cancer genomics

Oncology has emerged as the most successful disease area for precision medicine. Last year, as the genetic testing industry went through a royal shake-up brought on mostly by external market forces, it's been no surprise that precision oncology has been touted as a core strength. As the industry now works "to be more lean and profitable"--new language one hears these days, cancer testing will be a big part of that effort.

Perhaps no company looked inward as intently as San Francisco based Invitae this past year. Their new CEO Ken Knight said last week at the annual JP Morgan Healthcare Conference the company has been “stabilizing” and would “double down” on its oncology franchise. He anticipates a return to growth in the next year.

For today's show, we caught up with Invitae’s General Manager of Oncology Jerome Madison to dig into Invitae’s approach to addressing the opportunities and challenges of cancer genetic testing. Jerome is also the Host of The Precision Medicine Podcast and was involved in selling some of the first precision cancer tests. We won't say when that was, Jerome.

We begin with an overview of the industry, then quickly drill down into how Invitae has been expanding its cancer line to be a "one-stop shop" for oncologists who will at some time be able to get all the tests they need from a vial of blood. Still, there are problems with access. For example, why are less than 50% of lung cancer patients being tested? We end with Jerome’s outlook for Invitae's fit in a very lively and innovative space in medicine today.

“I’ve seen a lot of revolutions. Now we’re at the beginning of spatial biology, and I think it has the chance to transform life science similar to next gen sequencing, but even more. It’s going to have more ramifications that spread through more disciplines than any of the revolutions I’ve seen in a while.”

That’s Joe Beechem speaking on today's program. He’s been working with or inventing life science instruments for thirty-five years. He’s now the Chief Scientific Officer at leading spatial biology company, NanoString Technologies, where he is also the chief designer of their GeoMx instrument introduced in 2019 and their new CosMx which they just unveiled last month at the 2022 Spatial Biology Summit.

Just how will the new CosMx instrument cause a revolution in our field? How does it open things up for biologists? How does it differ from NanoString’s popular pioneering instrument GeoMx? What new spatial applications have Joe excited? And how does NanoString fit in with the blossoming competition in this space?

Joe’s passion is contagious, and his perspective inspiring.

“We have a new generation of scientists that are getting into spatial biology. They grew up with the next gen sequencing revolution. They grew up with single cell RNA seq. They are totally comfortable doing thousands of things at a time. And they are taking this field by storm. It’s like, you’re either going to get on this train or you’re going to be left at the station holding a flag. And no one is going to look back and see where you are left. We’re taking a field that is 150 years old and reinventing it overnight."

"There's an entire field of fragmentomics with a whole lot of people working on it. The DNA which is shed into the bloodstream has a certain length. The length of ctDNA is shorter than cfDNA, and depending on where the cancer cell is located, the fragment size and pattern is different. So you can actually deduce information about the tissue of origin from the fragment length and pattern. And that's just the beginning."

That's Sugganth Daniel on today's show. He's the Director of Medical Affairs in Oncology at genetic testing company, Invitae, and he is passionate about the new field of "fragmentomics."

Sugganth says that his interest in cell free DNA began in obstetrics when he studied the now legendary papers of Dennis Lo out of Hong Kong. These papers have also spawned an entire field of new research and now clinical testing in cancer.

One of the new tests out are minimal residual testing or MRD which is used to see if a cancer patient's treatment is working and to guide follow up treatment. We discuss Invitae's new MRD program with Sugganth: What is the promise going forward? Will it be better than CT scanning? When might it be part of the guidelines? How is Invitae building up quantification standards?

We also discuss President Biden's new initiative for cancer research announced in his recent State of the Union address.

If one was going to be a cancer researcher, surely one would want to be Christina Curtis. She’s an associate professor of oncology and genetics at Stanford, and she studies tumor evolution. She’s the Darwin of cancer research.

Because scientists can’t see human tumors evolve in real life, in Christina's lab she creates what she calls "virtual tumors that recapitulate the size and spatial properties of an actual tumor. And evaluating patient data,” she says, "we have found that metastatic seeding could happen very early. That these tumors were born to be bad.”

No wonder that Christina was an early adopter for spatial technology where she can see actual tumors in context. What’s particularly great about her work is that she not only explores basic science on the one end, but is studying patients in treatment as well.

When Lee Schwartzberg did his training as an oncologist some thirty years ago at Memorial Sloan Kettering in New York, he had a dream. And after training, he set off to make that dream a reality: to bring the resources, expertise, and research that one enjoys at a major research hospital cancer center to the community level.

This landed him at the West Cancer Center in Tennessee where he was made Medical Director and also Chief of the Division of Hematology/Oncology at the University of Tennessee's Health Science Center. And two years ago, after serving on various boards and founding a couple journals, he was finally appointed Chief Medical Officer of a national parntership of community oncologists that includes practices across the country from the East Coast to the West called OneOncology. He is now living out his dream.

Today he talks to us about how well precision oncology has made it to the community clinics. Lee says we are moving beyond the debate over molecular and genomic profiling. It's not a matter of whether, but when and which tests to include in the panels. He says, in general these days, physicians--and patients-- would like to see more information, as soon as possible after diagnosis.

"Our current recommendation at OneOncology is to order profiling (comprehensive genomic profiling) at diagnoses of advanced disease across cancer types," he says.

Is Lee in favor of population screening for the three major mutations, BRCA, Lynch, and FH? And what does he think of the trend of consumer-initiated testing?

It's a great chance to hear from one whose lifelong mission has been to take precision oncology out to the communities of America.

