Xconomist of the Week: Peter Kuhn on Detecting Circulating Tumor Cells

2/16/12Follow @bvbigelow

Worrying whether a solid tissue tumor might spread elsewhere in the body represents one of the biggest unknowns for many cancer patients, according to Peter Kuhn, an associate professor of cell biology at The Scripps Research Institute in San Diego.

“As long as the disease is confined to the primary tumor, the oncologists can deal with it,” he says. “It’s only when it successfully starts spreading through the blood to distant sites that all hell breaks loose.”

In a step to unravel this mystery, a research team headed by Kuhn and diagnostic pathologist Kelly Bethel recently unveiled what Kuhn calls a “next-generation technology” for detecting and analyzing circulating tumor cells (CTCs) in patients’ blood samples. Their findings, published earlier this month in the journal Physical Biology, represent an encouraging opening in the development of a new diagnostic. Their technique for imaging and analyzing CTCs appears to be far more sensitive than existing blood tests, and may soon yield the kind of detailed information about individual cases that’s only available from certain types of invasive surgical biopsies.

In addition to helping doctors better understand the process of metastasis in patients, Kuhn says the test aims at being used some day to detect cancer in people who are unaware they have it.

“My favorite description is really that this is a blood fluid biopsy of the disease,” Kuhn says. “The reason why this is really important is because for the first time that we know of, we can monitor the cancer at the tissue level repeatedly in real time without risk to the patient.”

The approach developed by Kuhn’s team involves spreading a layer of all nucleated cells found in a blood sample onto a glass surface, and adding fluorescent antibodies to cytokeratin, an essential component of CTCs. The technology then uses a digital microscope and an image-processing algorithm to scan the slide for clumps of aberrant fluorescence. The process requires high-performance computing to help analyze and manage the data, and high-definition imaging to help cellular pathologists identify and analyze any of those fluorescent clumps that signify circulating tumor cells.

Kuhn’s group also licensed the technology to San Diego-based Epic Sciences, a startup formed in mid-2008 to commercialize the high-definition CTC technology. Kuhn agreed to answer a few questions about the technology, and how broader advances in molecular diagnostics are expected to dovetail with the emerging fields of quantified health and personal medicine.

Xconomy: Does the type of primary tumor make any difference as a source for circulating tumor cells?

Peter Kuhn: We are only talking about the carcinomas—so the approximately 7 million Americans with breast, prostate, pancreatic, lung, ovarian, liver and kidney cancers. We have known for a very long time that cancer spreads through the blood. It’s just that we haven’t had the analytical tools to really track down the disease-derived cells. In terms of your question, we’re seeing different rates of cell [proliferation], and different types of cells in the different cases. In each case, [there is a] high degree of heterogeneity.

X: What’s the breakthrough that makes this possible?

PK: The set of fundamental breakthroughs intellectually was a) the recognition that there is a large degree of heterogeneity of these cells in the human blood, and b) being conscious of what it means to be dealing with the challenge of a needle-in-the-haystack type of problem.

Kelly Bethel and Peter Kuhn

We had to bring together deep vertical expertise in engineering and math with pathology and oncology. All parties had the simple unifying goal of doing something that could have real impact on individual patients at some point in the near future. The most important thing, you know, is to flip a challenge into an opportunity. That is what we did with the way we are preparing the samples as well as the way in which we are analyzing the data.

The analysis is a large-scale form of backend computing that has grown out of a longstanding collaboration with Microsoft. More and more, scientists are using fluorescently tagged antibodies to label particular proteins in cells. So we started using a very standard approach, of using these fluorescing antibodies to label these cells. Then we had to translate that into something that was technologically robust and that we could calibrate within and across sample.

X: How long have you been working on this?

PK: We began collecting the data that went into the papers two and a half years ago. We were funded with a $4M grant by the American Recovery and Reinvestment Act as a National Cancer Institute initiative in Physical Sciences in Oncology.

X: How was Epic Sciences born out of this?

