Abstract

The identification of effective chemotherapy and appropriate surgical treatment for patients with osteosarcoma has led to significant improvements in outcome. The determination of prognosis in osteosarcoma continues to be based on clinical staging systems. The identification of additional prognostic factors would allow stratification of therapy, which may improve the durability of """"""""high risk"""""""" patients and minimize toxicity to the """"""""good risk"""""""" patients. Investigation of biological features related to chemotherapy response may identify prognostic factors. Advances in the understanding of the molecular basis of resistance to methotrexate, an agent routinely used in high doses for the treatment of this disease has emerged, allowing the development of in vitro assays which may predict response to this drug. Studies of these biological factors may identify new antifolate inhibitors of dihydrofolate reductase which overcome the relevant mechanisms of resistance as being potentially more effective for the treatment of osteosarcoma. The purpose of this study is to investigate biological factors related to methotrexate resistance as predictors of histologic response to preoperative chemotherapy and outcome in patients with osteosarcoma. Osteosarcoma tumor samples obtained from patients treated by the Childrens' Cancer Group and the Pediatric Oncology Group will be assayed for alterations in methotrexate uptake, methotrexate polyglutamylation as well as reduced folate carrier, dihydrofolate reductase, folylpolyglutamate synthestase and gamma- glutamyl hydrolase expression. The results of these assays will be correlated with the histologic response of the tumors to preoperative chemotherapy and patient survival to potentially identify these assays as prognostic factors. These studies may define the incidence of intrinsic and acquired methotrexate resistance in tumor samples and suggest the use of new antifolates and therapeutic strategies in the treatment of osteosarcoma.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083132-03
Application #
6377492
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Wu, Roy S
Project Start
1999-07-01
Project End
2002-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$134,839
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Roth, Michael; Linkowski, Marissa; Tarim, John et al. (2014) Ganglioside GD2 as a therapeutic target for antibody-mediated therapy in patients with osteosarcoma. Cancer 120:548-54
Li, Nan; Yang, Rui; Zhang, Wendong et al. (2009) Genetically transforming human mesenchymal stem cells to sarcomas: changes in cellular phenotype and multilineage differentiation potential. Cancer 115:4795-806
Mizobuchi, Hiroo; Garcia-Castellano, Jose Manuel; Philip, Shaji et al. (2008) Hypoxia markers in human osteosarcoma: an exploratory study. Clin Orthop Relat Res 466:2052-9
Yang, Rui; Piperdi, Sajida; Gorlick, Richard (2008) Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma. Clin Cancer Res 14:6396-404
Yang, Rui; Li, Wei-Wei; Hoang, Bang H et al. (2008) Quantitative correlation between promoter methylation and messenger RNA levels of the reduced folate carrier. BMC Cancer 8:124
Yang, Rui; Hoang, Bang H; Kubo, Tadahiko et al. (2007) Over-expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma. Int J Cancer 121:943-54
Yang, Rui; Kolb, E Anders; Qin, Jing et al. (2007) The folate receptor alpha is frequently overexpressed in osteosarcoma samples and plays a role in the uptake of the physiologic substrate 5-methyltetrahydrofolate. Clin Cancer Res 13:2557-67
Laverdiere, Caroline; Hoang, Bang H; Yang, Rui et al. (2005) Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin Cancer Res 11:2561-7
Yang, Rui; Sowers, Rebecca; Mazza, BethAnne et al. (2003) Sequence alterations in the reduced folate carrier are observed in osteosarcoma tumor samples. Clin Cancer Res 9:837-44
Sowers, Rebecca; Toguchida, Junya; Qin, Jing et al. (2003) mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma. Mol Cancer Ther 2:535-41

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