Developing an effective targeted therapy for undifferentiated round cell sarcomas by directly targeting CIC-DUX4 fusion and Myc oncoproteins

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic cancer that mainly affects children and young adults, and the prognosis for the affected is very poor with an overall survival of only 14 months. Currently, without effective treatments available for CDS patients, most of CDS patients are treated as Ewing’s sarcomas. However, the recent studies reveal that CDS is a distinct cancer type from Ewing’s sarcoma and the CDS patients should be treated differently. In addition to no effective chemotherapy available, no targeted therapy and cancer immunotherapy for CDS treatment have been developed. Due to its highly metastatic potential to the lungs, a systemic treatment that can treat CDS effectively is urgently needed. CIC-DUX4 fusion oncogene product is critical for CDS development and metastasis. Further, frequent MYC amplification has been shown to be positively correlated with CIC-DUX4 fusion. In addition to their oncogenic roles, DUX4 and Myc are known to downregulate major histocompatibility (MHC) class I antigen presentation, leading to immune evasion. Thus, we hypothesize that targeting CIC-DUX4 and Myc will not only block their oncogenic signaling but also sensitize CDS tumors to immunotherapy. We recently developed an intracellularly targeted therapy to effectively block challenging intracellular targets such as CIC-DUX4 and Myc, with potent antitumor effects and low toxicity. Our preliminary data showed that systemic blocking Myc using intracellularly targeted therapy in a xenograft tumor model successfully suppressed tumor growth. We also show that using the same approach to block CIC-DUX4 fusion protein in CDS patient-derived tumor cells induced significant cell death. Here we propose to evaluate the antitumor effects of our intracellularly targeted therapy against CIC-DUX4 and Myc in CDS, through direct tumor cell killing and activating immune responses. We will test 1) whether blocking DUX4 and Myc proteins by intracellularly targeted therapy will reduce tumor progression and lung metastasis in CDS xenograft models, and 2) whether blocking DUX4 and Myc proteins by intracellularly targeted therapy will promote MHC class I antigen presentation, leading to response to immunotherapy in CDS. We will first test our hypothesis in lab established patient-derived tumor cells. The efficacy of antitumor effects will be determined by cell viability, apoptosis and CIC-DUX4/Myc oncogenic signaling. We will also examine the changes of MHC class I expression on CDS cells under the treatments of intracellularly targeted therapy against DUX4 and Myc. To provide the clinical relevance, we will test the antitumor effects of our intracellularly targeted therapy in CDS xenograft model. CDS syngeneic mouse model will be used to evaluate whether our intracellularly targeted therapy will sensitize CDS tumor to cancer immunotherapy. Our proposed study will be the first one to directly target CIC-DUX4 and Myc, for potential treatment options for CDS.