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NIH Earmarks $1.6M in July to Fund Research into Role of miRNAs in Cancer

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By Doug Macron

The National Institutes of Health this month awarded more than $1.6 million to fund four research projects examining the role of microRNAs in various cancers.

The first grant was issued to Case Western Reserve University's Subrata Haldar to fund his research into the potential interaction between the dietary chemopreventive agent benzyl isothiocyanate and miR-16 in pancreatic cancer.

The down-regulation of the anti-apoptotic protein Bcl-2 by benzyl isothiocyanate is commonly observed in pancreatic cancer cells, but how the agent does so is not clear, Haldar wrote in his grant's abstract.

Previous research suggests that miRNAs such as miR-16 trigger apoptosis by targeting the BCL2 gene, and Haldar and his colleagues have previously discovered that the miRNA was up-regulated in cells treated with benzyl isothiocyanate, he noted.

With the support of the NIH funding, Haldar aims to follow up on these findings by investigating the role of benzyl isothiocyanate-mediated miR-16 expression and down-regulation of BCL2 and another putative target, the pro-angiogenic molecule FGF-2, in pancreatic cancer cells.

He also plans to see whether ectopically expressed miR-16 can "cooperate" with benzyl isothiocyanate to exert an anti-tumor effect in heterotopic xenograft models of the disease, and evaluate the efficacy of orally administered benzyl isothiocyanate on miR-16 levels during the progression of pancreatic cancer in a mouse model, according to the abstract.

"Since microRNAs are increasingly being accepted as playing a crucial regulatory role in normal and dysfunctional cellular processes, this novel observation implication [the small, non-coding RNAs] with the anti-tumor effect of [benzyl isothiocyanate] should provide new insights in regard to the control of pancreatic cancer," Haldar stated.

The grant runs from July 1 until the end of June 2012, and is worth $204,885 in its first year.

The second grant went to Johns Hopkins University's Shawn Lupold to support his efforts to explore the role of miR-21 in prostate cancer.

Lupold and colleagues have "identified miR-21 as an androgen receptor-regulated and oncogenic microRNA [that] is elevated in human prostate cancer," and is "sufficient to drive castration-resistant tumor growth," he wrote in his grant's abstract.

"In light of these discoveries, and the existing knowledge of miR-21 in other malignancies, we hypothesize that the miR-21 gene locus contributes to the development of advanced prostate cancer," he added.

To test this, Lupold will use the NIH award to "characterize the mechanisms of elevated miR-21 gene expression into human prostate cancer … [and] elucidate the pathways utilized by the miR-21 gene locus to promote cancer progression," according to the abstract.

He and his team will also compare miR-021 gene copy number and expression between human prostate cancers that have been cured by primary therapy or recurred, progressed to metastasis, or proven castration resistant.

His grant runs from July 1 until April 30, 2015, and is worth $340,300 in the first year.

Ralph deVere White, a researcher at the University of California, Davis, received the third grant, which will support of his research into the role of miR-125b in castration-resistant prostate cancer.

DeVere White and colleagues recently discovered that the miRNA was abnormally expressed in prostate cancer, and have hypothesized that its expression in castration-resistant prostate cancer cells is controlled by aberrantly activated androgen receptor, according to the grant's abstract.

Additionally, the investigators predict that miR-125b facilitates the cancer's growth by repressing the tumor suppressor p53, and that the miRNA could be used as a biomarker and therapeutic target in patients with castration-resistant disease.

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To test these hypotheses, deVere White will confirm whether androgen receptor signaling regulates miR-125b, and determine if the nuclear receptor is abnormally over-expressed in prostate cancer cells, thereby up-regulating the miRNA.

To characterize the functions of miR-125b in prostate cancer, deVere White and colleagues aim to see if its stimulates tumorigenesis and prostate cancer cell growth by repressing p53 and other tumor suppressors; determine the miRNA's role in apoptosis and cell proliferation; and evaluate its effects on androgen receptor levels and activity, according to the grant's abstract.

The team proposes to characterize miR-125b's potential as a biomarker and drug candidate by looking for its abnormal expression in clinical samples of prostate cancer tissue, as well as serum from patients, "and determine if miR-125b alters the response of [castration-resistant prostate cancer] cells to therapy," he wrote in the abstract.

The grant runs from July 9 until May 31, 2014, and is worth $285,728 this year.

Albert Einstein College of Medicine's Thomas Rohan received the final grant, which will help fund his work to examine miRNA expression in relation to breast cancer risk.

With his colleagues, he will identify and validate miRNAs related to breast cancer development in formalin-fixed, paraffin-embedded samples as part of an ongoing cohort study of 15,395 women who had a biopsy for benign breast disease and are being followed to monitor the occurrence of malignancies.

"In the identification phase, RNA extracted from … tissue blocks of 415 case-control pairs will be analyzed … to identify the top 70 miRNAs that are differentially expressed between cases and controls," Rohan wrote in the grant's abstract.

These miRNAs will be confirmed using qRT-PCR, with the top 20 candidates being tested for case-control differences using qRT-PCR in a separate study with 210 case-control pairs, the abstract added. "In additional analyses, we will examine the association between miRNA expression and risk of breast cancer classified by estrogen/progesterone receptor status, and, for a random sample of cases, we will compare miRNA expression in benign breast disease tissue with that in the corresponding breast cancer tissue."

The grant runs from July 13 until May 31, 2015, and is worth $788,171 in the first year.

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