Advanced Method for Generating Gene- or Pathway-Targeted Functional Probe Set
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Currently, a number of companies market custom-synthesized individual siRNAs, full mammalian genome siRNA sets, and off-the-shelf targeted siRNA subsets (e.g. for the kinome). After these are used for screening, ex post facto analysis applies bioinformatics tools to identify significant patterns. Disadvantages of full genome screens include cost and time considerations; disadvantages of kinome screens include likelihood of missing meaningful hits. Recent studies in systems biology integrated with classic paradigms of synthetic lethal analysis have led to the realization that genes with interrelated functions are biased towards those interacting in parallel, in sequence, or in higher order structures. This implies that for a protein or protein set of interest, custom libraries that integrate multiple classes of information about the physical neighborhood around the gene will be particularly rich sources of functional modulators, allowing screen of a smaller gene set with a higher ratio of informative hits. Researchers at FCCC have used a network-based bioinformatics methodology, incorporating known pathways and protein interactions around a central core, to identify potential interacting or parallel pathways. This allows a selective, knowledge-driven approach to elucidating potentially complementary approaches to inhibition of complex pathways.
Researchers at Fox Chase Cancer Center have developed a new bioinformatics method for identifying functionally important components of complex, redundant signaling pathways, based on integration of orthogonal datasets. This approach allows selection of a manageable number of probes for assessment of physiological regulators of high-value gene targets, facilitating the discovery of new pathway components.
The method enables a customer to select sets of secondary targets highly enriched for those potentially interacting with a core target. Such highly enriched sets of gene targets can then be provided to the customer in the form of antisense or siRNA for use in focused screens for the identification of novel secondary targets for the development of combination, targeted chemotherapeutic agents, or for use in academic research. Incorporation of this novel bioinformatics approach into a company's web portal will provide customers with significant added value, maximizing favorable outcomes from their research into complex pathways. The method can also be used by a supplier company to devise probe sets or arrays for sale to customers. FCCC researchers have demonstrated the value of this approach by using it to identify novel targets for drugs to be used in combination with anti-EGFR drugs for treatment of cancer to minimize the chances of emergence of resistance (Astsaturov, I. et al. Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. Science Signaling, 2010 in press).
The technology is available for licensing.
For licensing information, contact
Inna Khartchenko, MS, MBA
Associate Director, Office of Corporate Alliances
Fox Chase Cancer Center
610 Old York Road, Room 409
Jenkintown, PA 19046
For licensing information, contactInna Khartchenko, MS, MBA
Associate Director, Office of Corporate Alliances Fox Chase Cancer Center
610 Old York Road, Suite 400
Jenkintown, PA 19046