Finding the hidden patterns: single-cell omics to reduce late effects

Abstract

Currently, over 80% of children with cancer survive due to effective treatments. However, these treatments can also damage the patient’s healthy cells, leading to side effects. Some of the side effects only develop months to years after the end of treatment. These are known as late effects and include cardiovascular diseases, kidney disease, and second cancers. Reducing the number and severity of late effects of cancer treatment is attempted via two approaches.

First, the total dose of the most toxic drugs in a treatment regimen might be reduced. To that end, the most toxic drugs first need to be identified. This thesis describes molecular research that investigates which (chemotherapeutic) drugs cause the most DNA damage in healthy cells, and which lead to the development of second cancers. These drugs might be potential candidates for dose reduction. As toxic effects on normal tissues, but especially blood, can be dose limiting, healthy blood cells, and second cancers of the blood were investigated. We found that a specific group of drugs, called topoisomerase inhibitors, induced most of the genetic alterations that were driving the development of the second cancers. Two other groups, thiopurines and platinum compounds, induced the most DNA damage in healthy cells, which also resulted in mutations that drove second cancer development. In addition, platinum compounds prevented rapid expansion of most second cancers. These could only fully develop after the administration of platinum compounds had ended. Only second cancers with a genetic alteration in the TP53 gene could grow out under platinum compound treatment. Second cancers therefore developed earlier in these patients. This might influence the need and timing for screening of these patients. Surprisingly, not only chemotherapeutic drugs, but also an antiviral agent, ganciclovir, proved to be highly mutagenic and in some patients had likely contributed to cancer development. This drug is administered to transplantation recipients that develop a viral reactivation after transplantation. Ganciclovir belongs to the group of nucleoside analog drugs. The DNA damage caused by other drugs in this group was studied, but none caused DNA damage to the same extend as ganciclovir.

The second strategy to minimize late effects involves developing therapies that kill the cancer cells more specifically than conventional chemotherapeutic drugs and that thereby reduce the damage to healthy cells. In this thesis, potential therapy targets in childhood Hodgkin lymphoma were investigated. Molecular processes were identified that were consistently active in the cancer and immune cells of this cancer type but not in healthy reference cells. These could therefore be potential targets for developing targeted therapies.

The results of the research in this thesis contribute to our understanding of how late effects develop and which drugs are involved in this process. In addition, it will contribute to more efficient development of future clinical research into the reduction of late effects.