Understand and target ATRX mutation in undifferentiated sarcoma

Haoqiang Ying, MD, PhD,  University of Texas M.D. Anderson Cancer Center
Recipient of the: $50,000 Sarcoma Foundation of America Research Award

Soft tissue sarcomas are a collection of rare tumor types originated from soft tissues such as muscle, tendon, fat, etc. Among them, undifferentiated sarcomas represent a group of the most common types of soft tissue sarcomas. Unfortunately, undifferentiated sarcomas are often associated with poor patient survival. Unlike other soft tissue sarcomas which are classified based on the organ/tissue of origin and the similarity of the cell morphology with the corresponding normal tissues, undifferentiated sarcomas can develop from different types of soft tissues and lack any discernible morphological features of differentiated tissues, such as muscle or fat, which makes it challenging to define the origin of these tumors. To date, very little is known about how undifferentiated sarcomas are developed in the body. As a consequence of these major knowledge gaps, effective therapeutic strategies for undifferentiated sarcomas remain elusive. Therefore, the goal of our study is to define the molecular mechanisms leading to the development of undifferentiated sarcomas and identify potential therapeutic targets. Recent large scale genome sequencing efforts have identified genetic changes in undifferentiated sarcomas, with TP53, RB1 and ATRX among the most commonly mutated genes. TP53 and RB1 are well-known tumor suppressors. Unfortunately, therapies targeting the TP53 and RB1 pathways have not shown benefit in sarcoma patients. On the other hand, although ATRX gene is known to be mutated in 25-30% undifferentiated sarcomas, how its mutations contribute to tumor development is largely unknown. Such lack of molecular insight is largely due to the absence of relevant model systems to study the function of ATRX during sarcoma development. To address this, we have recently developed a novel genetically engineered mouse model of undifferentiated sarcoma by targeted deletion of ATRX and TP53 genes in mouse soft tissue. Our model faithfully recapitulated both the genetics and pathology of human disease. Interestingly, our preliminary analysis of both our mouse model and human tumors indicates that loss of ATRX may block the normal differentiation process of soft tissue cells, which explains the pathological features observed in human undifferentiated sarcomas. Therefore, we hypothesize that ATRX mutations function to block cell differentiation during sarcoma development and ATRX mutant tumors represent a unique subgroup that can be therapeutically targeted. To achieve this, cutting-edge single cell analysis tools will be used to elucidate the detailed molecular mechanisms underlying ATRX-regulated cellular differentiation. In addition, we will use a novel large-scale CRISPR-mediated screen platform to identify potential gene targets that are uniquely required for the survival of ATRX mutant tumor cells. The outcome of the proposed research will not only offer deep molecular insight for sarcoma development, but also provide rationale to develop novel therapeutics.