Irradiation of colorectal and liver tumors: Novel applications and mechanisms of resistance

Abstract

Radiation therapy is a cornerstone in cancer treatment, but for a large proportion of cancer patients it will prove ineffective. This thesis explores how radioresistance develops as well as a technique called radiation lobectomy to treat patients with liver cancer. In Part I of this thesis, we employed organoid technology, single-cell whole genome sequencing, and RNA sequencing to investigate the mechanism by which cancer cells are or become radioresistant. We reveal that within organoids, subclones respond differentially to radiation and that this response may be associated with chromosomal instability. We also identified a combination of two drugs; -RRx-001 (which increases oxidative stress) and BSO (which inhibits a key antioxidant enzyme)- as very effective in killing radioresistant cancer cells. Part II explores the effects and clinical utility of radiation lobectomy, which is used for patients with liver cancers to improve the outcome of liver resection. Radioactive microspheres are infused in the tumor-bearing liver parts, as such treating the tumor locally, but also stimulating the non-treated parts of the liver to grow sufficiently to sustain liver function after resection. We find that the response of tumor cells to radiation lobectomy is correlated with the number of cancer stem cells and that the function of lymph vessels surrounding the tumors is impaired. Finally, the clinical outcome of surgical resection following radiation lobectomy is discussed, as well as the first prospective study of radiation lobectomy, the RALLY study.