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

Currently, the survival rate of childhood cancer is higher than 80%. The treatment that makes this possible also damages the healthy cells in the patient. This results in side effects, some of which only develop months or years after the end of treatment. These are called late effects and consists of, among others, heart and kidney diseases and second cancers. The number of late effects can be reduced by two methods.

First, the amount of the most toxic drugs that is administered could be reduced. This thesis describes molecular research that investigates which chemotherapies and other drugs cause the most DNA damage in healthy cells and can therefore contribute to the development of second cancers. These drugs might therefore be potential candidates for dose reduction. Of the investigated chemotherapies, thiopurines and platinum compounds induced the most DNA damage in healthy cells. In addition, platinum compounds also influenced when second cancers could develop. Surprisingly, not only chemotherapeutic drugs, but also an antiviral agent, ganciclovir, proved to be highly mutagenic. This drug is administered to some transplantation recipients that develop a viral infection.

The second approach to reduce late effects is to develop therapies that kill the cancer cells more specifically and that therefore damage healthy cells less. In this thesis, molecular processes are identified that are active in childhood Hodgkin Lymphoma that could be potential targets for developing targeted therapy.

The results of the research in this thesis contributes 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.