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NIH Awards Three Grants In January to Help Develop RNAi-based Cancer Therapies

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By Doug Macron

The National Institutes of Health this month awarded more than $700,000 in funding to support three research projects focused on developing new ways of using RNAi to treat cancer.

The grants, which are all being funded by the National Cancer Institute, will specifically support efforts in prostate cancer, melanoma, and malignant solid tumors.

The first, worth $165,983 in 2010, was awarded to Kun Cheng, a researcher at the University of Missouri, Kansas City, to fund his investigations into the targeted delivery of siRNAs to prostate cancer cells.

Although therapies to treat prostate cancer exist and are "relatively effective in the short term, [the] majority of patients initially diagnosed with localized prostate cancer ultimately relapse," Cheng said in the grant's abstract. "Therefore, the major risk faced by prostate cancer patients is the development to metastasis."

Gene modulation is a promising strategy to combat the disease since genomic instability is a "hallmark of cancer development … [and] IKK1 is recently identified as the critical activator of prostatic epithelia cells to the metastatic fate," he added. As such, Cheng has identified an siRNA against the target and demonstrated its ability to inhibit the migration of two prostate cancer cell lines.

To extend this work, he and his colleague aim to create "an aptamer-conjugated siRNA targeting IKK1" that will incorporate backbone modifications and ligand conjugations to overcome in vivo stability and targeting issues, the abstract states.

"Our overall hypothesis is that the prostate cancer cells' growth and metastasis can be inhibited by the targeted delivery of IKK1 siRNA to tumor cells via conjugation with an aptamer [that] can recognize and bind to the … prostate-specific membrane antigen on the surface of prostate cancer cells," it notes.

Using the NCI funding, Cheng will determine whether silencing IKK1 can inhibit the invasive properties of prostate cancer cells and restore the gene expression of the tumor-suppressor gene maspin. Additionally, he will see whether 2'-O-methyl modification in the sense strand of IKK1 siRNA will increase the oligo's in vivo stability without interfering with its silencing effect, and if conjugation of the anti-PSMA aptamer to the siRNA will increase its uptake by prostate cancer cells, according to the abstract.

Finally, he will see if the increased uptake of siRNA in the tumor cells will correlate with higher anti-metastasis effect in the mouse prostate cancer model.

The project began on Jan. 1 and will run until the end of 2011.

The second grant, worth $321,833 this year, was awarded to Pennsylvania State University Hershey Medical Center's Gavin Robertson to support his efforts to develop an siRNA-based treatment for melanoma.

To treat the disease, it is believed that therapies targeting key cancer-related proteins or pathways need to act synergistically, he wrote in his grant's abstract. "While it's thought that the MAP and PI3 kinase pathways need to be inhibited along with other key pathways, the identity of particular genes to target and therapeutics to accomplish this objective do not currently exist for melanoma."

And while RNAi appears to be a promising approach to do so once the targets are identified, delivery continues to remain a hurdle facing the gene-silencing technology, he noted.

"Our long-term goal is to develop therapeutic agents inhibiting proteins deregulated in metastatic melanoma to shrink tumors in a synergistically acting manner," he stated. "To accomplish this objective, the central hypothesis proposes that siRNA-targeting Akt3, V600EB-Raf, and other key kinases deregulated in melanoma can be loaded into nanoliposomes and used to synergistically inhibit metastatic disease development."

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To test this hypothesis, Robertson plans to identify key kinases that, when targeted along with V600EB-Raf and Akt3, synergistically inhibit tumors. "An siRNA-based screen will be used to identify kinases deregulated in melanoma cell lines, validate involvement in tumor, as well as metastasis development and determine whether inhibition along with V600EB-Raf and Akt3 leads to synergistic inhibition," he noted.

With the support of the NCI funding, Robertson's team will then evaluate whether nanoliposomes containing siRNAs against V600EB-Raf, Akt3, and other melanoma-associated kinases can inhibit metastatic disease in a synergistically acting manner, according to the grant's abstract.

"Nanoliposomes containing siRNA designed to target V600EB-Raf, Akt3 and other key kinases in melanoma will be developed and efficacy for synergistically inhibiting metastatic melanoma development evaluated in animals," the abstract adds. "Development of synergistically acting therapeutic agents targeting key kinases promoting melanoma metastasis development would be a significant, novel and innovative scientific advancement … [and] lay the foundation for a new category of therapeutic drug to more effectively treat patients suffering from disseminated melanoma."

Robertson's project began on Jan. 1 and runs until Dec. 31, 2014.

The last grant, which supports a project that began in 2005 and is worth $224,174 in 2010, was given to the University of Southern California's Xue Huang to assist in his development of a novel oncolytic vaccine for the systemic treatment of solid tumors.

"Tumor vaccines are attractive therapy because tumor cells harbor numerous genetic mutations that could induce specific anti-tumor immunity," he wrote in the grant's abstract. "Yet, tumor cells are generally incapable of stimulating an immune response, probably due to inadequate antigen presentation."

The goal of the NCI-funded research is to "develop a local oncolytic virus therapy that can induce systemic antitumor responses by combining the advantageous features of oncolytic viruses and [heat shock protein]-based tumor vaccines," he stated.

Hypothesizing that a recombinant oncolytic virus expressing a HSP can be active against a local tumor and trigger the release of tumor antigens, while at the same time being effective against metastatic tumors, Huang and his colleagues previously generated a recombinant oncolytic adenovirus expressing heat shock proteins-70, according to the abstract. This agent was found to "retain oncolytic activity against various tumor cells, and [induce] systemic anti-tumor responses [following] … intratumoral injection."

To follow up on these findings, Huang aims to see whether "systemic anti-tumor immune responses are induced by local therapy with [the adenovirus] in murine tumor models capable of supporting human adenovirus infection," the abstract states. He will also see whether enhanced HSP expression by treatment with the adenovirus promotes dendritic cell tumor infiltration and antigen presentation and determine which subtypes of tumor-infiltrating dendritic cells are required to trigger anti-tumor immune responses.

He also plans to investigate whether intratumoral immunization with the oncolytic vaccine, designed to co-express siRNAs against the SOCS1 gene, which plays a role in suppressing cytokine signaling, will overcome tumor-mediated immunosuppression by "persistent activation of pro-inflammatory STAT and NF-kappaB signaling in infected, SOCS1-silenced tumor-infiltrating [dendritic cells] and other immune cells," the abstract states.

The project began on Dec. 27, 2005, and will run until Nov. 30, 2010.

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