In healthy tissue, antigrowth signals halt the proliferation of cells, preventing uncontrolled growth and cellular transformation that would otherwise lead to cancer. Cells bypassing the repression from antigrowth signals —one of the original hallmarks of cancer— are a step closer to becoming cancerous. The ability to bypass antigrowth signals can be driven by epigenetic variants.
Antigrowth signals work by pushing cells out of the cell cycle, preventing cell growth and division, and into a quiescent state, termed G0. Given the appropriate proliferative signals, these cells can later re-enter the cell cycle. Alternatively, cells may permanently lose their ability to proliferate. This typically occurs through a differentiation process as cells reach their terminal, post-mitotic state.
Various tumour suppressors function as antigrowth signals and their loss contributes to oncogenesis. While loss of function mutations to tumour suppressors can silence them, they can also become silenced by epigenetic variants.
Synovial sarcoma is an aggressive soft-tissue malignancy that primarily affects adolescents and young adults, and accounts for five to 10 per cent of all soft-tissue sarcomas. The disease is characterized by a pathognomonic mutation that leads to the production of an oncoprotein called SS18-SSX. In other words, while normal cells do not express SS18-SSX, 100 percent of patients with synovial sarcoma will have cancer cells expressing this specific oncoprotein.
The exact oncogenic mechanisms by which SS18-SSX drives synovial sarcomas are under investigation, but epigenetic variants are central. In one proposed model, SS18-SSX functions as a bridge that recruits complexes to silence tumour suppressor genes. To dive into greater detail, SS18-SSX specifically recruits polycomb repressive complex 2 (PRC2), a transcriptional repressor complex, to tumour suppressor genes. When PRC2 is recruited to these genes, the chromatin state is altered and the genes are turned off; as a result, these genes, which are responsible for the antigrowth signals in cells, are turned off. Subsequently, synovial sarcoma cells are able to grow uncontrollably.
Given the lack of targeted therapies for synovial sarcoma, understanding how epigenetic variants result in insensitivity to antigrowth signals has led to potential novel therapeutic avenues. Histone deacetylase (HDAC) inhibitors are a class of epigenetic drugs being investigated. In cell line models of synovial sarcoma, HDAC inhibitors can reverse SS18-SSX-mediated recruitment of PRC2 to target tumour suppressor genes. Ultimately, after HDAC inhibitor treatment, these tumor suppressor genes are turned back on, and the antigrowth signals of the cells are rescued.
To date, monotherapy use of HDAC inhibitors has yielded modest results. For example, a phase II trial of oral panobinostat for 47 patients with advanced soft tissue sarcoma saw 17 patients with stable disease and six patients as progression-free at six months. Another phase II study of SB939, an oral pan-HDAC inhibitor, reported a three-month progression-free survival rate of 49 per cent in patients with recurrent or metastatic translocation-associated sarcomas.
It is well-established that alterations in epigenetic mechanisms contribute to the insensitivity of cancer cells to antigrowth signals and while epigenetic therapies are promising, more detailed investigations looking at cancers, such as synovial sarcoma, as well as the use of HDAC inhibitors in combinations is needed.
