The identification of effective chemotherapy and surgery 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 may allow stratification of therapy. Investigation of biological features related to chemotherapy resistance or 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 osteosarcoma treatment, will allow the identification of in vitro assessments which may predict response to this drug. Recently identified mutations and polymorphisms in the reduced folate carrier which is involved in methotrexate uptake may also be important determinants of tumor chemotherapy response and patient treatment related toxicity. Studies of these biological factors may allow prioritization of therapeutic strategies as newer agents which avoid antifolate resistance have been developed.
The aim of this study is to investigate biological factors related to methotrexate resistance as predictors of prognosis in patients with osteosarcoma. Osteosarcoma tumor samples obtained from patients treated as part of Children's Oncology Group therapeutic studies will be assayed for changes in reduced folate carrier, dihydrofolate reductase, folylpolyglutamate synthetase and gamma-glutamyl hydrolase expression as well as functional assays for methotrexate uptake and polyglutamylation. The results of these assays will be correlated with the histologic response of the tumors to preoperative chemotherapy and patient survival in a large uniformly treated cohort of patients with newly diagnosed localized osteosarcoma to potentially identify these assays as prognostic factors. Osteosarcoma tumor samples and patient's normal cells will be screened for alterations in reduced folate carrier sequence. The presence of the reduced folate carrier host polymorphisms will be related to the toxicity observed following high-dose methotrexate administration and the time required to clear the methotrexate to determine their utility at predicting patient toxicity. The tumor specific mutations will be evaluated as prognostic factors. It is hoped that the information obtained through this proposal will allow the development of risk stratified therapy for osteosarcoma that takes into account patients' likelihood of therapy related toxicity and probability of response to new agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083132-07
Application #
7219972
Study Section
Special Emphasis Panel (ZRG1-CBSS (01))
Program Officer
Timmer, William C
Project Start
1999-07-01
Project End
2008-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
7
Fiscal Year
2007
Total Cost
$149,529
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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
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
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

Showing the most recent 10 out of 13 publications