Reimagining Liquid Biopsy Applications with Epigenomics

Hannah Loss:
Hi everyone. Welcome to this podcast from Cambridge Healthtech Institute for The Liquid Biopsy Summit, which runs June 17th through 19th in San Francisco, California. I'm Hannah Loss, conference production assistant. We have with us today one of our speakers from the Liquid Biopsy Summit, Dr. Samuel Levy, Chief Scientific Officer of Bluestar Genomics. Thanks for joining us Sam. What is it like working in the cell-free diagnostics field today, and how has this area of precision medicine changed?

Samuel Levy:
Well thank you very much Hannah for the opportunity to talk today about this area -- cell-free diagnostics. It's a very interesting trajectory that we're going through right now in the development of how cell-free diagnostics are evolving, and I think we have to sort of acknowledge the earlier human genome work that I was actually involved in at Celera Genomics, in generating also a personalized and individualized genome that enabled us to sort of define genetic variation. And then subsequent to that, the area that has really developed over the years has been the application of our knowledge of the genome into genomic assays that can help patients develop tailored therapies, and basically treatment regimens. I did some work with Eric Topol at the Scripps Translational Science Institute that enabled us to sort of generate data sets that ended up become very useful for patient care.

And the cell-free diagnostic spaces has really witnessed an expansion and development over the last 10 years thanks to taking the knowledge of the genome that has been developing over the last 20 years, and characterizing the person-to-person variation that has been developed and measured in the genome, and has enabled them the development of assays that can answer clinical questions in a very precise fashion. Some of these developments in cell-free DNA analysis have expanded in notable areas over the last 10 years. The very first has been the development of a non-invasive prenatal test to detect trisomies in pregnancies. So the infants in mothers in pregnancies that are potentially at higher risk, and one of our founders at Bluestar, Steve Quake, actually helped lay out the technology and the science behind those kinds of early assays, just looking at cell-free DNA in maternal blood to try and detect the fetal genome. And in so doing, determine whether trisomies were present -- these additional chromosomal copies.

And that development of the assay really helped over the years to not just reduce the number of amniocentesis that were done, which are risky procedures in advanced pregnancies, to a point now where they're almost eliminated in rare cases. And that was an incredible development of the cell-free DNA technology using underlying knowledge of the genome and sequencing.

The other area that has developed obviously has been in oncology, and the detection through the cell-free DNA of mutational events that arise from tumor cells apoptosing and releasing their DNA into the plasma can be detected. And this detection of mutations from the tumor in the plasma through the cell-free DNA has really enabled the direction of how therapies are applied. The detection in a noninvasive fashion to tailor both a mutational load present in a patient to a relevant therapy. And more recently, looking at the scope of mutational changes to come up with tumor mutational burdens scores that can help essentially determined whether immunotherapies would be effective or not.

Some of the fertile areas of research in academia and industry are really teaching us how we can detect cancer noninvasively, how we can track the progression of disease, and how we can essentially combine that with a response to therapy and even recurrence of disease.

Hannah Loss:
Bluestar Genomics takes an epigenomic approach to precision medicine. So, what can epigenomics offer to the field of liquid biopsy?

Samuel Levy:
Well recently in our hands, it's emerging ideas that one can probe DNA to look at the regulation of genes. Much of what I've just mentioned has primarily focused on the detection in cell-free DNA of mutational events in cancer, and the regulation of genes and their mis-regulation in cancer has been instrumental in trying to define dynamic changes that happen over the course of disease, and are likely to underpin the signatures for disease. The epigenomic space is an area that also stemmed out of an additional effort from the human genome to actually characterize the ways in which the human genome is functional, and the ways in which cells control the genome by modifying chromatin. The DNA and the protein interactions that essentially can be regulated, and how the histone proteins that make up that interaction can be modulated to change interactions with DNA. It’s very instrumental in understanding disease signatures.

