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UCLA Team Developing Electrochemical Detection Tech as Lung Cancer Liquid Biopsy Test


NEW YORK – Researchers at the University of California, Los Angeles School of Dentistry are advancing an electric field-based liquid biopsy assay that analyzes EGFR mutations in single-stranded, ultrashort circulating tumor DNA (usctDNA) in blood and saliva for the early detection of lung cancer.

Using a recently awarded $4.6 million grant from the National Cancer Institute, David Wong, the project leader and a professor of oral biology at the UCLA School of Dentistry and his colleagues recently launched a clinical study to assess the ability of electric field-induced release and measurement (EFIRM) to determine whether indeterminate pulmonary nodules (IPN) in non-small cell lung cancer (NSCLC) are malignant at the time of detection.

Low-dose spiral CT (LDCT) is the current standard clinical screening tool for lung cancer in high-risk patients such as smokers. LDCT detects IPN but does not determine malignancy.

"Current practice is that these patients wait six months for a follow-up LDCT to evaluate changes in nodule size," Wong said.

Only nodules that grow larger get biopsied, potentially missing others that are malignant but slower growing, while providing six months for the cancer to progress untreated.

"Our project is to assess malignancy of IPN at the time of detection by LDCT while the patient is still in the radiology suite in the hospital," Wong said. "We'll access a sample of blood and saliva and evaluate a panel of somatic mutations associated with non-small cell lung carcinoma."

In an interim analysis, Wong added, EFIRM detected tumor-associated usctDNA in 55 percent of IPN detected by LDCT, using a panel of 12 NSCLC-related genes.

The study aims to recruit 360 patients by August of next year. Wong anticipates the outcome of the study to be made available that December.

The UCLA team will also scale up the technology's multiplexing capability while further identifying and characterizing the broad range of usctDNA fragments that EFIRM detects.

"This platform has a unique advantage, in that it directly detects these circulating targets in biofluids without the need [for] processing and in a minimal volume," Wong said.

Wong and his colleagues at UCLA first published EFIRM in 2014 as a noninvasive, saliva-based gene detection method and have since conducted a feasibility study of adapting the method as a liquid biopsy for NSCLC, funded by a separate $5 million NCI grant.

EFIRM uses an electrical field to trigger the release of ctDNA from tumor cells. The ctDNA is then captured by polymer-coated and mutation-specific conducting probes on a microarray without needing the processing steps found in PCR and next-generation sequencing protocols. The polymer-coated probes generate signals that indicate the presence of a mutation, such as EGFR, as is common in NSCLC.

Wong said that although his team is seeking to demonstrate EFIRM's capabilities first in blood and saliva, the method is biofluid agnostic. It is also capable of detecting even vanishingly small amounts of target sequences, making it potentially ideal for uses such as early detection, minimal residual disease (MRD) monitoring, and therapy response monitoring.

"A year ago, it detected circulating targets at the femtomolar range," Wong said. "We are [now] advancing our technology towards an attomolar range."

Wong said that the immediate next milestone in EFIRM development is to multiplex the technology, aiming to detect 120 targets in a single well.

Earlier this year, Wong and his colleagues published a paper in the International Journal of Molecular Sciences demonstrating a prototype multiplexed EFIRM platform, in which they simultaneously detected three EGFR mutations in a single well. The EGFR sequences captured in that study ranged from 50 to 54 base pairs in length, and Wong's group calculated that the dynamic range for detection by EFIRM runs from 40 to 160 base pairs, potentially making usctDNA a viable new biomarker in cancer detection and treatment response monitoring.

Min-Han Tan, founder and CEO of biotechnology company Lucence, commented that the EFIRM technology appears "interesting and promising," particularly for point-of-care applications.

"If mutant [single-stranded] DNA is relatively more abundant than mutant [double-stranded] DNA," Tan said, "there will be advantages to more sensitive detection, though this has not yet been directly demonstrated."

Tan further commented that the ability to sample biofluids such as saliva is another attractive point for the technology, while cautioning that "the clinical utility of focusing on ultrashort ctDNA needs to be demonstrated versus existing approaches [involving] longer ctDNA fragments."

Tan also mentioned that PCR-based and NGS-based methods like Lucence's AmpliMark can capture both ssDNA and dsDNA, although Lucence has not yet sought to explore ssDNA capture.

The company is currently conducting a clinical study of the validity of ctRNA in plasma for screening and expects to present interim results in December of this year.

EFIRM, too, can be used to detect molecules other than DNA, such as microRNA, protein, and other small molecules, simply by using appropriately designed capture probes.

EZLife Bio, a company founded by Wei Liao, a former postdoctoral researcher in Wong's lab and now EZLife's CEO, has commercialized EFIRM as the EFIRM96, a 96-well plate device for research use only.

The company has supplied EFIRM readers, software, and E-plates, and delivered comprehensive technical support to a variety of academic and governmental institutions.

In 2019, for instance, it partnered with China's Dalian Custom District to test the device's use in detecting contamination in imported meat. Scientists from EZLife Bio and the Dalian Custom District published their results the following year in the journal Analytica Chimica Acta.

EZLife Bio is currently developing an updated version of the EFIRM96, which it hopes to field soon, although Liao commented that the actual release date remains uncertain, "contingent upon the marketing demands of EFIRM applications and investment considerations."

EFIRM 2.0 will be "an entirely automated molecular diagnostics system, capable of concurrently processing and measuring 96 samples without any human intervention" Liao said by email.

UCLA has patented that EFIRM technology, and Wong hopes that demonstrating its utility in early breast cancer detection will pave the way to studies in more cancers, something his lab has already been looking into.

"We have applied this broad-range cfDNA biomarker development approach to lung, oral, and gastric cancer," he said. "If we can advance [EFIRM] towards regulatory approval in lung cancer, then I think the question could be asked, could you do this for colon, head and neck, and gastric cancer."

Wong hopes to be able to win this approval within the grant's five-year funding period.

EFIRM could be "paradigm-changing" for early cancer detection, he said.