NEW YORK – Liquid biopsy firm Angle looks to expand its business through dual analysis of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) for early cancer detection and monitoring, and to advance companion diagnostics for targeted drug development.
Angle CEO Andrew Newland explained that sequencing both ctDNA and nucleic acids derived from CTCs together provide information that would not be found by focusing on one of the analytes alone, such as distinct actionable gene variants and information on how a tumor is evolving and responding to therapy.
"CtDNA [are] fragments of dead cells," Newland said, "whereas CTCs must have evaded the immune system and drug therapy."
Newland added that because CTCs are alive, they enable researchers and physicians to track clonal evolution, the process by which cancer cells change and multiply over time, both through random variation and in response to therapies.
Angle recently conducted a small study to assess the usefulness of analyzing both ctDNA and CTCs simultaneously and presented the results on Thursday as a webinar sponsored by Illumina for the European Association for Cancer Research (EACR).
The study involved two cohorts of patients with various lung cancers. One cohort consisted of eight untreated individuals and the other of 19 individuals who had been on at least one treatment. Angle isolated CTCs with its Parsortix system and analyzed CTC-DNA and ctDNA with a customized 79-gene lung cancer panel from Illumina. Sequencing was done on the Illumina NextSeq 2000 platform.
Among the untreated patients, all cancer-related mutations were identified in CTCs and not in ctDNA. In the second cohort, 90 percent of all identified cancer-related mutations were identified only in CTCs. Each analyte, however, provided several distinct and "potentially clinically relevant" mutations that did not appear in the other.
Angle replicated these results in a separate cohort of 10 patients who were undergoing treatment.
Across all cohorts, Newland said the company found approximately twice as many cancer-related variants using the dual-analysis method than by using either analyte alone. Analysis of CTCs in particular, he said, appeared to be better suited to early cancer detection.
"Even when the CTC level is as low as one CTC in 1 billion blood cells, we can still recover those CTCs," he said.
Angle has not submitted the study for peer review and publication, although Newland said the company may "possibly" do so in the future.
Anthony Lucci, professor of breast surgical oncology at the MD Anderson Cancer Center, also thinks that a dual approach using both ctDNA and CTCs offers advantages over single-analyte metrics in cancer monitoring. Lucci, who uses Angle's Parsortix CTC isolation technology in his research but has no financial or other association with Angle, echoed Newland in saying that each analyte provides distinct and frequently complementary information.
"We can see that a tumor is either dead or dying [when] the ctDNA is decreasing significantly," he said. "However, when patients get older, they accumulate mutations that are not related to cancer, but that get picked up as potential tumor mutations, giving us a false reading."
In contrast, he said that CTCs are unambiguously related to a patient's cancer. Additionally, they are viable targets for evaluating the success of functional studies, such as in the case of therapies and diagnostic tools that target cell surface proteins and in cases where customizing a gene panel for use with ctDNA is sometimes complicated by the lack of an available primary tumor for comparison.
Carolina Reduzzi, an assistant professor of cancer biology and director of the Cristofanilli Circulating Tumor Cells Laboratory at Weill Cornell Medicine, agreed with this assessment, stating via email that while ctDNA can only give you genomic information about the tumor, CTCs can extend that analysis, providing insights at the phenotypic level, including information based on RNA and proteins.
"They can help complement the information obtained by ctDNA to better understand the biological mechanisms happening in the tumor, for example during the development of resistance to treatment," Reduzzi said.
"There's definitely a need for both approaches, because you can't get all the information from just one," said Lucci.
Furthermore, ctDNA and CTCs can each be more or less informative at different stages of cancer development, although the science here is not completely settled.
Lucci said that one potential benefit of ctDNA is that it is likely the more sensitive analyte because –– depending on one's choice of platform –– "you can detect down to levels that are infinitesimally smaller than whole cancer cells."
Newland, however, said that Angle has been finding CTCs to provide a more sensitive readout of early-stage cancer than ctDNA.
"In undiagnosed ovarian cancer studies," he said, "the Parsortix system detected ovarian cancer from benign pelvic mass with an [area under the curve] of 95.4 percent, far higher than protein or ctDNA analysis."
Illumina partnership
At the EACR webinar where Angle discussed its recent results, Angle and Illumina also announced that they recently agreed to a joint marketing initiative, although Newland said that the details of that initiative are still being finalized.
Newland said that combining Parsortix with Illumina's gene panels and next-generation sequencing instruments will benefit Angle by allowing it access to Illumina's much wider customer base, while adding value to Illumina's customers by enabling them to now assay both CTC-DNA and ctDNA.
"Some of those [customers] will want to engage with us and adopt Parsortix, and we will be looking for those customers to launch laboratory-developed tests off the back of this technology," Newland said.
Adding another analyte to a clinical diagnostic workflow is likely to add some cost to testing on a per-patient basis. Newland said, however, that the high specificity of this approach could "dramatically reduce" overall healthcare costs by helping physicians better assess drug responses and efficacy.
The US Food and Drug Administration cleared Parsortix for use in metastatic breast cancer in 2022, and Newland said that the company intends to extend that clearance into multiple other cancer types. That same year, for instance, the company supported a study in ovarian cancer, which identified gene expression biomarkers of disease progression and of progression-free survival.
Newland said that the company is now planning to begin studies in brain cancers, for which it has already completed some initial work.
"Brain cancer is a really important one because you can't tissue biopsy the brain," Newland said.
Beyond the nascent Illumina deal, Angle has recently been active in forging collaborations in the pharmaceutical space.
The company recently partnered with Japanese pharmaceutical firm Esai, for example, to conduct a pilot study of a HER2-targeting antibody-drug conjugate using Angle's Portrait HER2 assay.
The company has also signed multiple agreements with AstraZeneca, including a project to develop an androgen receptor assay for use in assessing prostate cancer treatments and another to develop and validate a method for detecting micronuclei in CTCs using its DNA damage response assay.
"We expect to see pharmaceutical companies bringing more targeted drugs to market … and using our technology as a companion diagnostic," Newland said. "I would expect this technology ultimately will replace tissue biopsy for secondary cancers."