Evaluation of DNA damage and endoplasmic reticulum stress in cancer patients in a Phase 1b dose-escalation trial of selenium compounds

Abstract

Selenium (Se) is an essential trace element needed in a healthy human diet. Past clinical trials have shown Se to be a promising co-drug for cancer patients undergoing treatment to minimise the effect of the cancer treatment on non-malignant cells. This project is a continuation of a 2019 Phase 1 clinical study “Comparative Safety, Pharmacokinetic and Pharmacodynamic Evaluation of Three Oral Selenium Compounds in Cancer Patients”, that set out to analyse which Se compound and what dosage point is recommended for use in a Phase 2 clinical trial at the Waikato Hospital, New Zealand.

Nine cancer patients were recruited into the trial from Waikato Hospital with informed consent. They were randomised to take one of three Se compounds, the organic compounds Seleno-L-methionine (SLM) or Se-methyl-selenocysteine (MSC), or the inorganic compound sodium selenite (SS), at a starting dose of 1600 mcg/day for 28 days and then a higher dosage of 6400 mcg/day for another 28 days. Patients were then taken off the compounds and watched for the last 28 days of the trial. Patients were asked to keep a diary and record any adverse events (AEs) that they experienced while on the trial. Western blot methods were used to investigate ER stress, and the LORD-Q assay was used to investigate the genotoxicity of the three compounds. Samples were also sent away for Se speciation studies.

Out of the three compounds, patients on MSC experienced the fewest AEs, with five Grade 1 and two Grade 2 events. SS patients experienced seven Grade 1 and two Grade 2 events. Patients on SLM reported the highest number of AEs, with six Grade 1 and five Grade 2 events. Notably, one case of encephalopathy was observed in the SLM cohort.

In the LORD-Q assay the three Se compounds exhibited sustained mtDNA protection throughout the trial. SLM exhibited fluctuating nDNA lesions at the lower dose. As the concentration increased, no measurable nDNA damage was detected. However, a transient spike in nDNA damage was later observed, followed by a decrease towards the end of the trial. Both SS and MSC exhibited an increase in nDNA relative to the baseline which was sustained throughout the trial.

Western blot analysis was performed in two out of the nine patients to provide a preliminary point of evaluation of ER stress. The western blot data showed a sustained decrease in protein expression of eIF2a and sXBP1 throughout the trial. In contrast, GRP78 decreased throughout the lower dosage phase and then increases in expression at the higher dose point.

The preliminary findings of this thesis suggest that MSC should be the compound recommended to be used in the Phase 2 trial. This is based on findings on adverse events, genotoxicity, and total Se plasma levels. It is important to note that further results are required to elucidate this recommendation.