PK: As scientists on the research side, we were doing a fairly large number of observational studies, testing the technology and trying to understand the disease. Eventually, one has to do trials under a regulatory compliant framework so that can go forward through an FDA submission to become a real product for standard use in clinical care, only then will you have a breakthrough that makes a difference in individual cancer patients. That of course is something we cannot do in the research world. Instead you do that in a commercial setting where you develop the practices that adhere to what is regulatory compliant. Recognizing that, we started Epic Sciences as a spinout out of Scripps. David Nelson is the CEO and president of Epic, and Epic has exclusive license to the technology itself for full commercial use. Epic is set up to push this as a fluid biopsy for biomarkers, and develop predictive tools that stratify patients for particular drugs at any particular time.

X: How do you see this advance, along with other advances in diagnostics, fitting into the notion of quantified health and personal medicine?

PK: The next stage of personalized medicine and effective healthcare must have an approach that I call the ‘companion for life’. The fluid biopsy and the HD-CTC technology are just the initially validated product that can predict response to a particular drug but the next step is the integration of this test at one time point with many time points during the entire lifetime of the patient. Obviously each time the patient has a different question but the decision will get better and better with time. For that same reason, we want to add other data items into this equation. Just like a search engine gets better with more and more queries being run, the ‘companion for life’ will perform better and better the more data we feed into it. Our current advances in cancer diagnostics have to be connected with new products in wireless medicine and then drive the data assimilation to provide high-quality guidance on treatment strategies over long periods of time.

X: Does a tumor have to reach a particular stage before it begins shedding these circulating tumor cells? Does it shed these cells more or less continuously, like a leak, or is it more like a dandelion blossoming?

PK: That’s where the science is fascinating. To be perfectly honest, we don’t know very much about this process. We needed to develop these highly, highly sensitive analytic tools to be able to investigate this question and all related aspects of cancer development in a patient.

A cluster of lung circulating tumor cells (in red-blue) interacts with normal blood cells (green-blue) recovered from a blood sample of patient with lung cancer. (Image courtesy of the Kuhn lab.)

We know that from a growth perspective that there is a lot of blood vessel growth in the tumor and lots of it is aberrant growth or leads to aberrant growth. I think you could build the hypothesis that the exposure of the initial tumor to the circulatory system leads to the release of these circulating tumor cells early on. The question is when do you have enough of that burden in the blood to be able to measure it? And how do you tell the difference between those CTCs that just sort of float around and get cleaned up by the immune system and those that actually have a chance at causing metastasis at a distant site?

You start with the research questions at the patient level, and then you work backwards toward identifying the right analytical tools and the right experiments to try to answer some of these questions. And the fluid biopsy is the first step in that direction. We have now taken these tools back to test our hypotheses while simultaneously applying these tools towards direct patient care.

Bruce V. Bigelow is the editor of Xconomy San Diego. You can e-mail him at bbigelow@xconomy.com or call (619) 669-8788 Follow @bvbigelow

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  • http://www.nrlbh.com/ Steven Quay, MD, PhD, FCAP

    The availability of CTC tests is important to two groups of patients: Those at the time of diagnosis, so that therapy can be tailored for both the primary tumor and monitoring recurrence in ‘survivors’ as an early warning system, to permit intervention before the there is clinically evident metastatic disease.

    The National Reference Laboratory for Breast Health launched the ArgusCYTE Breast Health Test in December 2011, to provide information to help inform breast cancer treatment options and to help monitor potential recurrence. It can monitor breast cancer distant recurrence by obtaining a “liquid biopsy” or blood sample, and analyzing it for the presence of circulating tumor cells, which can then be analyzed to determine the expression of Estrogen Receptor/Progesterone Receptor, or ER/PR, and Human Epidermal Growth Factor Receptor, or Her2, in those cells, a predictor of the cancer’s sensitivity to existing treatment options. The presence of circulating tumor cells in the blood sample may serve as an early indicator of the recurrence of breast cancer and the data obtained from the ArgusCYTE sensitivity analysis may help physicians better select which treatment options to use with a particular patient.

    This is available today for doctors and patients.

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