Professor Klaus Pors and his PhD student Enrica have been working for three years on a project to improve an extremely toxic chemotherapy, so that it can be used to treat breast cancer. The researchers are working on duocarmycins which have been known to science for a long time. However, despite over 40 years of research on them, no duocarmycin has been approved for clinical use because in their original form they are too toxic to be used as cancer treatments. To overcome this, Professor Pors and his team have been changing the drug so that it only becomes active when it reaches the tumour, greatly limiting damage to other areas of the body. Their aim was to make this drug effective at killing breast cancer cells whilst minimising harmful side effects.
A group of proteins called CYP proteins are frequently overproduced in breast cancer cells. Professor Pors and others have designed a duocarmycin-based drug that relies on these proteins to turn it on. The team have been testing this modified duocarmycin in the laboratory to see if it is effective. If successful, this new treatment could be further tested in clinical trials for people living with secondary breast cancer.
The objectives for the third year of this project were to explore the effectiveness of their modified duocarmycin under different oxygen and nutrient levels in order to mimic the variations of these conditions found inside tumours and to analyse the tumour tissue penetration of the modified duocarmycin to better understand how it would move through tissue and its potential to treat breast cancer. Finally they wanted to test potential combination therapies with the modified duocarmycin.
Interestingly, the cancer cell killing ability of the modified duocarmycin was not significantly impacted by low nutrient and oxygen levels. This is an exciting and desirable property for a potential new treatment, as these harsh conditions can be found inside aggressive, fast-growing tumours. The effectiveness or the potency of the modified duocarmycin is dependent on the levels of the CYP protein needed to switch it on. Fortunately, the levels of the required CYP protein remained the same even under these stressed conditions.
Professor Pors and Enrica also tested potential new combination treatments with their drug. They tested it with the PARP inhibitor olabarib, and radiotherapy. The results were promising, suggesting that the treatments synergise together, boosting the cancer cell killing ability. However, further work is required to fully understand how this happens. The modified duocarmycin in its pre-activated form was also found to have good tissue penetration of 3D mini-breast tumours grown in the lab. The pre-active drug was better at getting to the centre of the 3D mini-tumour than the active duocarmycin.
Enrica is currently writing up her thesis whilst also working part time at the University of Bradford as a research assistant. She expects to submit her thesis in June, and be examined on it in July. During the course of her PhD, Enrica has presented her work to colleagues at conferences and meetings in the UK and internationally.
