Tracing evolutionary routes to treatment resistance in childhood cancer across time and space

Rationale: Most children dying from cancer in the modern world do so because of widespread treatment-resistant disease.

The mechanisms underlying resistance are largely unexplored but we know that Darwinian evolution of tumor cells under chemotherapy is a key contributor.Aims and purpose: We will explore the fundamental principles for how childhood cancer genomes evolve under therapy and up to relapse to find new prognostic instruments and vulnerabilities in tumor evolution that could be targeted by novel therapeutic efforts.Work plan: Using multiregional sampling and bioinformatic methods inspired by species evolution we will analyze >100 childhood cancers to (1) catalog mutations that remain stable over tumor evolution, (2) define mutational signatures of treatment resistance, (3) trace the ancestral origin of metastatic relapses, (4) test the prognostic value of evolutionary parameters from singe cell sequencing, and (5) identify host cells types that promote the evolution of resistant cancer cells.Significance: Our preliminary data show that a multitude of clones is often present in the primary tumor after therapy, in an environment enriched for specific immune cells that can act as therapeutic targets.

In contrast, most relapses emerge from a single ancestral cell, offering a critical time window for early detection.

We find relapses to be related only distantly to the primary tumor, suggesting that resampling of relapses is important when targeted therapy is considered.