Overcoming fusion oncoprotein dependence through CIC-DUX4 target gene inhibition in undifferentiated sarcoma

The CIC-DUX4 fusion oncoprotein is an understudied molecular entity that characterizes a rare but lethal subset of undifferentiated round cell sarcomas. CIC-DUX4 patients have dismal clinical outcomes due to 1) an incomplete understanding of how the CIC-DUX4 fusion oncoprotein drives tumor progression and survival; 2) no CIC-DUX4 focused clinical trial options; and 3) the un-informed therapeutic approaches that leverage “salvage” chemotherapy options from other round cell sarcomas to treat CIC-DUX4 sarcoma. To overcome these challenges, we have recently integrated “Omics” (RNA-seq and ChIP-seq) profiing with a deep mechanistic dissection of the CIC-DUX4 fusion oncoprotein and identified key target genes that…  Read More »

Redirecting B7H3 CAR T cells To Sarcoma using Midkine Receptors

Advances in pediatric oncology have occurred for some cancers, however, new therapies for sarcoma (osteosarcoma and rhabdomyosarcoma) have been sparse. The 5-year disease-free survival is 20-30% for patients with metastatic sarcoma at diagnosis or recurrent disease after front-line therapy. Cellular immunotherapy using chimeric antigen receptor (CAR) T cells has shown dramatic benefits in leukemia but has not been successful in solid tumors, including sarcoma. One limitation of CAR T cell therapy has been the inability of modified immune cells to traffic into the tumor. Thus, improved cell homing is necessary and expected to be a critical step to improve CAR…  Read More »

Function and targeting of a 5hmC-methylosome complex in synovial sarcoma

Synovial sarcoma is a deadly form of malignant soft tissue tumors, most commonly affecting children and young adults. Approximately all the patients bear a pathognomonic chromosomal translocation, t(X;18), which fuses the SS18 gene with SSX1, SSX2, or SSX4. The resulting SS18-SSX fusion oncoprotein has been proven to function as a central driver of synovial sarcoma. The known mechanisms of its action primarily depend on aberrant transcriptional regulation that involves both upregulation and downregulation of target gene expression. Over the past decade, it has become increasingly clear that chromatin modifying molecules and their catalyzed histone modifications play important functions in SS18-SSX-mediated…  Read More »

Uncover principles underlying cryoablation-induced immunotherapy effects in sarcomas

Malignant sarcomas comprise 12% of all pediatric cancers. Despite its rare occurrence, sarcomas are life threatening and difficult to treat, and nearly half of all patients will have recurrence and metastasis.  The two most prevalent sarcomas in the pediatric and adolescent population are Osteosarcoma and Rhabdomyosarcoma (RMS). Osteosarcoma (OS) is the most prevalent malignant bone cancer with a high propensity for lung metastasis in children and adolescent and young adults (AYA), with ~400-600 cases a year in the United States. Despite aggressive chemotherapy and surgery, the outcome for unresectable pulmonary metastatic or recurrent/refractory OS remains poor over the past 4…  Read More »

Characterising the Proteomic Landscape of Angiosarcomas

Angiosarcoma (AS) is an aggressive disease that accounts for 2-3% of soft tissue sarcomas (STS). The long-term outlook of patients with incurable advanced or metastatic disease is poor, with a median overall survival of less than 12 months. Current options are limited with chemotherapy being the mainstay of palliation and other systemic therapies having little durable impact on the disease course. While large-scale genomic and transcriptomic analyses of patient specimens have deepened our understanding of the molecular pathology of AS, there remains a large gap in translating this knowledge into effective treatments and prognostic biomarkers. In contrast to DNA and…  Read More »

A novel precision medicine approach to treat advanced liposarcoma

Liposarcomas (LPSs) are heterogenous group of soft-tissue sarcomas, which outcome depends strongly on the site of the primary tumor and tumor histotype. At the moment, there are not available any efficacious targeted therapies to treat advanced LPSs. We have discovered recently several new LPS-specific oncogenes, which could serve as a diagnostic biomarkers or precision medicine targets in distinct LPS subtypes. In the present study, we will investigate a role of phosphodiesterase 3A (PDE3A) as a therapy target for anagrelide, and drug combinations, which could show synergy with anagrelide treatment. In addition, we will study prognostic biomarkers, which could predict efficacy…  Read More »

Dissecting the contribution of germline genetics to pediatric sarcoma pathogenesis

Amongst pediatric cancers, bone and soft tissue sarcomas are often associated with the poorest prognoses and most limited effective treatment options. Understanding the genetics that predispose to the development of childhood cancers generally, and sarcomas specifically, is critical to discover novel mediators of oncogenesis, better screen children at-risk, and enable earlier diagnoses that could make cure more achievable. Prior research has suggested that while 7-10% of all pediatric cancers arise in part due to pathogenic germline variants in cancer predisposition genes, this rate may be >20% in many sarcomas. Existing work has largely focused on the role of germline single…  Read More »

