Exploiting radiation to improve the outcome of centrosome-based therapies

Centrosome amplification is prevalent in human tumours and is associated with malignancy, poor prognosis and metastasis, possibly by inducing genomic instability and invasion [1]. Interestingly, the presence of such abnormalities creates an ‘Achilles heal’ to cancer cells, which can be targeted [2]. Advances on how centrosome abnormalities could be exploited to selectively kill cancer cells have been made. However, efforts to translate these findings into the clinic have been hindered by the fact that these aberrations typically occur only in a fraction of cancer cells. Previous work has shown that DNA damage, which is induced by radiation, can cause centrosome amplification [3]. Here, we propose to investigate how radiation therapy could be used to sensitize tumours to therapies that target cells with amplified centrosomes.

Strategies that target centrosome amplification have been proposed. Cancer cells with supernumerary centrosomes have unique requirements for their cell division and survival, such as centrosome clustering [4]. Inhibiting centrosome clustering drives multipolar mitoses and cell death selectively in cells with amplified centrosomes. Drugs that selectively target centrosome clustering are available but due to the subclonal nature of these abnormalities it has been difficult to test these drugs in the clinic.

A link between radiation and increased centrosome abnormalities has been previously established. As drugs that target extra centrosomes are available and radiation therapy achieves greater spatial precision [5], we hypothesise that using radiation to locally induce centrosome amplification in tumours would make cancer cells sensitive to drugs that target centrosome clustering. We propose to exploit radiation and centrosome-based therapies as a novel combination therapy approach to treat patients. To test this, the student will address the following questions:

1. Characterise the effect of radiation on centrosome abnormalities in cancer cells. Established panel of breast cancer cell lines will be used to test how x-ray and proton beam radiotherapy impacts centrosome integrity using confocal and super resolution microscopy. Available human tumour samples will also be used.
2. Mechanisms of radiation-induced centrosomal abnormalities. The student will dissect mechanistically how radiation induces centrosome abnormalities using a combination of cell biology, biochemistry and microscopy. This will be important to further tailor centrosome-based therapies to be used in combination with radiation.
3. Sensitivity of radiation-treated cells/tumours to centrosome-based therapies. We will use cancer cells and syngeneic mouse breast cancer models to assess the efficacy of drugs that target centrosomal abnormalities upon radiation. We will use the XStrahl preclinical radiotherapy platform at UCL in collaboration with Rebecca Carter.

Outcomes: This project will offer for the first time the opportunity to characterise and understand centrosomal aberrations that occur in cancer in response to radiotherapy. This will be important to tailor centrosome-based therapies that can be used in combination with local radiotherapy, which it will be tested in cells and animal models. Moreover, it is possible that centrosome-based therapies could be used to treat tumours resistant to radiotherapy, an exciting possibility we want to expand in future studies.

Suitable candidates must have a minimum upper second-class Honours degree in molecular/cell biology or a closely related field, or an oversees qualification of an equivalent standard. They much have knowledge in life sciences, required for this project. Experience of laboratory techniques such as tissue culture, confocal microscopy and in vivo experience would also be desirable.

Potential research placements

1. Centrosome and cancer biology. Training in basic tissue culture and cell biology techniques, immunofluorescence and microscopy, quantification of centrosome amplification and cell irradiation. Susana Godinho, BCI, QMUL.

2. Principles of radiation interactions with tissue and the concepts of radiotherapy. Understanding clinical radiotherapy treatments for breast cancer (both proton and x-ray), methods of delivery and clinical pathways for breast cancer patients. UCL/H radiotherapy research team.

3. DNA damage response in normal and cancer cells. Training in basic methods used to study and quantify DNA damage. Zuzana Horejsi, BCI, QMUL.

For further details on how to apply please visit the CRUK CoL PhD training programme web page: https://www.colcc.ac.uk/phd-studentships/