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Asuragen, microRNA Rx Subsidiary Awarded NIH Grants to Support Rx, Dx-Development


By Doug Macron

Asuragen and its subsidiary Mirna Therapeutics this month received nearly $600,000 in grant funding from the National Institutes of Health to fund their respective efforts to develop microRNA-based diagnostics and drugs.

The first grant was awarded to Asuragen researcher Elizabeth Mambo to support her work identifying biomarkers for determining a patient's risk of colon cancer recurrence.

Colon cancer is primarily treated through surgical resection, and the overall survival rates partially depend on whether the cancer recurs, the likelihood of which is "directly related" to the stage of the cancer as determined by the depth of tumor penetration into the wall of the colon, according to the grant's abstract.

"However, colon cancer staging is not an accurate method for predicting recurrence," it notes. "In fact, all existing approaches to post-operative surveillance of patients with colon cancer are inadequate because disease recurrence is only detected when interventions have relatively little benefit on patient survival."

At the same time, prognostic biomarkers have been proposed but not approved for clinical applications due to a lack of specificity and sensitivity, the abstract states.

To address this issue, Asuragen aims to develop a molecular diagnostic assay based on miRNA expression patterns that can be used at the time of resection of a primary colon tumor to identify patients with a high risk of recurrence.

The small, non-coding RNAs have already been shown to play a role in a number of cancers, while their expression patterns "have been shown to be highly predictive of cancer type, making them ideal as prognostic indicators," it notes.

Asuragen has already generated data suggesting miRNAs can be highly predictive biomarkers of colon cancer recurrence. Last year, Mambo presented data at the Association for Molecular Pathology's annual meeting showing that certain miRNA signatures are associated with early-stage colorectal cancer tumors and may be useful in determining the risk of recurrence.

According to poster data from that presentation, the cancer recurs in 20 percent of stage I patients and in 40 percent of stage II patients, but adjuvant therapy is only accepted as the standard of care for those with stage III and IV cancer, in part due to the lack of markers that can predict which early-stage patients will experience recurrence.

In order to identify potential markers, Asuragen investigators examined miRNA expression in tumor and normal adjacent tissue, as well as in primary colorectal cancer tumors from both recurrent and non-recurrent patients.

The team showed that "several" miRNAs were down-regulated in cancers, including miR-21, miR-31, miR-182, miR-143, and miR-145. Meanwhile, only a few were up-regulated in cancers relative to the normal tissue specimens.

"Importantly, our results showed that newly identified miRNAs can be used in predicting disease outcome by distinguishing tumors from patients that had [colorectal cancer] recurrence from those that did not," the poster adds. Further, the investigators found a miRNA signature "that could be useful in identifying node-negative early-stage colorectal cancer patients with likelihood of having recurrence."

But this and other early work needs to be validated and expanded, according to the grant's abstract. As such, the company will use a "comprehensive miRNA expression profiling system" to discover and build biomarker sets that could be used to predict colorectal cancer recurrence.

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"Bioinformatics analyses will be used to establish prognostic indices with high performance in predicting recurrence," the abstract notes. After this work is completed, Mambo and colleagues aim to "implement design features on the validated biomarker set to develop a robust, reliable, and reproducible qRT-PCR assay for miRNA analysis."

The grant, which began on Sept. 1, is worth $312,292 and is set to run until the end of August 2011.

The second grant was given to Mirna's Andreas Bader to support the company's development of a miRNA-based treatment for prostate cancer.

Mirna has a pipeline of drug candidates for various cancers including miR-Rx34, which mimics miR-34 as a treatment for prostate and other solid cancers. Last year, it released preclinical data showing that systemic administration of the agent to mouse models using a recently in-licensed neutral lipid-based delivery vehicle inhibited the proliferation and viability of a "variety of cultured cancer cells, including those derived from patients with melanoma, lung, prostate, liver, and colon cancers" (GSN 6/18/2009).

Additionally, miR-Rx34 inhibited the growth and metastasis of established human tumors in mouse models of lung and prostate cancer, while the lipid delivery vehicle, either alone or with the miRNA payload, showed no signs of causing toxicity or immunogenicity.

Mirna's President and CEO Paul Lammers recently told Gene Silencing News that the compound is expected to be ready for human trials next year.

But according to the grant's abstract, Mirna has "substantial preliminary data that suggest a number of miRNAs may have therapeutic potential." With the NIH award, the company will test the therapeutic potential of these miRNAs in animal models of prostate cancer, including one that mimics invasiveness and metastasis.

"Additionally we will evaluate stabilizing and release compounds that will allow systemic delivery of miRNA therapeutics," the abstract adds.

Bader's grant began on Sept. 22 and is set to run until Aug. 31, 2011. It is worth $282,967.

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