Endoglin CAR T cells for Immunotherapy of Ewing Sarcoma

Ewing sarcoma is the second common bone cancer in children and young adults. It is an aggressive type of cancer that spreads rapidly to other organs in the body. Ewing sarcoma that recurs or that has spread to other parts of the body often fails standard treatment and is fatal. An alternative approach using genetically engineered T cells can potentially address this treatment failure. T cells modified to express an artificial molecule named chimeric antigen receptor (CAR) can redirect the T cells to cancer sites and specifically kill cancer cells. CAR T cells have proved transformational in treating leukemia, a…  Read More »

Multi-faceted immunostimulatory therapy for Ewing Sarcoma (MITES)

Ewing sarcoma (ES) is the second most pediatric common bone cancer (1,2). While patients with localized disease have a five-year survival rate of ~75%, this plummets to 20% for metastatic and recurrent disease. Immunotherapy has had limited success in ES, in large part because it is considered immunologically “cold,” with few tumor infiltrating T lymphocytes (TILs) (3-5). However, TILs actually vary significantly, and high levels portend greatly improved survival (6,7). TIL abundance correlated with the interferon (IFN)g-inducible chemokines CXCL9/CXCL10 and CCL5 (6). These immune features (i.e. IFNg response, CXCL9/10 production, and high CD8+ TIL recruitment) define a “hot” TME, and…  Read More »

Development of T cell receptors targeting the common cancer antigen PRAME in pediatric malignancies

Antigen presentation is a universal process in which proteins in a cell are degraded into small fragments (peptides) and displayed on the cell surface for interrogation by the immune system. If a peptide is derived from an abnormal protein (i.e. viral or mutated protein), T cells of the immune system recognize it as foreign and destroy that cell. Since malignant cells also present peptides, T cells recognizing abnormal, cancer-specific peptides can stimulate a potent anti-tumor immune response. This immune response is the basis of modern immunotherapy and can produce complete and durable regression of solid tumors. Pediatric sarcomas are associated…  Read More »

Mechanisms of Arginine Starvation Induced Cell Death

PEGylated Arginine Deiminase (ADI-PEG20) is a therapeutic that degrades extracellular arginine.  In tumors like sarcoma that cannot make their own arginine due to a urea cycle defect, this agent put tumors into a starvation state.  As ~90% of sarcomas are resistant to arginine starvation due to the loss of the expression of Argininosuccinate Synthetase 1 (ASS1), therapies involving ADI-PEG20 cross the numerous histologic barriers in sarcoma.  The aim of the proposal is to define the mechanisms of resistance to the arginine starvation to improve therapy based on intrinsic tumor metabolism.  In order to better understand what happens when sarcomas are…  Read More »

Analysis and Implications of the Difference in Response Rates to a Treatment For Metastatic Osteosarcoma

Osteosarcoma is the most common childhood malignancy, with a sharp decline in survival rates upon metastasis. We have previously demonstrated administration of immune checkpoint blockade (ICB) of anti-CTLA-4/anti-PD-L1 to mice inoculated with a K7M2 metastatic osteosarcoma (mOS) cell line resulted in ~50% survival with complete tumor clearance. Differences in response rates to ICB treatment are common among patients with the same malignancy across various cancers. However, unlike inbred lab mice, human patients have diversity in genetic makeup and other factors, causing the discrepancy in ICB response to remain poorly understood. There is an urgent need to identify the cause of…  Read More »

Hippo pathway targeting in uterine leiomyosarcoma

Leiomyosarcoma is the most common type of uterine sarcoma (uLMS), with an annual incidence of slightly less than two women per 100,000, characterized by a very poor response to standard therapies and an aggressive clinical course regardless of initial stage at diagnosis. The genetic profile of uLMS revealed the presence of recurrent somatic oncogenic events, dominated by frequent TP53 mutations, whose impact on the development of novel therapeutic opportunities is still marginal. Therefore, the discovery of novel and more effective therapeutic options for uLMS is an area of high unmet clinical need.  Hippo pathway is a central regulator of organ…  Read More »

Genomewide therapeutic target screens in novel preclinical models of liposarcoma

 Liposarcoma is one of the most common soft-tissue sarcomas, with well-differentiated/dedifferentiated liposarcoma subtype forming the majority of cases. Although recurrences are frequent, surgery remains the mainstay of treatment when feasible due to the limited role of currently available systemic treatments. Response rates to front line sarcoma regimens like doxorubicin or gemcitabine-based combinations are reported to be 20% or less, dropping further for therapies in the later lines. Reliable preclinical models help accelerate the pace of development of newer therapies as they can identify agents with a higher likelihood to succeed in the clinical setting. This helps increase our ability to…  Read More »

Chromatin accessibility regulates tyrosine kinase inhibitor resistance in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumor (GIST), the most common sarcoma, results from oncogenic mutations that usually occur in the KIT genes. Though anti-KIT tyrosine kinase inhibitors (TKIs) can be initially effective, half of patients with metastatic GIST develop drug-resistance within 20 months of starting first line (IM-imatinib) therapy, and the efficacy of later line therapies (SU-sunitinib, REG-regorafenib, RIP-ripretinib) are all <10%. This is thought to be primarily due to the accumulation of secondary resistance mutations in KIT, but treatment refractory disease often occurs even in the absence of these or other mutations. This suggests that additional mechanisms, such as changes in expression…  Read More »