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Studies Show Promise of Inostics' BEAMing Tech to Detect Drug Resistance Markers in Cancer Patients

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Two studies published earlier this month in Nature have demonstrated how Inostics' BEAMing digital PCR/flow cytometry technology can be used to detect drug resistance mediated by KRAS mutations in colorectal cancer patients months before treatment failure is observed.

Although the research papers focus more on the potential benefit of noninvasive, blood-based monitoring in patients undergoing targeted therapy — and not on the unique capability of Inostics' platform to enable such testing per se — the studies are still a feather in the cap for the German company's plans to establish itself as "the plasma DNA testing company," Frank Diehl, Inostics' co-founder and CSO, told PCR Insider this week.

To that end, Inostics recently received GCP/GMP certification for its Hamburg-based laboratory facilities, which will allow it to begin supporting the analytical arm of clinical trials to investigate whether using the BEAMing technology to test the plasma of colorectal cancer patients undergoing treatment will result in positive patient outcomes, Diehl said.

In addition, Diehl said, Inostics expects to receive CLIA certification for its US subsidiary lab at Johns Hopkins University in Baltimore within the month, which would enable the company to perform similar patient testing.

Inostics was founded in 2008 by German clinical services firm Indivumed and scientists from Johns Hopkins University, including Bert Vogelstein and Kenneth Kinzler, some of the earliest innovators of digital PCR and inventors of the company's core technology, BEAMing (short for beads, emulsion, amplification, and magnetics).

The method combines emulsion-based digital PCR with magnetic beads, hybridization, and flow cytometry. BEAMing assays can detect and enumerate mutant DNA in a background of wild-type DNA at ratios greater than one in 10,000, according to the company.

Initially considered potentially too complex a technique to implement for routine mutation testing in cancer, Inostics has over the past few years worked to streamline the method, and currently uses it to offer research-use-only mutation detection assays out of its Hamburg laboratories. In addition, in August Inostics began beta-testing BEAMing-based assay kits with various early-access users; and opened the doors to its US offices at the Science and Technology Park at JHU (PCR Insider, 8/18/2011).

Diehl told PCR Insider this week that beta testing of the BEAMing mutation-detection kits is still ongoing, and that the company hopes to be able to offer its first such product by the end of this year, although he added that "it's still too early to make a firm prediction" about their availability.

However, Inostics has been making progress in its attempt to break into the clinical market under a service and laboratory-developed test model, and the two recent Nature publications provided the company with an extra boost in those efforts.

In the first study, led by Alberto Bardelli of the University of Torino in Italy, researchers described the development of secondary resistance mutations to the anti-EGFR monoclonal antibody cetuximab (marketed by Eli Lilly and Bristol-Myers Squibb as Erbitux) in patients with metastatic colorectal cancer.

More specifically, the team used a handful of technologies, including BEAMing and deep sequencing, to demonstrate that a substantial fraction of colorectal cancer patients who exhibit an initial response to anti-EGFR therapies have, at the time of disease progression, tumors with focal amplifications or somatic mutations that were not detectable prior to initiating therapy – likely a result of both pre-selection of pre-existing KRAS mutations and new mutations arising during therapy.

In the second study, researchers from several companies and institutions, led by Vogelstein and fellow JHU researcher Luis Diaz, reached similar conclusions after studying metastatic colorectal cancer patients treated with a monotherapy of the EGFR inhibitor panitumumab (marketed by Amgen as Vectibix).

To detect and quantify circulating mutant KRAS DNA, the JHU-led team used previously described ligation assays, some of which featured probes containing locked nucleic acid linkages from Exiqon; as well as BEAMing assays, which they showed could provide an absolute quantity of mutant fragments per milliliter of serum.

"For us, the clinical application [of BEAMing] is most significant for our business, because that's what's driving the whole field," Diehl said. "These papers weren't so much focused on the technology as [they were] showing the clinical significance of … plasma testing."

Diehl said that currently, these types of mutational changes in response to therapy can be assessed by performing molecular biology techniques on patient biopsies, which are invasive and "only sample a certain area of the tumor in patients; whereas testing the plasma DNA gives a systemic view of the makeup of the tumor mutations," Diehl said.

In the Vogelstein-led study, the researchers went so far as to demonstrate, based on their data, a possible scenario for the development of resistance to panitumumab, noting that such resistance generally takes hold about five to six months after initiating therapy. This, the researchers noted, suggests that combination therapies targeting at least two different pathways might be necessary to make patient remissions last longer than five to six months.

In addition, Diehl said, the findings suggest that it may be beneficial to test patients for resistance mutations using a technology like BEAMing as soon as a they begin therapy or begin to show some positive response, and then continuously monitor them using routinely collected plasma samples.

Inostics and collaborators will now set out to show whether such a tack is feasible and whether it would benefit patients. To that end, the company made sure it modified its laboratories in Hamburg to be GCP and GMP compliant so they could support clinical trials. Similarly, the company is waiting for CLIA certification at its Baltimore office to begin patient testing there.

"These were just small studies done to show that there is a benefit of detecting [mutations] early, and the next step would be to do this in a larger setting," Diehl said. "We are looking for partners that are able to do these multicenter studies with us. We would be very open … both [in the Europe and US] to partner on a multi-center study."

And, Diehl said, the company is currently developing mutation analysis panels that could potentially provide a similar benefit in other cancers by monitoring other mutation resistance-related genes, such as EGFR and c-kit.

Inostics' final goal in the coming months is to begin exploring partnerships with pharma in this area, which would likely require commercial mutation-detection kits and more industry familiarity with implementing the BEAMing technology.

"Moving forward now, there are two steps to take: one is patient testing with a laboratory-developed test; and then coming up with a product that would ideally allow us to do [plasma testing-based] companion diagnostic co-development with pharma companies."

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