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Publications of the Week

Deep Whole-Genome ctDNA Chronology of Treatment-Resistant Prostate Cancer

By August 2, 2022No Comments

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This week we profile a recent publication in Nature from first authors Cameron Herberts,  Matti Annala, and Joonatan Sipola. Drs. Alexander Wyatt (pictured) and Kim Chi at the Vancouver Prostate Centre and UBC, and Dr. Felix Feng at University of California San Francisco  jointly supervised this work.

Can you provide a brief overview of your lab’s current research focus?

The Wyatt laboratory studies the genomics of lethal prostate and bladder cancer. Our overall objective is to use our experience in genitourinary cancer genomics and bioinformatics to enable real-time precision oncology in the clinic. To achieve this, we perform a variety of innovative next-generation sequencing techniques on clinical specimens including tissue and liquid biopsies from individuals with metastatic castration-resistant prostate cancer (mCRPC) and metastatic bladder cancer. Our research is closely integrated with the clinic through several ongoing clinical trials with heavy correlative components.

What is the significance of the findings in this publication?

We have developed new blood-based biopsy technology to study the DNA that metastatic cancers shed into the bloodstream. This DNA is known as circulating tumour DNA (abbreviated to ctDNA) and is also sometimes known as the ‘liquid biopsy’. Blood ctDNA tests have already begun to influence the clinical management of people with cancer, but their full potential to tell us about metastatic cancer biology had not been previously defined. Our new paper published in Nature demonstrates the unprecedented depth of information about metastatic cancer that can be obtained from ctDNA, collected in just a tablespoon of blood from a standard blood draw. This paper, and the new methods that we developed, represent a paradigm-shift for how the scientific community can learn about metastatic cancers in people around the world. In our paper, we performed deep whole genome sequencing of ctDNA in people with prostate cancer. 

From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those people whose quality or length of life will be improved. A new generation of comprehensive ctDNA tests have potential to help clinicians choose treatments better tailored to metastatic cancer spread across the body, improving the likelihood that people will benefit. These ctDNA tests can also be used to quickly detect treatment resistance and appropriately adjust clinical care. 

However, our research has implications beyond individual cancer patient management. How drug resistance emerges in living patients receiving treatment has historically been extremely challenging to understand. Repeat metastatic biopsies were previously the only tool available to learn how tumours evolve over time but are highly invasive, expensive to perform, and do not necessarily accurately reflect a patient’s overall disease (established in part by our research). Our research proposes serial ctDNA testing as a novel research modality to accelerate the discovery of treatment resistance mechanisms to common cancer drugs. This methodology can be applied to other cancer types to reveal new biological insight, but also help design the next generation of cancer therapies that more effectively target resistant disease. Using state-of-the-art ctDNA nucleosome footprinting (an emerging technique our paper helps develop), we can now also use ctDNA to understand tumour cell signalling pathways—this is important because not all drug resistance occurs through mutations, but instead can be caused by more nuanced changes in cell signalling pathways (previously extremely challenging to detect with existing technologies). Collectively, this expansion of liquid biopsy technology represents a paradigm shift for how we can learn about and ultimately combat late stage cancers.

What are the next steps for this research?

This minimally-invasive, relatively inexpensive, and highly-scalable whole-genome ctDNA sequencing technology is now being deployed across large clinical trials to facilitate discovery of new treatment resistance mechanisms. This includes leading-edge ‘precision oncology’ clinical trials in Canadian cancer patients being conducted at BC Cancer and the Vancouver Prostate Centre.

All software, methodology, and data from our paper is publicly available. This means that the advancements proffered by our paper can be rapidly implemented into existing commercial ctDNA testing platforms, and that patients are therefore soon able to directly benefit from more comprehensive liquid biopsy testing.

If you’d like to mention your funding sources, please list them.

This work was generously funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Terry Fox New Frontiers Program and the BC Cancer Foundation.

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