A recent study undertaken by researchers from Weill Cornell Medicine and the University of Trento sought to examine the effects of chemotherapy on bladder cancer cells.1
The research team collected tumor samples from 32 participating patients with advanced urothelial cancer for DNA analysis (28 of the respondents developed metastatic urothelial cancer, either when they joined the study or afterward). The tumor samples were obtained at different points of time during the course of the disease. Two participants also gave the investigators permission to conduct autopsies shortly after their death, which aided the research team in observing the natural evolution of tumors in different bodily locations. Bioinformatic analysis was conducted on the tumor samples at the University of Trento in Italy by co-first author, Dr Davide Prandi, and co-senior author, Dr Francesca Demichelis.
After their analysis, the researchers determined that as the disease spread through the body, the tumors developed new mutations not found in the primary tumor. On examination, the integrin signaling and L1-cell adhesion molecule signaling pathways indicated higher mutation rates following chemotherapy. The researchers identified both these molecular pathways as potential targets for prevention of chemotherapy resistance. In addition, their examination of the mechanisms behind the development of chemotherapy-resistant tumors indicated that proteins called APOBECs bind to the splintered DNA strands that result from chemotherapy treatment, which in turn spurs mutation.
The research team feels that chemotherapy affects the evolution of urothelial cancer, helping to produce chemotherapy-resistance in surviving cancer cells. Indeed, most patients with urothelial cancer who are treated with chemotherapy, one of the few treatment options available, become resistant to further treatment after several months. Co-first author Dr Faltas also stated that clinical genomic testing done on the primary untreated tumor site gives an incomplete genetic picture and does not reveal genetic changes taking place after chemotherapy; something with implications for targeted therapies.
The results of this study were published in the Nature Genetics journal.
1. Faltas BM, Prandi D, Tagawa ST, et al. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nature Genetics. 2016 Oct 17. doi: 10.1038/ng.3692. [Epub ahead of print]