Contextual synthetic lethality to optimise glioblastoma cell responses to proton and X-ray irradiation: an upscaling approach to study radiosensitisation and radioresistance

Cancer is responsible for more than 9 million of deaths worldwide. The
major treatments are surgery, chemotherapy and radiotherapy. During the
course of their treatment, about 50% of the patients will undergo
radiotherapy using X-rays. This represents more than 95% of the
radiotherapy treatments but the use of high energy charged particles like
protons or carbon ions presents clear benefit thanks to their depth dose
profile. Although improvements were made over the years, radioresistance
is still a major challenge and a lot of work is performed at the tissue, cellular
and molecular levels to better understand cancer and to find ways to
sensitise tumour cells to radiation. In this context, the fact that cancer cells
are often deficient for DNA repair response may be exploited.
In this work, we propose to take advantage of the combination of PARP and
RAD51 inhibitors. This strategy is promising not only to counteract the
resistance associated to PARP inhibition but also to extend its use to
patients without BRCAness phenotype. More particularly, we propose to
work with contextual synthetic lethality. We will use PARP and RAD51
inhibitors at concentrations that lead to limited cytotoxicity (alone or in
combination) but to an increased cell death when the cells are irradiated.
This will allow to widen the therapeutic window as the enhanced cell killing
will only happen in the irradiated area.
We will study the sensitising effect of the inhibitors alone or in combination
after irradiation of glioblastoma cells with protons or X-rays. This effect will
be studied through an upscaling approach starting with in vitro 2D cell
model, then in vitro 3D neurospheres and, finally, in vivo implementation.
The results of this project will bring new insight in the radiosensitising
effects of DNA repair inhibition but also on the pathways involved in
resistance to treatment. This work will evidence the possible use of
contextual synthetic lethality for the treatment of glioblastoma.