The National Institutes of Health this month handed out nearly $1 million to fund three microRNA-related projects, two exploring the use of the non-coding RNAs as biomarkers for cancer and one to develop new approaches for identifying their targets.
The first cancer-related grant was awarded to Memorial Sloan-Kettering Cancer Center clinician Prasad Adusumilli to support his efforts to validate an miRNA-based risk model for stage I lung adenocarcinoma.
“Currently, the only accepted prognostic factor guiding treatment decisions for both surgeons and oncologists is tumor size, and its prognostic performance remains unclear,” he wrote in the grant's abstract. ”Better prognostic tools are needed to provide good quality individual risk prediction, identify patients at high risk of recurrence, and help to guide treatment decisions by both oncologists and thoracic surgeons.”
To that end, he and his colleagues have conducted a clinical and pathological examination of a large cohort of stage I lung adenocarcinoma patients to develop a prediction score combining clinical, histological, and cytological criteria that can predict the risk of recurrence or death with “high accuracy.”
To further enhance the scoring approach, Adusumilli aims to incorporate a prognostic lung cancer-associated miRNA signature developed by his lab. The miRNA analysis would use formalin-fixed paraffin-embedded tissue, "thus avoiding the requirement of complex tissue processing protocols," the abstract states.
“We hypothesize that the comprehensive clinico-pathological score, enriched with miRNA expression data, can be combined into a simple, cost-effective predictive instrument that will accurately determine the risk of recurrence or death following curative-intent surgical resection for stage I [lung adenocarcinoma], and will identify those patients who are primary candidates for aggressive surveillance and adjuvant therapy,” Adusumilli wrote.
With the help of the NIH funding, which is worth $241,931 in its first year, the Memorial Sloan-Kettering team plans to validate and refine its existing miRNA signature and “examine its ability to enrich the predictive quality of our clinico-pathological score,” according to the abstract.
“As the model is built upon simple clinical, pathological characteristics and miRNA analysis from [formalin-fixed paraffin-embedded tissue], the results of our proposal are immediately implementable, timely, and are of high translational significance,” it adds.
The grant runs from July 10 until June 30, 2014.
The second grant went to Thomas Jefferson University's Hushan Yang to help with his work using miRNA signatures from tumors as prognostic biomarkers of colorectal cancer.
Most early-stage colorectal cancer patients undergo curative surgery but do not receive chemotherapy or radiation treatment, due to cost and significant side effects, he wrote in his grant's abstract. “Nonetheless, there are more than 20 percent of early-stage [colorectal cancer] patients who do not realize the expected benefits from the initial curative surgery,” and suffer recurrence, disease progression, and metastases.
“In order to achieve the desired therapeutic efficacy and reduce the overall mortality in early-stage ... patients, it is critical to accurately predict the prognosis of these patients, and identify those with high risk of recurrence and death for more intensive and targeted treatments,” he added.
Noting that miRNAs are implicated in colorectal cancer but have not yet been used clinically to predict the prognosis of the disease, Yang and his colleagues plan to conduct a discovery and validation study in well-characterized colorectal cancer patient populations in order to systematically evaluate miRNA expression profiles in relation to disease survival.
“In addition, we will conduct extensive statistical analyses to characterize the gene-gene and gene-environment interactions [in these patients], as well as bioinformatics analyses to construct an in silico exploratory network of genes putatively targeted by the significant miRNAs,” he stated in the abstract. “Finally, we will conduct additional validations of the identified significant miRNAs to test their generalizability in advanced-stage Caucasian patients and African American patients.”
This pilot study, Yang added, is expected to lay the groundwork for a larger-scale, multi-institution study in the future.
His grant is worth $77,500 in its first year, and runs from July 15 until June 30, 2014.
The final grant was issued to Ye Ding of the New York State Department of Health's Wadsworth Center to help advance his efforts to develop mammalian miRNA target prediction methods.
In his grant's abstract, Ding notes that computational miRNA target prediction methods have shown promise, but suffer from “a number of limitations that hinder progress.”
“We have developed a high-throughput methodology to experimentally test thousands of miRNA-3' UTR interactions, and have acquired mRNA/miRNA expression data on hundreds of cancer cell lines,” he wrote. “These experimental advances have presented us the opportunity to develop state-of-the-art miRNA target prediction algorithms.”
With the NIH grant funding, Ding and his colleagues plan to develop a target-prediction algorithm based on deep sequencing data from biochemically purified miRNA-target complexes. They aim to then use large-scale miRNA-3' UTR reporter assays to “derive functional miRNA-target interactions … [and] develop algorithms and perform analyses and validation for more informative predictions on the level of miRNA-mediated regulation and miRNA-regulated pathways and networks.”
Ultimately, they hope to leverage this work to develop software tools and a database that can be made available to the scientific community.
His grant is worth $606,225 in its first year, and runs from July 18 until April 30, 2016.