Francisco Liberal, Mr.

RABBIT PhD student (PD/BD/114448/2016)

“Modelling the Effectiveness of alpha-particle radionuclides in Prostate Cancer" (2016-2020)

Radionuclides have been widely used in cancer treatment for some time, with varying degrees of success. Both alpha and beta emitters have been used, with varying degrees of impact on both symptoms and overall survival. Prostate bone metastases are a topic of particular interest in this area, due to the recentlydemonstrated survival benefit of Radium-223 (223Ra) in this setting.2,3 However, the reasons for its efficacy in comparison to previous beta-emitters remains poorly understood. Low Linear Energy Transfer (LET), such as Strontium-89, Samatium-153, Rhenium-186 and Rhenium-188, radionuclides have been utilised to allow targeted delivery of radiotherapy to disparate sites of disease, with evidence of palliative benefit.1,4 More recently, the bone targeting, high LET radionuclide 223Ra has been shown to not only have a palliative effect but also a survival prolonging effect in metastatic, castration resistant prostate cancer with bone metastases.2,4,5 This has encouraged the use of 223Ra in a more extensive range of setting including earlier in the disease setting and combined with external beam radiotherapy which is forming part of a trial (ADRRAD) being led from the Centre for Cancer Research & Cell Biology and the Northern Ireland Cancer Centre. Despite this clinical utility, little is known regarding the mechanisms of action of 223Ra in this setting and accurate assessments of the dosimetry underpinning its effectiveness are lacking. From a radiobiological perspective alpha particles are known to be more effective at killing cells in comparison to low LET radiations such as X-rays with increased relative biological effectiveness of around a factor of 3 in most models. Alpha-particle irradiated
cells also show a reduced a dependency on radioresistance mechanisms observed in the absence of oxygen with Oxygen Enhancement Ratios (OER) close to 1.0. As well as direct effects it is also thought that alpha-emitters are capable of producing effects in non-irradiated bystander cells.4,6 There is a pressing need to model and quantify alpha-emitter effects in pre-clinical models so the next generation of trials utilising 223Ra can be optimally designed. However, quantitatively comparing the impact of different radionuclides to identify optimal choices remains challenging. In addition to the calculation of absolute dosimetry, different agents have different half-lives and spectra of decay products, which leads to significant differences in both the timescale of radiation exposure and the spatial distribution of damage throughout both normal and cancerous tissue.
f.liberal@campus.fct.unl.pt