Another area that helps us to understand disease signatures are modifications of the DNA bases. So the notion…that certain bases in our hands, particularly cytosine can modify chemically has led to this notion of, as well as four bases, we have a fifth and a sixth base. Those being methylcytosine and hydroxymethylcytosine. What we are doing at Bluestar is really probing biology of gene activation and gene regulation using a hydroxymethyl signature, and what this enables us to do is to integrate dynamic changes associated with gene activation and gene regulation into a larger biological concept. So what in our hands with this novel assay, we've been able to enrich and identify regions that have this differential hydroxymethyl signature that we can derive directly from DNA in cancer patients. And we've been able to essentially show that you can answer two questions. The first question is, from the cell-free DNA coupled with this hydroxymethyl assay that we are employing, answer the question, "Do I have cancer?" And then the second question is, "If I do have cancer, what type is it?"

And so some of the pilot work that started about three years ago in Steve Quake’s lab by a talented researcher there, Chunxiao Song, both co-founders of Bluestar, essentially showed a proof of concept study indicating these two questions can indeed be answered. At Bluestar, we took this approach one step further by making the whole process scalable to essentially acquire DNA fragments that have this hydroxymethyl signature, sequence them, and then using a machine learning based pipeline essentially try and discover signatures that are relevant to disease and cancer in this case. Our team is made up of a talented group of lab scientists, technologists. Some of them from Sequenom who have worked in this area before, and the data analysis team is from some of the folks at Genomic Health.

So in a way, what we're trying to do by looking at cell-free DNA is leveraging a kind of blunt tool if you like, with the five hydroxymethyl tool, to answer a specific question about what biological changes are occurring and driving disease. And coupling the interrogation in the lab with sophisticated machine learning based approaches, it's possible to characterize in each sample, given their hydroxymethyl profile, the presence or absence of disease in each patient.

And so the fact that we can essentially interrogate directly from cancer patients through the cell-free DNA is a very novel kind of application of this technology. And then we're looking across, as I mentioned, multiple cancer types and have some very intriguing results for which we will provide more details at the Liquid Biopsy Conference this coming June.

Hannah Loss:
What challenges and opportunities remain in precision medicine?

Samuel Levy:
As mentioned, the interrogation of gene expression, and gene regulation, enhancer modulation in a single assay has enabled us to develop very precise ways of detecting specific cancers, and we have shown that basically the possibility of applying this on a cancer-by-cancer basis leaves us with some very exciting proof of concept data, and enables us to consider the prospect of translating our findings to clinically relevant applications. It also, in parallel, offers the opportunity to develop a Pan-Cancer assay. Essentially one that uses the data and the algorithms that we developed to de-convolute from the DNA in the patient's blood, the precise classification of what kind of disease is present. And so that is a kind of useful way of applying the technology that we have. We've also gone further and initiated studies not just classifying tumor molecules from the plasma and the cell-free DNA, but also how normal tissues in the body contribute to the cell-free DNA population.

Taken together, this gives us a lot of power to actually dissect from the cell-free DNA population that the relevant contributors to disease, and even to normal tissue degradation. So we're actually now in a parallel effort trying to use these technologies to monitor how a patient can indeed respond to therapy given that, in a way, the cell-free DNA is a sink for many cell types, one of which are immune cells. And parallel data in the literature has shown that immune cells themselves have a very distinctive 5-hydroxymethylcytosine signature. And so this gives us a real opportunity to look at the responses to immunotherapy in patients undergoing them, to try to discover a biomarker for response.

And so we think taken together the ability of these new tools and analytical methods, and the ability now through cell-free DNA, to probe active biology, dynamically changing biology, provides us with a kind of tool set that will bring to the fore, the ability to translate some of these novel assays to really guide patient care in oncology.

Hannah Loss:
Sam, thanks for your time and insights today.

Samuel Levy:
Great. Thank you very much for inviting me.

Hannah Loss:
That was Dr. Samuel Levy, Chief Scientific Officer of Bluestar Genomics. He'll be speaking at the Liquid Biopsy Summit taking place June 17th through 19th in San Francisco, California. If you'd like to hear him in person, go to www.LiquidBiopsySummit.com for registration information, and enter the Keycode "podcast." I'm Hannah Loss, thanks for listening.