Identifying targeted treatments for DICER1-associated sarcomas
Sarcomas are malignant tumors that affect connective tissues. While generally rare, in patients with DICER1 syndrome, sarcomas are not rare. They primarily arise in the brain and the urogenital tract (e.g. cervix) at a young age, leading to potentially severe consequences. Existing treatments, namely surgery and systemic chemotherapy, do not often lead to positive outcomes. This is due to the inaccessibility of many of the tumors, their inherent chemoresistance and long-term secondary health issues that result from intervention, such as infertility. There is currently no model system to study these tumors in the laboratory.
In this proposal, we will use the latest genetic engineering techniques to create an experimental model system that can be used to identify new therapies; we will take advantage of the DICER1 mutations present in sarcomas of patients with DICER1 syndrome to selectively kill the tumor cells while not affecting healthy tissues. To do this, we will genetically manipulate cells from sarcomas to create cell pairs with and without DICER1 mutations, to enable comparisons. We will then use these cells to perform various genetic and drug screens focusing on FDA-approved drugs, which could be incorporated into new treatment strategies relatively quickly, without the need for lengthy clinical trials to assess their safety. If we are successful, these new therapies would allow treatment of sarcomas that are not accessible to surgery. This will eliminate the unwanted side-effects of systemic chemotherapy, dramatically improving prognosis for affected children.