develop treatments. However, the interaction with other proteins is protein A partner who confuses their activities.

Using genetic techniques and compounds that inhibit KDM4B in the lab, researchers have been able to significantly slow tumor growth. The combination of KDM4B inhibition and the currently used chemotherapy regimen resulted in tumor shrinkage in a preclinical xenograft model of the disease.

“We searched for epigenetic upstream regulators that could regulate these. Transcription Ahmed Abu-Zaid, co-lead author of St. Jude Surgery, said: Chemotherapy has shown a very effective anti-cancer effect. KDM4 inhibition has not been attempted in this disease, so it is also stimulating. “

Currently, there are targeted inhibitors of KDM4B that are clinically tested for adult colon cancer. Additional research is needed before transforming this approach into pediatric clinical trials. Rhabdomyosarcoma..

Controlling the identity of rhabdomyosarcoma cells provides clues to possible treatments

For more information:
Shivendra Singh et al, Targeting KDM4 for the treatment of alveolar rhabdomyomyoma with PAX3-FOXO1, Scientific translation medicine (2022). DOI: 10.1126 /scitranslmed.abq2096

Quote: Aggressive type rhabdomyosarcoma obtained on July 13, 2022 from https: // by research: 2022 July 13) New therapeutic targets revealed

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Studies reveal new therapeutic targets for aggressive types of rhabdomyosarcoma

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