Osteosarcoma is an aggressive bone cancer that affects children and adolescents. Osteosarcoma is considered a disease of disrupted differentiation wherein tumor cells are unable to differentiate into proper bone-forming mature osteoblasts. Osteosarcoma is often advanced at presentation and current treatments consist primarily of chemotherapeutic regimens and surgery. Osteosarcoma has a high rate of recurrence and often leads to limb amputations in young patients. The survival rate for metastatic osteosarcoma remains around 30% and alternative treatments are badly needed for this devastating disease. In this collaborative study, we propose to test a novel approach for treating osteosarcoma by harnessing intrinsic multipotency features of the osteosarcoma cancer stem cells. Osteosarcomas arise from mesenchymal stem cells that normally have the ability to form bone and fat cells. Our differentiation therapy approach is to use agents that preferentially inhibit the growth of osteosarcoma cancer stem cells while steering them to become adipocytes. We will use a class of drugs, the TZDs, that are agonists for PPAR?, the master regulator of adipogenesis. Several TZDs are approved for their unrelated effect in insulin clearance and treatment of diabetes. We have found that TZDs can inhibit the growth of osteosarcoma cells and promote adipogenic differentiation. We will test the effects of TZD on primary mouse and human osteosarcoma cells in mice, and examine their effects on cells and tumors. In particular, we will determine whether the TZDs can activate genes needed for adipogenesis. If successful, this proposal will provide the basis for new strategies to treat osteosarcoma in the clinic.

Public Health Relevance

(for all audiences) The studies proposed would lead to a novel differentiation therapy to preferentially target the cancer stem cells in osteosarcoma, a devastating childhood bone cancer. We aim to slow the growth of tumors and convert them into benign fat tissue using drugs that are already approved for safety by the FDA. If this approach works, this treatment can be easily transitioned to patients and provide a much-needed targeted therapy for this disease and other cancers of similar origin.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-RTRB-8 (J1))
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Arya, Suresh
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New York University
Schools of Medicine
New York
United States
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Basu-Roy, Upal; Han, Eugenia; Rattanakorn, Kirk et al. (2016) PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity. Oncotarget :
Huang, Zhifeng; Marsiglia, William M; Basu Roy, Upal et al. (2016) Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ. Mol Cell 61:98-110
Basu-Roy, Upal; Bayin, N Sumru; Rattanakorn, Kirk et al. (2015) Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells. Nat Commun 6:6411
Seo, Eunjeong; Basu-Roy, Upal; Gunaratne, Preethi H et al. (2013) SOX2 regulates YAP1 to maintain stemness and determine cell fate in the osteo-adipo lineage. Cell Rep 3:2075-87