Elimination of Macrophages to Improve T cell Therapy in Synovial Sarcoma

Elimination of Macrophages to Improve T cell Therapy in Synovial Sarcoma

Synovial Sarcoma is a soft tissue sarcoma subtype with poor outcomes in the advanced setting. Although it is immunologically “cold,” it generally expresses the highly immunogenic protein NY-ESO-1. Although NY-ESO-1 has been successfully targeted in Synovial Sarcoma using adoptive cellular therapy and vaccine-based approaches, in most cases patient ultimately progress. Our group, as well as others, have identified tumor-infiltrating macrophages as a key inhibitory mechanism in these tumors. In this proposal, we will use both xenograft and ex-vivo organoid models to explore macrophage-manipulating strategies with NY-ESO-1 specific T cells.

Modeling, Characterizing, and Targeting Aggressive, STAG2-mutated Ewing Sarcoma

Loss of function mutations of STAG2 occur in 10-15% of Ewing sarcoma (ES) patients. This is clinically significant, as loss of STAG2 is associated with poor clinical outcomes. STAG2 encodes a protein that is central to the cohesin complex, a highly conserved chromosome-associated multi-subunit protein complex which mediates chromosome segregation during mitosis. STAG2 is also implicated in DNA repair and gene expression but exactly how its loss affects ES tumorigenesis and biology is unclear. Recent studies have shown that tumors containing STAG2 loss of function mutations are highly susceptible to inhibition of its paralog STAG1, representing a synthetic lethal interaction….  Read More »

BMI1 as a Novel Driver and Target in Alveolar Rhabdomyosarcoma

Despite significant efforts within oncology, effective therapies for alveolar rhabdomyosarcoma (ARMS) remain unrealized. Patients with ARMS are treated with intensive multimodal therapy, but outcomes still remain unacceptable. Hence, we are focused on better understanding the oncogenic networks underlying this extraordinarily aggressive sarcoma. ARMS displays an extremely quiet genomic landscape, primarily characterized by the PAX-FOXO1 fusion protein. However, the role of the epigenome in shaping malignancy has become increasingly appreciated and previous gene expression studies demonstrated that ARMS is specifically enriched for Polycomb target gene methylation, suggesting that Polycomb complexes may be deregulated in ARMS and play oncogenic roles. Thus, we…  Read More »

Evaluating myeloid cells as targets to promote anti-tumor immunity in undifferentiated pleomorphic sarcoma

The vast majority of patients with soft tissue sarcoma present with localized disease, yet nearly half of these patients develop incurable distant metastases. Chemotherapy has been marginally effective in reducing the rate of metastasis or prolonging survival. However, undifferentiated pleomorphic sarcomas (UPS) appear to respond well to immune checkpoint blockade, which has sparked interest in immune based approaches to improve outcomes in these curable patients. Still, the majority of patients with UPS do not respond to immune checkpoint blockade and long-lasting responses are sparse. We have observed that the immune microenvironment of UPS is dominated by myeloid cells. Although macrophages…  Read More »

Global impact of the DNA/RNA helicase DHX9 on the processing of coding and noncoding transcripts in Ewing sarcoma pathogenesis

Ewing Sarcomas (ES) are biologically aggressive tumors of bone and soft tissues, characterized by in frame chromosomal translocation leading to the expression of the EWS-FLI1 oncogene. They affect mainly children and adolescents. A combination of surgery and radiation therapy, followed by chemotherapy is the only treatment up to date. Unfortunately, radiation and the drugs used in chemotherapy damage normal cells as well as cancer cells, and in the long term can have deleterious effects on the other organs of children affected. The DNA/RNA helicase DHX9 has been identified as a molecular partner of the oncoprotein EWS-FLI1. DHX9 interacts with EWS-FLI1…  Read More »

Clinical Evaluation of BET and HDAC Inhibition in Canine Sarcoma

Targeting chromatin-remodeling enzymes holds great promise for treating soft tissue sarcomas (STS) since 1) the key oncogenic drivers in many sarcomas are translocation-derived chimeric transcription factors whose activities critically depend on chromatin remodeling factors; and 2) recent work from our group and others has highlighted the role of epigenetic deregulation and chromatin status in sarcomagenesis. Together these finding suggest that epigenetic therapy may be a particularly effective approach against these tumors. Recent data from our group reveal the dramatic in vivo effects of the BET bromodomain inhibitor, JQ1, and the histone deacetylase (HDAC) inhibitor Vorinostat, in multiple sarcoma subtypes suggesting…  Read More »

Exploring sarcoma functional genomics to identify disease-specific vulnerabilities

Sarcomas are uncommon and poorly understood malignancies of mesenchymal tissues. Their histologic diversity and diagnostic complexity bring tremendous challenge to optimal clinical management. The lack of understanding of the biological underpinnings of sarcoma development and neoplastic drivers is underscored by both the frequency of misdiagnosis and lack of targeted therapies. Strategies that shed light on the development of these tumors may offer means of better diagnosis and identify sarcoma subtype-specific tumor dependencies that represent therapeutic targets. Sarcomas are uncommon and poorly understood malignancies of mesenchymal tissues. Their histologic diversity and diagnostic complexity bring tremendous challenge to optimal clinical management. The lack…  Read More »

Plexin-Semaphorin: a new signaling axis in Sarcomas

The Plexin-Semaphorin pathway is previously unexplored as a target in sarcomas but may play a central role in the progression of the soft tissue sarcoma, rhabdomyosarcoma. Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood, and the alveolar subtype of this tumor is known to have the poorest prognosis. More than half of children have unresectable primary tumors or metastatic tumors at diagnosis, and survival for non-localized unresectable recurrent disease is only 8 percent. Therefore, development of novel therapeutic strategies is urgently needed to improve cure rates. Our laboratory has developed a novel mouse model of alveolar rhabdomyosarcoma by…  Read More »

Combination therapy with a novel humanized antibody to secreted frizzled related protein 2 for sarcoma

Sarcomas are a heterogeneous group of malignancies with a 50% mortality at 5 years across all subtypes and stages. The 5 year survival for patients with metastatic disease is only 15%.The results from chemotherapeutic agents for unresectable or metastatic disease have been disappointing with minimal long-term benefit. Single-agent doxorubicin is currently the standard of care and has produced response rates of 20% to 25%. Anti-VEGF therapy has activity in sarcoma but with response rate of only 12%. New targeted agents are greatly needed to improve response and survival. Recent reports provide evidence that SFRP2 can enhance tumor aggressiveness and progression…  Read More »

Determining Doxorubicin Effects on Plasma Extracellular Vesicles Using Proteomics Analysis

Sarcomas are a group of over 100 types of tumors of mesenchymal origin that can be divided into soft tissue sarcomas (STS) and bone sarcomas. The most common agents used to treat all sarcomas are anthracyclines, such as doxorubicin. To date, no real time method of assessing tumor sensitivity and resistance to doxorubicin is available from patient blood samples. If biosignatures of early treatment response or failure can be identified, a future trial that validates the findings will be of great interest to patients. SARC21 was a trial of Doxorubicin plus Evofosfamide versus doxorubicin alone in locally advanced, unresectable or…  Read More »