Osteosarcoma (OS) is an aggressive bone cancer that primarily affects children and adolescents. Standard OS treatment includes pre- and post-operative chemotherapy and aggressive surgical resection. Nonetheless, approximately 30% of patients with localized disease and 80% of patients with metastatic disease at diagnosis will fail therapy and die due to tumor progression or relapse. The main reason for treatment failure is the development of tumor therapy resistance. Clearly, it is important to identify the molecular basis for therapy resistance in OS, and ways to target therapy resistant cells. Cisplatin (CP) has been a mainstay OS therapy agent for over 30 yrs, though mechanisms for resistance to CP remain ill-defined. We established Cisplatin (CP) resistant clones from OS cells and compared them with sensitive counterparts. P53 was induced to a lower level and less active after CP in resistant clones. Resistant clones also displayed a heightened DNA damage response after CP treatment that included DNA repair and heightened/prolonged activation of the ATM-ATR-CHK1/2 damage response pathways. Importantly, we determined that small molecule MDM2 antagonists that activate p53 and p73 and which are currently in clinical development (Nutlin-3, MI-319) could effectively kill the CP resistant OS clones. Moreover, we observed that a small molecule Chk1 inhibitor (UCN01) could sensitize multiple resistant OS cell lines and selected clones to CP. Based on these findings, we hypothesize 1) that CP resistance in OS will associate with lower levels/activation of p53 or p73, a heightened DNA damage response, and DNA repair, and 2) that MDM2 antagonists and/or Chk1 inhibitors will effectively target CP resistant OS, and will block tumor regrowth in a novel animal model of human OS tumor recurrence.

Public Health Relevance

Osteosarcoma is a devastating cancer and the most common primary bone tumor in children. Standard osteosarcoma treatment includes chemotherapy and surgery to remove the tumor. Survival rates of ~70% can be achieved using this standard treatment. However, the remaining 30% of patients respond poorly to chemotherapy and, as a result, have an increased risk of tumor relapse and the development of metastasis. Most of these patients will ultimately fail therapy and die from their disease. The goals in this grant are first, to examine why osteosarcoma cells can become resistant to the chemotherapy agent cisplatin, and second, to use this information to more effectively target the cisplatin resistant cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRB-V (O1))
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Kondapaka, Sudhir B
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Rush University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Duan, Lei; Perez, Ricardo E; Chen, Ling et al. (2018) p53 promotes AKT and SP1-dependent metabolism through the pentose phosphate pathway that inhibits apoptosis in response to Nutlin-3a. J Mol Cell Biol 10:331-340
Zhou, Yalu; Perez, Ricardo E; Duan, Lei et al. (2018) DZNep represses Bcl-2 expression and modulates apoptosis sensitivity in response to Nutlin-3a. Cancer Biol Ther 19:465-474
Davaadelger, Batzaya; Perez, Ricardo E; Zhou, Yalu et al. (2017) The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis. Cancer Biol Ther 18:895-903
Duan, Lei; Maki, Carl G (2016) The IGF-1R/AKT pathway determines cell fate in response to p53. Transl Cancer Res 5:664-675
Davaadelger, Batzaya; Duan, Lei; Perez, Ricardo E et al. (2016) Crosstalk between the IGF-1R/AKT/mTORC1 pathway and the tumor suppressors p53 and p27 determines cisplatin sensitivity and limits the effectiveness of an IGF-1R pathway inhibitor. Oncotarget 7:27511-26