Pooja Hingorani

R1507, a fully human monoclonal antibody targeting IGF-1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts.

The combination of rapamycin and R1507, a fully human IgG1 monoclonal antibody targeting the IGF‐1 receptor (IGF‐1R), in osteosarcoma xenograft tumors in vivo is evaluated in this report.

Enhanced T-Cell Immunity to Osteosarcoma Through Antibody Blockade of PD-1/PD-L1 Interactions

Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand for PD-1 (PD-L1) and that tumor-infiltrating CTLs express PD-1, suggesting this pathway may limit CTLs control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor-infiltrating CTLs during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTLs in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. Our results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy.

Inhibition of Src Phosphorylation Alters Metastatic Potential of Osteosarcoma In vitro but not In vivo

Purpose: Pulmonary metastasis remains the major cause of mortality in osteosarcoma. Src tyrosine kinase is a key player involved in metastatic pathways in multiple human cancers. c-Src has been shown to be expressed and phosphorylated in osteosarcoma cell lines and inhibiting Src phosphorylation in these cells causes inhibition of the metastatic phenotype in vitro. We studied the effect of inhibition of Src phosphorylation in preventing the growth and development of pulmonary metastases in osteosarcoma. Experimental Design: Dasatinib, a dual Src-Abl kinase inhibitor, was used to study the effect of Src kinase inhibition on proliferation, adhesion, and invasion of osteosarcoma cell lines in vitro and in preventing the development of pulmonary metastases in a spontaneously metastatic mouse model. Results:In vitro, phosphorylation of Src and its downstream signaling molecules such as focal adhesion kinase, Crk-associated substrate, and c-Jun was inhibited at nanomolar concentrations of dasatinib. Dasatinib was not cytotoxic against the osteosarcoma cells with the IC50 ranging from 10 to 20 μmol/L but effectively inhibited the adhesion and migration of osteosarcoma cells at 10 to 100 nmol/L. However, in vivo, dasatinib did not inhibit the development of pulmonary metastases despite complete inhibition of Src phosphorylation in the primary tumors. No effect was seen in the primary tumor growth and the degree of apoptosis. Conclusions: These results suggest that Src kinase activation might not be the primary pathway involved in the development of pulmonary metastases in osteosarcoma.

Combination immunotherapy with α-CTLA-4 and α-PD-L1 antibody blockade prevents immune escape and leads to complete control of metastatic osteosarcoma

BackgroundOsteosarcoma is one of the most common bone cancers in children. Most patients with metastatic osteosarcoma die of pulmonary disease and limited curative therapeutic options exist for such patients. We have previously shown that PD-1 limits the efficacy of CTL to mediate immune control of metastatic osteosarcoma in the K7M2 mouse model of pulmonary metastatic disease and that blockade of PD-1/PD-L1 interactions can partially improve survival outcomes by enhancing the function of osteosarcoma-specific CTL. However, PD-1/PD-L1 blockade-treated mice eventually succumb to disease due to selection of PD-L1 mAb-resistant tumor cells. We investigated the mechanism of tumor cell resistance after blockade, and additional combinational therapies to combat resistance.MethodsWe used an implantable model of metastatic osteosarcoma, and evaluated survival using a Log-rank test. Cellular analysis of the tumor was done post-mortem with flow cytometry staining, and evaluated using a T-test to compare treatment groups.ResultsWe show here that T cells infiltrating PD-L1 antibody-resistant tumors upregulate additional inhibitory receptors, notably CTLA-4, which impair their ability to mediate tumor rejection. Based on these results we have tested combination immunotherapy with α-CTLA-4 and α-PD-L1 antibody blockade in the K7M2 mouse model of metastatic osteosarcoma and show that this results in complete control of tumors in a majority of mice as well as immunity to further tumor inoculation.ConclusionsThus, combinational immunotherapy approaches to block additional inhibitory pathways in patients with metastatic osteosarcoma may provide new strategies to enhance tumor clearance and resistance to disease.

Systemic administration of reovirus (Reolysin) inhibits growth of human sarcoma xenografts.

Despite advancement in therapies, overall survival rates for relapsed pediatric sarcomas are dismal. Newer therapies are needed to effectively salvage these patients. Oncolytic viruses (such as reovirus) and other genetically altered viruses (such as herpes simplex viruses and adenoviruses) have shown efficacy in a variety of solid tumors including sarcomas. Reolysin is an unmodified oncolytic reovirus that selectively replicates in Ras‐activated cancer cells while not causing any significant human illness in its wild form.

Body mass index (BMI) at diagnosis is associated with surgical wound complications in patients with localized osteosarcoma: A report from the Children's Oncology Group†

Malnutrition is common at diagnosis and during treatment for sarcoma patients. Poor nutritional status is associated with increased risk of complications, particularly infections. We investigated the role of body mass index (BMI) on the incidence of surgical wound complications in patients with localized osteosarcoma treated on the Childrens Oncology Group (COG) legacy trial, INT‐0133.

A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: A Children's Oncology Group Phase I Consortium report

Reovirus is a naturally occurring human virus that is cytopathic to malignant cells possessing an activated Ras signaling pathway. We conducted a phase I trial of Reolysin, a manufactured, proprietary isolate of purified reovirus, in children with relapsed/refractory extracranial solid tumors to define the recommended phase 2 dose (RP2D), toxicities, and pharmacokinetic properties when administered as a single agent or in combination with cyclophosphamide.

Incidence and Outcomes of Desmoplastic Small Round Cell Tumor: Results from the Surveillance, Epidemiology, and End Results Database

Desmoplastic small round cell tumor (DSRCT) is a rare but highly fatal malignancy. Due to the rarity of this neoplasm, no large population based studies exist. Procedure. This is a retrospective cohort analysis. Incidence rates were calculated based on sex and ethnicity and compared statistically. Gender-, ethnicity-, and treatment- based survival were calculated using the Kaplan-Meier method. Results. A total of 192 cases of DSRCT were identified. Peak incidence age was between 20 and 24 years. Age-adjusted incidence rate for blacks was 0.5 cases/million and for whites was 0.2 cases/million (P = 0.037). There was no statistically significant difference in survival based on gender or ethnicity. When adjusted for age, there was no statistically significant difference in survival amongst patients who received radiation therapy compared to those who did not (HRadj = 0.73; 95% CI 0.49, 1.11). There was a statistically significant survival advantage for patients who received radiation after surgery compared to those who did not (HR 0.49; 95% CI 0.30, 0.79). Conclusion. DSRCT is more common in males and in people of African-American descent. Although overall survival remains poor, radiation therapy following surgery seems to improve outcome in these patients.

BIRC5 Expression Is a Poor Prognostic Marker in Ewing Sarcoma

BIRC5 (Survivin), an inhibitor of apoptosis protein (IAP), is over‐expressed in several human cancers and increased expression is associated with poor prognosis. The goal of the current study was to evaluate the role of BIRC5 in Ewing sarcoma (ES), the second most common pediatric bone sarcoma.

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene-Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group.

Purpose: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX–FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas fusion gene–negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion gene–negative RMS (FN-RMS) patients, but this has not been independently validated. The goal of this study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS. Experimental Design: Cases were taken from the Childrens Oncology Group (COG) D9803 study of children with intermediate-risk RMS, and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathologic characteristics as well as overall and event-free survival. Results: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N = 57; HR, 7.3; 95% CI, 1.9–27.0; P = 0.003) and failure-free survival (N = 57; HR, 6.1; 95% CI, 1.9–19.7; P = 0.002). Conclusions: This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk stratification in future prospective clinical trials. Clin Cancer Res; 21(20); 4733–9. ©2015 AACR.