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UCLA Researchers Using $3.5M NIH Grant to Develop RUO Liver Cancer Assay

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NEW YORK (GenomeWeb) – After recently winning a five-year, $3.5 million grant from the National Institutes of Health, researchers at the University of California, Los Angeles have begun developing a blood-based liquid biopsy tool to help screen for early-stage liver cancer.

The funding, provided by the National Cancer Institute, will also help the team at UCLA's Jonsson Comprehensive Cancer Center validate and commercialize the assay as an affordable, clinical test through an early-stage startup called Early Diagnostics.

According to UCLA pathology and laboratory medicine professor Jasmine Zhou, her team aims to develop a method that would not only detect the type of cancer in its early stages, but also to find its location in the patient's body. However, she noted that her team will first focus on liver cancer before expanding to other cancer types.

As part of the project, Zhou's team will perform the test on patients with cirrhosis, which she noted is one of the biggest predictors of liver cancer. Steven Han, the project's co-principal investigator, will lead the researchers as they track the progression of around 6,000 liver cirrhosis patients over the next five years to develop a longitudinal clinical cohort to validate the assay. As part of the study, researchers will also perform ultrasound imaging screening and blood sample collection every six months.

In addition, the team has partnered with UCLA BioBank Codirector Sam French to establish a biospecimen repository that will include patient plasma samples, tissue from liver tumors after resection, and cirrhotic lesions after liver transplantation, accoridng to the grant's abstract. The researchers will use to the samples help validate the liquid biopsy tool in later phases of the study.

Zhou explained that the method tracks DNA methylation patterns of circulating tumor DNA in the bloodstream. To perform the assay, researchers first collect 7 to 10 milliliters of blood from the patient, then isolate cell-free DNA and prepare a library for sequencing performed by third-party companies.

After receiving the sequencing information, the team computationally analyzes the whole methylome, Zhou said. "We can exploit the information in the sequencing data to maximally extract the trace amount of tumor signals ... using our computational tools."

According to Zhou, the computational method allows researchers to examine the sequencing data read by read to detect any cfDNA produced by the liver tumor in the patient's blood.

"While we have already learned the signature pattern from the tumor, we are looking at each read to see if they harbor the [specific] cancer signature," Zhou said.

Zhou said that the overall process, including sample prep and sequencing, takes three days to detect traces of liver tumor markers. However, she also noted that her team is trying to improve the experimental protocol to shorten the workflow to two to three days.

Zhou's team previously developed cancer detection tools called CancerLocator and CancerDetector. According to Zhou, the new assay incorporates both computational methods employed by CancerLocator and CancerDetect, as well as a new "innovative and experimental method."

Zhou noted that her team chose to examine cfDNA versus other sample types because it "is stable and can be easily extracted" and "can be profiled genome-wide using sequencing technology."

Early Diagnostics, a spinout of UCLA and Stanford University co-founded by Zhou in 2017, has obtained an exclusive license from the university to develop the technology as a commercial test.

Zhou declined to provide additional information on Early Diagnostics, but noted her team is partnering with the company to generate reagent kits based on the library prep technology. She believes that the kits will help capture methylome information to "significantly reduce the sequencing cost" of current methods, which she said can be as expensive as $1,000 at a sequencing depth of 10x to 15x.

Numerous companies and research groups are also developing early cancer detection tools based on methylation patterns in tumor DNA. Firms like Grail and Freenome have incorporated methylation sequencing tools into their own programs for lung and colorectal cancer blood assays.

Startup IvyGene, founded by researchers at the University of California, San Diego, launched a CLIA lab last year to further develop a blood-based epigenetic assay that measures ctDNA methylation patterns in liver cancer patients.

In addition, another group at UCSD have developed a blood-based method using methylation haplotypes to detect cancer in patients and are now commercializing the tool as part of a startup called Singlera.

Researchers at the Princess Margaret Cancer Center and the University of Toronto have also published a study in Nature earlier this month regarding a cancer detection tool called cfMeDip-seq, which enriches CpG-rich, informative fragments to detect methylated DNA fragments from cfDNA.

Zhou argued that current methods normally employ a "population average" approach, where researchers average all the reads and match them to a specific locus. She noted that tumor signals are averaged out among the reads, potentially leading to a weaker signal-to-noise ratio.

In contrast, Zhou said that her team's method can produce a signal that researchers can use to trace and identify a specific set of reads as the source, even if "there are only a few signals."

Zhou noted that her team has filed for a patent family regarding the liquid biopsy tool. The researchers initially plan to offer the assay for research use only, and will later consider seeking regulatory approval to potentially launch it more broadly.

According to Zhou, her team aims to eventually optimize the assay by reducing the amount of blood needed per run and increasing the number of cancers they can detect using the test. While the team is examining the tool's utility in liver cancer, Zhou said the researchers also plan to validate the tool in other tumors, including lung and colon cancer.

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