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A collaborative research team, led by scientists at VCU Massey Comprehensive Cancer Center and Huntsman Cancer Institute at the University of Utah, has identified a targeted drug that could effectively treat an aggressive soft tissue cancer that occurs most often in pediatric and young adult patients. New findings—published in Nature Communications—suggest that blocking a specific genetic pathway could reverse a series of tumor-driving cellular interactions to restore DNA function and benefit patients with synovial sarcoma.

Synovial sarcoma is an uncommon type of cancer that grows in muscles and ligaments. It typically grows slowly, but once the cancer has spread, it is incurable.

“This disease is really tragic because it tends to strike younger patients, with poor long-term outcomes. Effective targeted therapies have become a scientific priority for treating this rare, but deadly cancer,” said Anthony Faber, Ph.D., study co-author and Natalie N. and John R. Congdon, Sr. Endowed Chair in Cancer Research at VCU Massey. “Our findings endorse a promising strategy to improve outcomes for patients with synovial sarcoma.”

Combined DNA drives sarcoma formation

In about one-third of sarcomas, a translocation event causes two chromosomes to trade arms, creating a fusion of two genes at the swapping point. This combination of rogue genes disrupts the regular biological functions of the cell, driving the formation of a tumor. In synovial sarcoma, this fusion gene is called SS18::SSX.

“When these genes combine, they rearrange the entire genome and activate genes that normally are not activated and deactivate genes that normally are not deactivated,” said Faber, who is also a professor of oral and craniofacial molecular biology at the VCU School of Dentistry.

One of the individual genes in SS18::SSX typically combines with other DNA-regulating proteins in the BRG1-associated factor (BAF) complex. When the genes are fused together, they override and dismantle the normal function of these regulator proteins, destroying a separate stabilizer protein—SMARCE1—in the process. Ultimately, the degradation of SMARCE1 collapses the ordinary DNA structure of cells, breaking down their biological motor and opening the door for tumor growth.

Using data to identify drug targets

Using DepMap—a massive resource of datasets and analytical tools that aim to map out the genetic landscape of all human cancers for the purpose of drug target discovery—the research team found that targeting a specific genetic pathway, known as the SUMOylation pathway, was particularly effective in preclinical models of synovial sarcoma.

By blocking this genetic pathway, the researchers:  

• Reversed the function of SS18::SSX
• Restored the routine activity of the BAF complex
• Prevented the destruction of SMARCE1

The team showed significant tumor reduction in synovial sarcoma cells using a targeted inhibitor drug—TAK-981–in combination with chemotherapy.

Looking ahead to a clinical trial

“SUMOylation inhibition should be viewed as an exciting new strategy to treat synovial sarcoma,” said Senthil Radhakrishnan, Ph.D., a study co-author, member of the Cancer Biology research program at VCU Massey and an associate professor in the Department of Pathology at the VCU School of Medicine. “Our data provides strong rationale to further test TAK-981 in patients through a clinical trial, either alone or combined with cytotoxic chemotherapy.”

Additional funding is needed to initiate further testing through clinical trials. Faber’s team is also investigating the efficacy of TAK-981 in combination with radiation therapy in synovial sarcoma.

“It is extremely exciting for our patients that this drug is capable of undoing the BAF complex destruction that is at the core of this cancer,” said Kevin Jones, M.D., study co-author, leader of the Sarcoma Disease Center at Huntsman Cancer Institute and L.B. and Olive S. Young Presidential Endowed Chair for Cancer Research in the Department of Orthopaedics at the University of Utah. “I am hopeful that we can mobilize efforts to bring this drug into a clinical trial for synovial sarcoma patients in the very near future, as there is nothing else that can predictably cure this deadly disease.”

Additional collaborators on this research include study lead author Konstantinos Floros, Ph.D., an assistant professor of oral and craniofacial molecular biology at the VCU School of Dentistry’s Philips Institute for Oral Health Research; Mikhail Dozmorov, Ph.D., Jennifer Koblinski, Ph.D., Masoud Manjili, DVM, Ph.D., Andrew Poklepovic, M.D., and Kristoffer Valerie, Ph.D., research members at VCU Massey Comprehensive Cancer Center; Elsamani Abdelfadiel, Ph.D., Krista Dalton, Ph.D., Carter Fairchild, Ronald Hill Nayyerehalsadat Hosseini, Bin Hu, Ph.D., Asha Jose, Vita Kraskauskiene, Richard Kurupi, Janina Lewis, Ph.D., Madelyn Lorenz, Durga Paudel, Jane Roberts, Shanwei Shen, M.D., Ph.D., Mayuri Shende, M.D., Jamie Slaughter, Angeliki Stamatouli, M.D., Yanli Xing, Kun Zhang, Ph.D., of Virginia Commonwealth University; and Jinxiu Li, Ph.D., Li Li, Mary Nelson and Kyllie Smith-Fry of The University of Utah Huntsman Cancer Institute.

This research was supported, in part, by funding from:

• Meryl and Charles Witmer Charitable Foundation
• Natalie N. and John R. Congdon endowment
• National Cancer Institute
• S. Department of Defense
• VCU Massey’s NIH-NCI Cancer Center Support Grant (P30 CA016059)

Written by: Blake Belden