Targeting the Pentose Phosphate Pathway for the Treatment of Synovial Sarcoma

Synovial Sarcoma (SS) is a translocation dependent subtype of soft tissue sarcoma that arises from the fusion of SYT and SSX. The hybrid transcript factor SYT:SSX modulates SWI/SNF chromatin remodeling and gene expression. As no targeted therapy has been developed for SS, we have applied a metabolomics approach to understanding SS and identified a unique glucose metabolism linked to the fusion. We have found that SS cell lines die exceedingly fast within two hours of glucose withdrawal by a mechanism not involving apoptosis or necrosis. In addition, we have identified that glucose-6-phosphate dehydrogenase (G6PD), a glucose metabolizing enzyme at the…  Read More »

BiCAR-VZV T cells for the treatment of Sarcoma

Sarcomas pose a significant therapeutic challenge as even intensifying chemotherapy has produced little improvement in the survival of patients with metastatic sarcoma. Therefore, a new approach to treating these tumors is desperately needed. T cells provide a highly targeted therapy with low intrinsic toxicity and the potential to persist long-term providing life-long protection against disease. Indeed, virus-specific T cells (VSTs) can safely and successfully treat virus-associated cancer. The use of T-cells for non-viral cancers has recently been facilitated by the use of chimeric antigen receptors (CARs), which combine the extracellular antigen binding domains of antibodies with intracellular signaling domains from…  Read More »

Unmasking Immunomodulatory Effects of Radiation in Synovial and Myxoid/ Round Cell Liposarcoma

Outcomes remain poor for patients with metastatic Synovial Sarcoma (SS) and Myxoid/ round cell liposarcoma (MRCL). Immunotherapies including T cell based therapies and checkpoint inhibitors have eradicated tumors and improved the survival of patients with certain cancer types. There is an urgent need to extend these approaches to sarcoma. Immunotherapeutic approaches may be well suited to SS and MRCL because both of these sarcoma subtypes characteristically express high levels of NY-ESO-1 and other cancer testis antigens, immunogenic proteins typically seen in the germ cells of testis, some cancers but not other normal tissues in adults. Interestingly, while brisk T cell…  Read More »

Kinase Activity Profiling in Soft Tissue Sarcoma

Arguably, the 518 protein kinases which make up the human kinome constitute the most tractable group of new cancer targets. However, despite its well-established ‘druggability’ and central position within key signaling networks, very few kinases have been studied in detail. In sarcoma, alterations in select kinases are thought to causally contribute to disease initiation, progression and therapeutic resistance (eg. PDGFRA, CDK4, ALK). We hypothesize that additional kinases display altered activity in sarcoma, and that these kinases represent immense diagnostic, prognostic and therapeutic value. Until recently, technical hurdles have prevented kinome-wide activity assessment and study; the understudied kinome may contain more…  Read More »

Identification of novel therapeutic targets in Ewing’s Sarcoma by modeling tumorigenesis in differentiating human embryonic stem cells

Ewing’s Sarcoma (ES) is a bone and soft tissue malignancy that occurs in children, adolescents and adults.  This cancer is defined by a recurrent chromosomal translocation between the EWSR1 gene and different ETS genes, such as FLI1, that generates a tumorigenic fusion protein (EWS/FLI1).  While the overall cure for patients with non-metastatic disease is approximately 70%, the five-year survival of patients with metastatic disease is less than 20%.  Consequently, there is a significant need for improved therapies for this cancer.  One roadblock in developing new therapies in ES has been the lack of a genetically-defined tumor model in human cells. …  Read More »

CAR T Cell Therapy for Sarcoma

Sarcomas are malignant tumors of mesenchymal origin with more than 50 distinct histologic subtypes. This disease can be found anywhere in the body, and it has a high rate of early metastasis. Despite advances in surgery and chemotherapy, the 5-year survival rate remains at 60-70% for patients with localized disease, and as low as 20-30% for patients with metastasis. Unfortunately, many patients are young.  New therapeutic strategies are clearly needed. Immunotherapy is emerging as a new therapeutic approach that has been unequivocally shown to work in some cancer patients. We propose to develop a novel immunotherapeutic approach, using genetically engineered…  Read More »

Desmoplastic Small Round Cell Tumor: Establishment and Validation of New Cell Lines and Therapeutic Targeting of the EWS-WT1 Transcription Factor using Splice Switching Oligonucleotides

Desmoplastic small round cell tumor (DSRCT) is an aggressive primitive sarcoma of adolescents and young adults. The hallmark and key genetic driver of DSRCT is the EWS-WT1 gene fusion, which encodes an oncogenic chimeric transcription factor. Although EWS-WT1 represents the ideal therapeutic target in DSRCT, direct targeting of transcription factors has so far proved elusive with conventional drugs. Furthermore pre-clinical studies to identify and develop new therapies have been hampered by the paucity of available DSRCT cell line. This proposal aims to tackle these issues by developing the first molecular targeted therapy for DSRCT based upon an innovative approach of…  Read More »

Proteomic and genomic approaches to understanding intrinsic and acquired resistance to CDK4 inhibition therapy in well differentiated/dedifferentiated liposarcoma

Well differentiated/dedifferentiated liposarcoma (WD/DDLS) is the most common form of soft tissue sarcoma, characterized by genomic amplification of the CDK4 and MDM2 oncogenes. This disease is both chemo- and radio- resistant, leaving surgical resection as the only treatment option. Recently, the CDK4 inhibitor (CDK4i) drug Palbociclib completed a Phase II clinical trial for WD/DDLS at MSKCC; the drug has received Breakthrough Designation from the FDA for its success in breast cancer. While 2/3 of WD/DDLS patients benefited from the drug, the remainder progressed while receiving therapy. Using a panel of patient-derived WD/DDLS cell lines, we found that all cells undergo…  Read More »

Targeting YAP/HIPPO pathway in embryonal rhabdomyosarcoma

Embryonal rhabdomyosarcoma (ERMS) is a cancer of skeletal muscle and is one of the most common pediatric sarcomas. The major clinical challenge is to identify novel and effective therapy for treating patients with relapse and advanced disease. The YAP/HIPPO signaling pathway is abnormally dysregulated in a variety of human cancers and has been shown to play an essential role in cellular processes essential for tumor progression. We have recently shown that expression of YAP is upregulated in ERMS compared to normal fetal muscle.  However, the role of YAP/HIPPO pathway in tumorigenesis of ERMS has not been previously explored. Our initial…  Read More »

B7-H3-Engager T cells for the immunotherapy of osteosarcoma

• Christopher DeRenzo, MD, Baylor College of Medicine • Recipient of the $50,000 Alexander Burdo/ZIOPHARM Research Award • Abstract: The long-term goal of this project is to develop an effective immunotherapy for patients with osteosarcoma (OS) using a novel genetic modification strategy to generate tumor-specific T cells. While patients with localized OS have a 5-year disease-free survival rate of approximately 60%, the prognosis for patients with metastatic disease is significantly worse, despite aggressive multimodality treatment. Given these results, novel therapies are needed to treat OS, especially for patients with metastatic disease. Immunotherapies have potential to meet these needs, as they…  Read More »