Understanding the control of a cancer causing protein in Desmoplastic Small Round Cell Tumour (DSRCT) to develop new targeted treatments.  

Desmoplastic Small Round Cell Tumour (DSRCT) is an ultra-rare subtype of sarcoma that affects children and teenagers/young adults. There are limited effective therapies and there have been no advances in treatment in over two decades. As such, outcomes for those affected are poor. DSRCT is caused when DNA has broken and repaired incorrectly resulting in a new fusion and an abnormal protein (EWSR1::WT1). This fusion drives the development of the tumour, is found in all tumour cells, and is not present in normal healthy cells. Removal of the EWSR1::WT1 fusion causes DSRCT cells to die. These features make EWSR1::WT1 an attractive therapeutic. However, direct targeting of fusions in cancer is incredibly challenging.

An emerging aspect of some fusion driven sarcomas is that this abnormal protein has to be kept under very tight control for the cancer cell to be able to survive. The cancer cell achieves this by balancing the production of the protein with the breaking down of the protein (degradation).

While removing the cancer driving fusion results in cell death, too much of the fusion also leads to cell death. This critical balance is often termed the “Goldilocks Principle”. We have evidence that the Goldilocks Principle is relevant to the EWSR1::WT1 fusion in DSRCT. By identifying the cellular components keeping the levels of EWSR::WT1 under control, we aim to disrupt this control using drugs, increase the levels of EWSR1::WT1, and selectively kill cancer cells. If we can achieve this, it will represent a completely different way of designing much needed therapies for individuals with DSRCT.

A key component of this research is to better understand the fundamental disease biology in DSRCT. While this is important, having defined the parts of the cell that are controlling the levels of the EWSR1::WT1 fusion, we aim to effectively translate this new knowledge for the direct benefit of patients.

Current therapies for DSRCT involve surgery, chemotherapy, and radiotherapy. These are intensive treatments and for most individuals with DSRCT ultimately ineffective. We are excited about this project as it has the potential to develop a completely new way of targeting DSRCT – blocking the breakdown of EWSR1::WT1 using drugs and increasing the amount of the EWSR1::WT1 fusion to levels that cancer cells cannot tolerate.

As this approach exploits the presence of the fusion (that is not found in normal cells), this approach has the potential to be more selective for the tumour cells and lead to less toxic yet effective therapies.