Raj Krishnan has a good story, and probably a good product. More data will tell. He's the CEO of Biological Dynamics, a new liquid biopsy company that is able to detect biomarkers in not only blood but other biological fluids. And the company's products are good for not only cancer but Alzheimer's and other disease areas as well.

Raj comes to precision medicine from electrical engineering. You don't hear that very often. One day in his lab while working on his PhD he had a classic eureka! moment. That unexpected discovery for which every scientist longs.

"The vast majority of methods for isolating biomarkers are either chemical or mechanical. Very few are electrical. And as an electrical engineer, I stumbled upon this methodology. At the time I was originally working on this, it was thought to be theoretically impossible. Late one night I came upon the answer."

The important thing about Biological Dynamics' technology, called ACE, is that it is able to draw the biomarker out of the sample without disturbing the biology. It is able to leave it in what Raj refers to as the "native state."

"Take a look at any Qiagen kit workflow or magnetic bead workflow and you can see 400 steps of which you have: destroy this, capture this, run this. How do you know fragmentation isn't being done by what you're doing to isolate the biomarker, as opposed to what it was in its native state?"

We have spatial biology. Should we call this native state biology?

First it was all about biomarkers. Then panels of biomarkers. But biology is complicated. Why does one patient respond to an immuno therapy when another which shares the same biomarker does not?

Welcome to the age of spatial biology.

Garry Nolan joins us today. He's a professor in the Department of Pathology at Stanford who's career has been a journey of seeing intracellular happenings more and more in context. Check out this cool analogy from a new paper his lab put out in Cell.

"The tumor micro environment (TME) is like a city composed of neighborhoods (e.g., industrial, residential, or agricultural), which are regions where specific functions of the city occur. These neighborhoods are distinguished by their composition of buildings, activities, and people, but they exhibit behavior of their own, such as industrial output or energy consumption. At a more granular level, people (e.g., teachers, doctors, and construction workers) play integral roles in the city’s function. The same concept applies when studying tissue.”

Today Garry walks us through the transition over the years from biomarker to spatial biology. He then discusses the Cell paper demonstrating that for the first time his lab is seeing that some "neighborhoods" react differently than others in the tumor micro environment. What will this mean in the clinic for patient treatment?

The technology making this possible is the CODEX platform, one of several developed in Garry's lab over the years. He tells of its conception and anticipates how it might evolve in the future.

Cathy Smith counts herself among the Gleevec Generation after the landmark targeted cancer therapy. She’s an optimist who believes in the possibilities of precision medicine.

“We are outsmarting cancer,” she says.

Cathy is an Assistant Professor of Hematology/Oncology at UCSF where she is also an MD treating patients. Her area of expertise is in acute myeloid leukemia or AML. She joins us today to discuss a recent group paper and collaboration using new technology to track and monitor cancer evolution at the single cell level.

“It’s not that we didn’t know that this heterogeneity was under the surface, it’s just been hard to get at before we had this technology.” She is talking about single cell technology made by Mission Bio, a company based in South San Francisco.

As she looks forward to creating a first ever clinical trial using single cell data, Cathy says there are very hard questions to answer. It’s not totally clear what treatment decisions should be made when answer A comes back vs answer B. Still, she is optimistic that she and her colleagues will begin to find more answers for their patients.

“You don’t go into oncology if you’re a pessimist. You have to have hope that you’re going to get ahead of it. And the first step is to know what is going on."

The history of biomedicine goes something like this:

1. A new tool is invented. 2. New tool is used in research labs to generate new data and new hypotheses. There is new science. 3. New tool is used in clinical setting to confirm this new science with real patients. 4. Then new tool is adopted into clinical use.

All the buzz these days, single cell DNA analysis instruments have just made it into step three.

Today we talk with Koichi Takahashi, Assistant Professor in the Department of Leukemia at MD Anderson and author of the largest clinical study to date using single cell analysis in the study of AML.

For years physicians and researchers have been testing patients for well known cancer driver mutations such as KRAS and BRAF with next generation sequencing tools, or what are now being called “bulk sequencers.” Koichi points out today that new single cell analysis tools are allowing researchers to see the unique genomic environment that lead to the common driver mutations and may be responsible for why each patient responds differently to the same therapies. Knowing each patient's individual tumor genomic environment--and not just the final driver mutation such as KRAS-could lead to effective tailored treatment.

“The development of cancer cells is like Darwinian evolution. They are adapting to the selective pressure of the tissue ecosystem. And by looking at the single cell clonal architecture of the mutations, we can actually build a phylogeny tree of how a particular patient's leukemia developed—like even before they were diagnosed with leukemia. Over the years how this leukemia was created—this single cell DNA sequencing can inform us of this history.”

Is this new scientific understanding able to impact yet how Koichi is treating his patients? What is next for this technology and for the field of AML research and treatment?

Today we engage in a rare discussion between a startup founder who is going beyond sequencing and working directly with cancer patient cells in 3D cultures and with one of his customers, the husband of a cancer patient.

Meet Christian Regenbrecht, the CEO of CPO or Cellular Phenomics and Oncology based in Berlin, Germany and Janos Flosser, a fund manager who invests in technology from Copenhagen, Denmark.

Today’s show is not only special for the fact that we have a researcher/entrepreneur sitting down directly with a patient for the interview, but also for a bold new approach to cancer genomics. Christian is not shy with his attitude about how we must shift our thinking toward oncology.

“Sequencing alone has proved remarkably unhelpful. And the belief that sequencing your DNA is going to extend your life is a cruel illusion,” says Christian at the outset of the interview.

So just what is Christian up to at CPO? How did Janos, a fund manager in another country, find Christian? And is this the new face of cancer treatment?