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Osteosarcoma


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Osteosarcoma

Osteosarcoma is the most common primary bone malignancy, with a high incidence rate in children and adolescents compared to other age groups. Tumors most often arise in the long bones from osteoid-producing neoplastic cells adjacent to the growth plates, occurring less commonly in the axial skeleton and other nonlong bones. Survival rates for osteosarcoma have remained at 60–70% for localised disease for decades despite ongoing studies. Unlike many sarcomas which are characterized by specific chromosome translocations, complex genomic rearrangements involving any chromosome characterize individual osteosarcoma cells. Because of this few consistent genetic changes that may suggest effective molecular targets for treatment have been reported.

In addition to traditional chemotherapy, there are multiple investigational agents being studied which target pathways that are believed to be active in osteosarcoma. Osteosarcoma expresses in varying degrees cell surface transmembrane receptors. These include vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), human epidermal growth factor receptor 2 (HER2), and MET. These all share common features of being transmembrane receptors with tyrosine kinase activity. Intracellularly they activate different signaling cascades which have been implicated in oncogenesis. As well as receptor tyrosine kinases, intracellular tyrosine kinases which serve as intermediaries in the signaling cascade have also been targets of drug development with possible implications for the treatment of osteosarcoma.

Most osteosarcoma samples harbor a complex karyotype, with cytogenetic heterogeneity with the cells of the same tumor. This may, in part, be due to aberrations in p53 in osteosarcoma. Osteosarcoma cell lines have been demonstrated to have loss of p53, mutations in p53, as well as wild-type p53. MDM2, a known suppressor of p53, is significantly amplified in osteosarcoma samples with wild-type p53. However, MDM2 amplification was observed only in 5 of the 32 samples studied. The Nutlins have been identified as small molecule inhibitors of the interaction between p53 and MDM2. In osteosarcoma cell lines that express wild-type p53, Nutlin-3a, an enantiomer of Nutlin-3, suppresses proliferation and promotes apoptosis. These agents are currently in preclinical testing, but may be promising for a subset of patients with osteosarcoma.

Currently, some related specific target inhibition using small molecules has been developed. These trials encompass small-molecule kinase inhibitors that inhibit serine/threonine kinases such as mTOR or Aurora A, or tyrosine kinases such as VEGFR, Src, IGF-1R, PDGFR, or c-Kit. Rapamycin, studied in relation to cancer since the 1990s, or analogous substances are potent inhibitors of mTOR, a serine/threonine protein kinase that promotes cell growth and cell survival. Four trials testing inhibitors of the tyrosine kinase Src are currently under-way, despite conflicting in vivo evidence. Finally, the multikinase inhibitors, which may limit the chance of tumor cell resistance, are a relatively new subclass of drugs under review.

Creative Biogene, as a leading biotechnology company, is able to offer various osteosarcoma pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.

References:

  1. Botter S M, et al. Recent advances in osteosarcoma. Current opinion in pharmacology, 2014, 16: 15-23.
  2. Gill J, et al. New targets and approaches in osteosarcoma. Pharmacology & Therapeutics, 2013, 137(1):89-99.
  3. Broadhead M L, et al. The Molecular Pathogenesis of Osteosarcoma: A Review. Sarcoma, 2011, 2011:1-12.
  4. Martin J W, et al. The genetics of osteosarcoma. Sarcoma, 2012, 2012.

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