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.
Project Goal: 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.
Project Update 2022: In our original grant application, we proposed engineering a model system was proposed because no living tumor cells derived directly from a patient were available at the time of the grant application. While that work is ongoing, we have since been able to start developing cell line and tumor experimental models derived from tumor cells from a DICER1 syndrome patient who recently underwent surgery for two tumors (a central nervous system sarcoma and an ovarian tumor). These cells naturally contain the genetic alterations found in patient tumors without the need for genetic engineering and are ideal model systems to study drug therapy options for patients. We are currently conducting some drug trials in model systems using these patient-derived tumor cells. This work is still ongoing but shows promising preliminary results.
