Circulating Tumor DNA to Serially Assess in vivo Transcriptional Evolution in Cancers

ASPIRE Award (2022-Present)

Sarah-Jane Dawson, MD, PhD, Peter MacCallum Cancer Centre, The University of Melbourne (Australia)

Sarah-Jane Dawson, MD, PhD

One of the most significant challenges to treating cancers is tumor evolution in response to therapies, which promotes drug resistance. These evolutionary changes are difficult to characterize in real time at the molecular level, and often the only indication that such evolution has occurred is manifestation of resistance and recurrence of cancer growth in the patient. Sampling DNA from primary tumors and metastatic sites in the body throughout the course of treatment is impractical and invasive. Moreover, it is now well appreciated that in addition to accumulating genomic changes in a classic Darwinian fashion, tumors may also evolve resistance through mechanisms which do not rely on changes in their DNA, but rather in plasticity of gene expression through epigenetic and regulatory alterations. These complexities underscore the need for developing methods to track and analyze tumor evolution in real time at both the genomic and transcriptomic level.

Here, Sarah-Jane Dawson will address these problems by optimizing and expanding a technique her group developed called SNIPER (Serial Non-Invasive Plasma Gene Expression Reconstruction), a novel method utilizing circulating tumor DNA (ctDNA) shed by cancerous cells. This technique harnesses the power to examine changes in DNA accessibility which correlate with gene expression to get a readout of changes in transcription over the course of tumor evolution. Previously, the team demonstrated a correlation between SNIPER measurements and gene expression changes in hematopoietic cells. With this award, they will expand this work and optimize it for solid tumors, which in general release much smaller amounts of ctDNA compared to the hematological cancers they have previously studied. Additionally, they will examine tumor evolution after treatment regimens to see if their methods can track these changes from patient samples. This work will provide an innovative framework for studying acquired treatment resistance to novel therapies, to unlock the full potential of liquid biopsies, and affect a paradigm shift in the way that cancer can be monitored in the clinic.