Radio- and Chemosensitivity
Here you can find information about our projects focusing on radio- and chemosensitivity of tumor cells.
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Molecular mechanisms of radio- and chemosensitivity
Achieving a successful tumor therapy based on irradiation and/or chemotherapy, induction of two essential effects are required. At first, blocking the uninhibited growth of tumor cells and secondly, to trigger cell death in resting as well as proliferative tumor cells. Ideally, the damaging effect of treatment should be tumor-specific and spare healthy cells, which is still very challenging.
Biomarker and therapeutic targets
The most important effect of radio and chemotherapy is the activation of p53, a central regulator of cell growth and cell death. Both treatments induce cell damage as well as damage to the DNA and thereby activating this important protein. Once transformed into its activated form, p53 can initiate cell cycle arrest in order to prevent cells from dividing before their damaged DNA has been repaired. If the cells are not able to repair the DNA damage, p53 activates a cellular program resulting in cell death.
The treatment of tumors with p53 mutation remains challenging, because these degenerated cells are not able to enter apoptosis and continue with proliferation. Thus, the tumor is progressive or even metastasize. This is the reason, why patients with p53 mutations have a poor response to radio- or chemotherapy. Therefore, p53 plays a central role in the occurrence of resistance and simultaneously acts as an important factor to overcome resistance.
Many solid tumors, including head and neck carcinomas, have a functional loss of p53, caused by mutations in the DNA-binding domain of p53 leading to structural changes and thereby to a loss of its transcriptional activity. Besides the genetic variations of the TP53 gene itself, the expression of viral oncogenes such as the E6 protein of the human papillomavirus (HPV) leads to a functional inhibition of the p53 protein. Furthermore, mutations in the genes MDM2 and p14ARF are also very frequent, whereby their important control function is influenced by p53. In addition to changes affecting the p53 network, there is a variety of other molecular mechanisms influencing the effectiveness of therapy in tumor and normal tissues. Further research is required to understand the molecular mechanisms and their interaction as well as to improve therapy efficiency.
- Detailed molecular characterisation of tumor cells derived from head and neck carcinomas ( focusing on the p53 mediated network and other DNA repair regulators)
- Analyzing human cancer cell lines for concordance of molecular profile and radio-/ chemosensitivity
- Investigating biomarkers used for therapy prediction within clinical trials, aiming the optimization of treatment strategies
- Identifying novel drugs in order to optimize efficiency of radio-/chemotherapy
- Authors:Bandyopadhyay S, Mehta M, Kuo D, et al.Journal:Science Year:2010; Volume:330Issue:(6003):Pages:1385-9.
- Authors:Poeta ML, Manola J, Goldwasser MA, et al.Journal:N Engl J Med Year:2007; Volume:357Issue:(25):Pages:2552-61.
- Authors:Eriksen JG, Alsner J, Steiniche T, Overgaard J.
Journal:Radiother Oncol Year:2005; Volume:76Issue:(2):Pages:135-42.
Title:The possible role of TP53 mutation status in the treatment of squamous cell carcinoma of the head and neck (HNSCC) with radiotherapy with different overall treatment times
- Authors:Alsner J, Sorensen SB, Overgaard J.
Journal:Radiother Oncol Year:2001; Volume:59Issue:(2):Pages:179-85.
Title:TP53 mutation is related to poor prognosis after radiotherapy, but not surgery, in squamous cell carcinoma of the head and neck
- Authors:Koelbl O, Rosenwald A, Haberl M, et al.
Journal:Int J Radiat Oncol Biol Phys Year:2001; Volume:49Issue:(1):Pages:147-54.
Title:p53 and Ki-67 as predictive markers for radiosensitivity in squamous cell carcinoma of the oral cavity? an immunohistochemical and clinicopathologic study