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Posters at AACR Underscore Caris Life Sciences' miRNA Microvesicle Diagnostics Work

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By Molika Ashford

Caris Life Sciences presented data earlier this month underscoring the company's work to develop a group of cancer diagnostics using a method of sub-selecting tumor-associated microvesicles for their unique microRNA profiles.

Caris researchers presented three posters at the annual meeting of the American Association for Cancer Research this month. The data represent investigations into the mechanisms of miRNA transport in microvesicles and the association of unique miRNA and other nucleic acid signatures with subclasses of vesicles selected by their surface proteins.

While the data shared at the meeting demonstrates more basic science than that being conducted in Caris' commercial programs, David Spetzler, vice president of discovery research at the company, told Gene Silencing News this week that the posters highlight Caris' accelerating effort to develop its Carisome platform for the capture and sub-selection of circulating microvesicles in blood for a range of cancer diagnostic and prognostic assays.

"Basically what we're doing is extracting microvesicles shed from tumors into the blood and profiling the protein and nucleic acid content in order to facilitate a clinical diagnosis," Spetzler said.

"The posters at AACR this year were focused mainly on the utility of the nucleic acid content” of vesicles, he explained. "We showed, for example, that by sub-selecting the population shed from the tumor, we can identify KRAS mutations, which are important in identifying treatment regimens."

Spetzler said that the company has initiated a clinical trial to evaluate an assay for prostate cancer. In the multi-center prospective study, the company is measuring the clinical performance of the so-called Carisome Prostate assay as an aid in the diagnosis of prostate cancer in men that have been scheduled for a prostate biopsy.

According to Spetzler, the study is slated to conclude by year end.

After prostate cancer , the company will target lung cancer, breast cancer, and colon cancer as the next diagnostic projects. According to Spetzler, preliminary research is going on for ovarian cancer, pancreatic cancer, head and neck cancer, and melanoma, as well.

He characterized the development of the Carisome platform and its protein-based vesicle sub-selection as the company's main achievement and noted that the creation of individual assays based on the technology will be a relatively easy progression.

"We feel the opportunity is more of a technological opportunity than a specific disease opportunity, so the number of different diagnostic assays we [think we] can develop is quite large," he said.

Caris has not released many details about its Carisome technology, but describes it as a platform that isolates vesicle groups using antibodies associated with unique surface proteins and then profiles the miRNA content of the resulting vesicle subgroups to identify predictive signatures or give a test result.

"The analogy we use is that the protein on the surface is kind of like an address. Certain cells will be able to take up the microvesicles and others won't, depending on whether there are complementary proteins on the surface," Spetzler explained.

According to Spetzler, the interest in looking at vesicle-specific miRNA and other nucleic acid signatures has grown "exponentially" in recent years.

Interest in miRNAs associated with sub-populations of vesicles has blossomed out of difficulties the field has had discovering disease-associated or predictive miRNA signatures from the global population of blood-borne miRNAs. "There aren't really any clear [microRNA] winners out there in terms of profiling the entire population, so the evidence has started to suggest sub-profiling is important," Spetzler said.

"What we've found … is that you don't just want to look at the global miRNA profile," he added. "It's actually important to sub-select based on protein phenotypes and then interrogate miRNA."

"A big problem when looking for mutations is that you have to have enough of the mutation in the presence of the wild-type gene in order to detect it. So being able to sub-select a population with more of the mutant strain in it is very advantageous," he explained.

A group of researchers from Chicago recently published a study in the Journal of Molecular Diagnostics highlighting the sample preparation issues hampering quantitative miRNA studies and biomarker signature identification. Isolating sub-populations of circulating vesicles could be a way to bypass the issue altogether by narrowing miRNA analysis to molecules within specific cancer-associated vesicles, they wrote (GSN 12/22/2011).

At the AACR meeting this month, Caris described three studies. One showed that by sorting microvesicles from colorectal cancer patients, the company researchers were able to identify the presence of KRAS mutations in blood samples.

In a second poster, the group showed data from a study of 22 individuals with breast, lung, and prostate cancer further supporting the conclusion that sorted sub-populations of circulating microvesicles contain unique miRNA profiles, distinct from non-sorted samples.

In the third poster, the researchers investigated the association of the protein GW182 with populations of circulating microvesicles in human plasma and urine, finding that GW182 maintains an association with the family of Argonaute proteins and a subset of vesicles in human plasma. Spetzler said the finding could have importance in the development of miRNA therapeutics.

"There's a lot of effort and work being put into utilizing siRNA as a therapeutic," he said. "What we know is that if you deliver a microRNA to a cell, in order for it to be functional, it has to get loaded into an Argonaute protein and taken back out into the cytoplasm where it can then start inhibiting messages, whereas if you have that molecule preloaded into AGO, as soon as it's in the cell it's going to be able to start functioning."

Spetzler said that as the Caris research group accumulates findings with therapeutic relevance, it plans to follow up on them eventually, but in the short term, the team is focused on its diagnostic goals.

He said that after the prostate cancer assay, the group plans to focus on breast cancer, then lung cancer and then colon cancer. "After we get that main four, we'll continue to work through the others," he said.

While he acknowledged that other companies are working on targeting miRNAs in microvesicles, Spetzler argued that Caris is unique in its approach of protein phenotyping to separate vesicle sub-populations.


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