Background and Significance

Clear cell sarcoma (CCS) is a rare non-rhabdomyosarcoma soft tissue sarcoma of children and young adults.  CCS often occurs in deep soft tissues or beneath the fascia, most commonly in the lower extremities and, less often, in the gastrointestinal tract.  The clinical course of CCS is often prolonged with multiple cases of local recurrence and late metastases.  Due to the delay in the onset of symptoms, up to 30% of patients often already present with metastasis at diagnosis, resulting in a dismal prognosis.  While local control for CCS usually includes wide surgical excision with radiation therapy, the propensity of the disease for metastases results in a core clinical challenge as only surgery is curative and chemotherapy and radiation are ineffective. Late relapse with metastases results in a significant unmet clinical need as surgery is not possible and effective targeted therapies have not been discovered.

To meet this clinical need by developing new therapies, the biology of CCS needs to be taken into consideration:  not only is the EWSR1-ATF1 chimeric transcription factor/fusion gene most commonly present, yet unidentified cooperating mutations may also be present and deserve therapeutic targeting.  A presumption is that CREB binding sites bound by EWSR1-ATF1 or alternative fusions drive the cancer by turning target genes on or off, but factors related to turning off EWSR1-ATF1 at its own promoter remains one alternative therapeutic approach (i.e., epigenetic drug therapy). Nevertheless, effective treatment regimens will likely consist of drug combinations.  In addition to a lack of biologically-inspired therapeutics, another challenge is evaluating drug efficacy using an affordable and timely tumor model.

Need to Consider Biology of CCS

Objective, Hypothesis, and Specific Aims

We hypothesize that a systems biology approach for Clear Cell Sarcoma (CCS) will lead to a biology-driven, tumor specific, response to combination therapy and propose the following three specific aims:

  1. Define the genetic landscape of CCS and utilize rapid chemical screening to identify promising biology-driven drug therapeutics. This aim is currently in progress and nearing completion. Development of a CCS-focused registry is currently in progress at cc-TDI. CC-TDI has also begun assembly and analysis of all sequencing results. Global CCS resources are being procured (to date 14 cell lines from 6 different patient models – including 2 positive and 2 negative control lines – and 14 CCS tissue specimens from 10 different patients have been obtained). High-throughput exome and RNA sequencing of available cell lines and patient samples is ongoing. Screen on all cultures on a 60+ agent chemical screen of clinical trial compatible therapeutics has been completed. Candidate combination testing completed. Assessing and correlating data from sequencing and drug screening results are underway.
  2. Define the class(es) of drugs effective against CCS and predict and validate efficacious combinatorial treatment strategies in vitro. (This aim is currently in progress.)

  3. Develop and validate ex ovo CCS quail models for predicted drug combination and evaluate combination in vitro at clinically-relevant doses. 

The childhood cancer community is extremely grateful to Sara’s Cure for their advocacy, partnership and funding support of this critical research project to accelerate treatment options for Clear Cell Sarcoma.