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Ariadne and Cellecta to Merge Pathway Analysis and siRNA Screens for Prostate Cancer Database

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By Uduak Grace Thomas

This article has been updated from a previous version to correct an error in the total number of genes targeted by Cellecta's Decipher modules.

This week, Ariadne Genomics, Cellecta, and Roswell Park Cancer Institute announced plans to use siRNA screening data to co-develop a knowledgebase of prostate-specific pathway models to support prostate cancer research and drug discovery.

The project, which began in 2008 and will wrap up its first phase next July, is sponsored in part by a $150,000 National Cancer Institute Small Business Innovation Research grant awarded to Cellecta. The partners plan to apply for additional funding to kick off the next phase of the project.

According to the grant abstract, the goal of the project is to “develop and make publicly available new, powerful bioinformatics research tools: a knowledgebase of functionally validated pathways specific for and controlling prostate cancer cell viability, and supporting software tools for data analysis and prediction of anti-prostate cancer drug targets.”

The partners said this week that they plan to use Cellecta’s siRNA library screening system to identify genes that are a vital part of prostate cancer cell survival. Ariadne will use its Pathway Studio software to combine data from the siRNA screens with -omics data from the scientific literature to identify gene pathways and to build mechanistic models that support the genes identified from the screen. For its part, Roswell Park will contribute expertise in prostate cancer research as well as cell lines and animal models.

The partners hope to identify important regulators and signaling mechanisms for prostate cancer that could eventually lead to the development of more effective treatment therapies for the disease.

Ilya Mazo, president and CEO of Ariadne, told BioInform that in addition to acquiring knowledge about prostate cancer mechanisms, the “scientific goal of the study” is to provide proof of principle that validates Cellecta’s method of identifying biomarkers and genes involved in cancer as well as to show that Ariadne’s bioinformatics tools can “suggest interesting hypothesis that can be validated.”

The Path to Prostate Cancer

Mazo said that Ariadne plans to use its computational tools to identify pathways and functional modules in protein networks that might be important for the viability of prostate cancer cells.

“We are using gene-expression data from the public domain to build mechanistic models from our proprietary knowledgebases,” he said.

Ariadne plans to use its Pathway Studio software in combination with its MedScan text-mining tool, which gathers information from the scientific literature on genetic activity such as gene pathways and metabolic cascades as well as information on drugs that can affect target proteins.

The information pulled from the literature will be combined in Pathway Studio with potential gene candidates identified from Cellecta’s siRNA library screens and used to create in silico models of prostate cancer-signaling networks.

“We can take this list of genes that come from their screens and cross-validate them against our databases to understand the mechanism,” Mazo said. “Checking how they map to the pathways might help to eliminate false positives and suggest additional targets for secondary screens.”

Mazo said that while Ariadne won’t have to make any changes to its software for the project, the company plans to build a database that will contain information about prostate cancer — everything from genes involved in the disease to drug molecules that can be used to treat it.

Mazo said the database will have several components, including an ontology of prostate cancer-related concepts, a collection of pathways, information on proteins and drugs gleaned from the scientific literature, as well as relevant -omics data and genetic information from Cellecta’s siRNA screens.

“The combination of information that we offer and siRNA screens is going to be unique,” he said. While there are a number of therapeutic area-specific databases available in the commercial sector and the public domain, Mazo said that this project is the first to use "the crossover between pathway analysis and siRNA library screening to enhance the knowledgebases.”

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Ariadne plans to have a product ready to market once the first phase of the project concludes next July. He expects the database to be of interest to pharmaceutical companies.

The Needle in the Haystack

Paul Diehl, Cellecta’s director of marketing and business development, told BioInform that much of the company’s Decipher technology is built around lentiviral short-hairpin RNAs, which are used to create genome-wide pooled screening libraries used primarily in drug-discovery projects and by groups involved in studies focused on understanding the functions of genes. He said that the method can be more “valuable and cost effective” than considering one gene at a time or many genes in an array format.

“You can look at some sort of [cell] response and analyze a whole range of genes, from several thousands to an entire genome in one simple experiment using our pooled format approach, and try to identify which ones might be critical for the response,” he said.

He said that the approach is particularly useful for viability assays that are focused on identifying the genes responsible for keeping cancer cells alive.

For this project, Diehl said that Cellecta plans to use three to four Decipher library modules targeting between 15,000 and 20,000 genes in total, to identify genes responsible for viability in the prostate cancer cell lines provided by Roswell Park researchers.

“The data collected from these screens will indicate which genes are really involved in the prostate cancer cell lines’ viability … because when you knock those genes out, the cancer cells die,” he said.

Based on the results of the initial screen, Cellecta’s researchers may develop smaller libraries to further narrow down the list of potential suspects.

“If a large number of genes, let’s say 200 to 500, look very interesting from the primary screen and need to be validated, we perform a more in-depth analysis using a focused library targeting only that subset of genes with a highly redundant set of shRNAs,” Diehl explained.

Calling in the Experts

Andrei Gudkov, senior vice president for basic science at Roswell Park, told BioInform that while Ariadne and Cellecta bring their respective technologies to the partnership, Roswell Park has one of the “strongest prostate cancer research groups in the country clinic-wise,” and will provide the “expertise in the disease, cell and animal models, and in screening under specific conditions which mimic the disease.”

He said that Roswell’s researchers are creating prostate-derived cell lines that will be used as models for Cellecta’s screening process to identify gene candidates that are linked to prostate cancer. These genes could be prospective molecular targets for drugs developed to treat prostate cancer, he said.

A drug that treats the cancer would be the ultimate goal of the study because, as Gudkov explained, most cases of prostate cancer are treated by surgery to remove the prostate. However, patients relapse frequently because dormant cells that metastasized from the tumor prior to surgery can “wake up” as a result of mutations in the cells.

“If we identify genes, [the] suppression of which is essential for viability of prostate as a tissue, we then will be able to use these genes and their products as targets to develop small molecules which eventually will become drugs to be used for treatment of prostate cancer,” he said.

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