Assessing Tumour Heterogeneity in Time
Understanding tumour evolution using longitudinal genomic information to identify mutational processes contributing to tumour progression, subclonal diversification and recurrence
About Our project
As our understanding of cancer complexity grows, we now recognize the challenges posed to successful treatment of adaptive changes which occur within tumours over time. However, at present we do not fully understand how to exploit these changes for patient benefit. We can readily conceptualize modifications to treatment when a novel mutation arises within cancers, but we lack deep understanding of the processes involved. By performing detailed molecular profiling of cancers at different intervals during treatment and using different treatment approaches we will be able to identify both common and treatment specific alterations which drive treatment progression. By using existing samples from phase II/III clinical trials, we will be able to place these changes directly into the context of modern therapeutic approaches and use this as a platform to design novel adaptive treatment approaches across the disease spectrum. Adaptive molecular changes during treatment are a challenge across all cancer types, and our results will be broadly translatable across multiple cancers; here we are using multiple breast cancer clinical trials as a platform to test key hypotheses and develop novel tools for tumour assessment.
The overall goal is to generate novel information on the emergence of clinical resistance to specific targeted therapeutics during treatment. By focusing on breast cancer, we will directly inform future adaptive oncology treatments in which the current agents are paired with targeted agents that inhibit the activation of resistance pathways. We will also test the hypothesis that pathways that increase molecular plasticity lead to the accelerated emergence of drug resistance, allowing patients at high risk of recurrence to be identified early and treated appropriately. Successful completion of these goals will provide a diagnostic approach to monitoring and identifying pre-existing and developing resistance, with the potential to rapidly extend to other cancer settings.
Our objectives are to:
Develop protocols to characterize changes in tumour heterogeneity in tissue biopsies at pre-, mid- and post-treatment time points using standard high coverage NGS, as well as exploring new sequencing technologies capable of simultaneously calling SNVs, methylation marks, and structural variants;
Evaluate tumour adaptation over time, at the molecular level, to treatments commonly used to eradicate breast cancer in the clinical setting;
Assess tumour characteristics linked to high mutational frequency in the context of adaptive changes during treatment;
Apply similar approaches to characterize cfDNA samples from multiple time points so as to correlate liquid biopsy-defined trajectories to those found in serial tissue samples;
Using data from the Heterogeneity in Space project, correlate evolutionary trajectories with ITH to develop prognostic and predictive biomarkers to guide treatment.
This project will provide a systematic, in-depth view of changes that occur in breast cancer over the course of different treatments, seeking to develop clinical tools for assessment of heterogeneity over time which can be used to monitor tumour and patient response under varying treatment regimens and direct novel treatment approaches for tumours with adaptive potential.