CART Cells for Sarcoma

Metastatic osteosarcoma has a poor prognosis, yet systemic standard of care therapies renders patients with great morbidity and life-long disabilities. Thus, there is an urgency to discover less toxic and more effective therapies for this patient population. The body’s natural defense against cancer relies on the immune system’s potential to recognize and destroy cancer cells. Immunotherapy provides an alternative or adjunct to current standard treatments for decreasing cancer-related mortality while also having the potential to decrease morbidity. Early studies on targeted immunotherapy and chimeric antigen receptor modified T cellular therapy have proven effective in relapsed hematologic cancers. These modalities are…  Read More »

Targeting the sarcoma tumor microenvironment using adrenergic receptor antagonists

Vascular sarcomas (e.g. angiosarcomas, hemangiosarcomas, and hemangioendotheliomas) represent a therapeutic challenge since new treatment approaches have not occurred in several decades. We and others recently published reports showing a remarkable 100% response rate (complete and partial responses) of angiosarcoma patients to the beta adrenergic receptor (beta-AR) antagonist propranolol. The clinical effectiveness of propranolol against angiosarcomas has led to Orphan Drug Designation for propranolol in the EU and accelerated approval in the US for the treatment of soft tissue sarcomas.Although all patients demonstrated durable responses versus standard-of-care approaches, disease progression eventually occurred. Based these outcomes, we pursued mechanisms of sarcoma resistance…  Read More »

Interrogating the regulation, function and therapeutic potential of monocarboxylate transporters in osteosarcoma

A distinguishing feature of cancer cells is their ability to undergo aerobic glycolysis (known as the Warburg effect), allowing them to thrive in a variety of microenvironments. Monocarboxylate transporters (MCTs) are key facilitators of aerobic glycolysis, moving lactate across the plasma membrane, and are critical for growth and metastasis of glycolytic tumors. Lactate enters cells through MCT1 and MCT4 and is converted by LDH to pyruvate. Forkhead box protein M1 (FOXM1), a transcription factor implicated in survival, metastasis, and chemotherapy resistance of cancer cells also influences cellular metabolism through transactivation of the LDH gene. Interestingly, another transcription factor, STAT3, directly…  Read More »

Dissecting Mechanisms of Immune Mediated Radiation Resistance in Sarcomas

Soft tissue sarcomas represent a rare, aggressive, and complex group of malignancies. Patients with large or high-grade soft tissue sarcomas often receive radiation therapy in combination with surgery. Some sarcomas may occur at an anatomic site where surgery is not feasible. In these patients, the sarcomas are treated with definitive radiotherapy with or without chemotherapy. Unfortunately, many sarcomas are resistant to radiation, but the mechanisms of radiation resistance are not well understood. Based on our preliminary preclinical data, we hypothesize that specific myeloid cell populations within the immune system drive radiation resistance in soft tissue sarcomas, which can decrease tumor…  Read More »

Targeting the retinoid acid pathway: a new therapeutic strategy for IDH1/2-mutant chondrosarcomas

Chondrosarcomas are the most common primary sarcoma of the bone in patients older than age 50. Although the majority of chondrosarcomas is of low or intermediate grade, high-grade chondrosarcomas are very aggressive tumors with high metastatic potential and a poor prognosis. Because chondrosarcomas are generally resistant to systemic chemotherapy as well as radiation, new therapeutic strategies for unresectable, metastatic or refractory disease are urgently needed. 71% of conventional chondrosarcomas and 57% of dedifferentiated chondrosarcomas carry a point mutation in the isocitrate dehydrogenase (IDH) 1 or 2 gene, which code for enzymes in the TCA (tricarboxylic acid) cycle. Mutant IDH leads…  Read More »

Pluripotent Stem Cell-derived Genome-edited Sarcoma-targeted T cells for Immunotherapy

Current approaches to adoptive cell therapy (ACT) for metastatic synovial sarcomas are limited by the difficulty of obtaining sufficient numbers of less-differentiated T cells and existence of immune suppressive pathways. We and others have shown that induced pluripotent stem cells (iPSCs) can provide an unlimited source of autologous less-differentiated T cells that persist long, mediate regression of large established tumors, and establish immunological memory in vivo. Similar to other tumor-specific T cells, however, iPSC-derived T cells that express Programmed cell Death-1 (PD-1) can be inhibited by Programmed cell Death Ligand-1 (PD-L1) which is upregulated in many tumors including sarcoma. Systemic…  Read More »

Towards precision immunotherapy for undifferentiated pleomorphic sarcoma (UPS)

A tumor must evade destruction by the host’s immune system in order to grow. Immunotherapy works by enhancing or restoring the anti-tumor effects of the immune system. Checkpoint blockade has demonstrated efficacy in multiple tumor types and has revolutionized their management. Initial trials of checkpoint blockade therapy in unselected sarcomas have generally shown low objective response rates (ORR). However, the anti-PD1 monoclonal antibody pembrolizumab demonstrated an ORR of 44% in patients with undifferentiated pleomorphic sarcoma (UPS), indicating a potential role for immunotherapy in certain sarcomas. An area of on-going research is understanding why most other subtypes of sarcoma, along with…  Read More »

Identifying chemoresistance pathways in Osteosarcoma

Chemotherapy response is the primary determinant of long term survival for patients with osteosarcoma (OS), where patients who are resistant to chemotherapy are considered incurable. The ultimate goal of this study is to identify the molecular pathways controlling chemotherapy resistance in OS. To achieve this goal, we will develop a novel transposon-mutagenesis mouse model to evaluate chemotherapy resistance and utilize transposon insertion sites identify which genes confer chemotherapy resistance. The results of this study may identify novel prognostic biomarkers and reveal new drug targets to overcome chemoresistance in osteosarcoma, The Sleeping Beauty (SB) transposon system can generate mouse OS with…  Read More »

Rational biomarker-guided PARP inhibitor combination therapy in pediatric sarcomas

The overall survival for recurrent and metastatic Ewing sarcoma (EWS) is dismal (15% and 10-30%, respectively). We previously showed that EWS has a defect in double-strand DNA (dsDNA) repair, and that the addition of Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi) to the existing standard of care (SOC) therapy of irinotecan (IRN) and temozolomide (TMZ) is remarkably successful at treating in vivo mouse models of recurrent EWS, resulting in >80% complete response compared to 100% mortality with SOC alone. Our EWS pre-clinical studies prompted several new questions. First, why is EWS sensitive to PARPi combination therapy, and could other…  Read More »

Targeting the alterations of Lipid Metabolism in ASS1 Deficient Sarcomas to Induce Synthetic Lethality

The most common defect in sarcoma is loss of expression of argininosuccinate synthetase 1 (ASS1), which occurs in approximately 90% of sarcomas. This defect primes sarcomas for treatment by the arginine starvation inducing therapy arginine-deiminase (ADI-PEG20). In sarcomas, treatment with ADI-PEG20 induces a cytostatic response. Recently published work by our group has demonstrated that a metabolic rewiring takes place in response to ADI-PEG20. This has led to the first trial of ADI-PEG20 with gemcitabine for the treatment of metastatic sarcoma that should open at Washington University in the next 6 months. As the overall goal of sarcoma metabolic therapy is…  Read More »