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    Awarded Grants
    Spiegelmers as Inhibitors and Targeting Vehicles Against ErbB Receptors

    Scientific Abstract:
    Overexpression of the ErbB2 (HER2) receptor correlates with more aggressive tumor growth, enhanced probability of drug resistance and reduced survival of patients. ErbB2 signals most potently through complexes with the kinase deficient but ligand binding ErbB3. Joint over-expression of both receptors correlates with increased emergence of drug resistance. ErbBs are targets for antibody-based therapies, largely due to the clinical success of Herceptin, an antibody against ErbB2. Spiegelmers are enantiomeric and hence serum stable forms of aptamers, RNA-based nucleic acids derived by in vitro selection. We have generated a set of aptamers against ErbB3 with antibody-like binding properties that inhibit ErbB2/ErbB3 signaling in vitro. Aptamers and spiegelmers are 1/10 the size of antibodies, are non-immunogenic and can be generated synthetically, providing a versatile platform for subsequent chemical modifications. Objectives and Hypothesis: The existing aptamers prevalidate regions of ErbB3 with respect to accessibility and susceptibility to inhibition. The corresponding Spiegelmers against those prevalidated target regions would be serum stable and maintain specificity. Spiegelmers can inhibit ErbBs directly or provide targeting vehicles for toxic cargo or the attachment of imaging probes. Lessons learned from the targeting of ErbB3 will also facilitate the design of Spiegelmers against ErbB2 and EGFR. Specific Aims and Study Design: 1) We will classify our exiting aptamers by their mode of binding and inhibition. 2) We will identify the target regions on ErbB3 for selected aptamer representatives and generate the corresponding Spiegelmers against the target regions. 3) Spiegelmers will be evaluated for their binding and inhibitory properties in cell culture and for tumor suppression in mouse xenograft studies. Potential Outcomes and Benefits: Compared to antibodies, Spiegelmers promise to have higher tissue penetration, cheaper production costs and a significantly broader spectrum of additional chemical modifications that could enhance their potency as cancer specific inhibitors or killing agents. Parallel to the therapeutic evaluation emphasized in this proposal, we will also evaluating the conversion of Spiegelmers into PET imaging probes through collaborations. The long-term goal is to provide parallel treatment and imaging options with a spectrum of compounds that could complement existing treatments and provide options for patients that either acquire resistance or fail to respond to existing antibody or kinase inhibitor based treatments.

    Lay Abstract:
    Elevated levels of the ErbB2 (HER2) cell surface receptor correlate with more aggressive tumors and a poorer patient survival. The success of Herceptin, an antibody against the portions of ErbB2 that are accessible on the cell surface, has demonstrated the validity of targeting this portion of the receptor. Several new antibody-based therapies are currently being evaluated. Some of those target the fact that ErbB2 partners primarily with ErbB3 to transmit signals. Simultaneous overexpression of both receptors is known to correlate with increased emergence of drug resistant tumors. We have recently selected a set of aptamers, small nucleic acid based compounds, against ErbB3 and have demonstrated their ability to inhibit ErbB2/ErbB3 signaling in cell culture. Aptamers have several advantages over antibodies, mainly their small size (1/10) while maintaining comparable binding affinity, and the ability to be generated fully synthetically. The later provides a greatly enhanced repertoire of chemical modifications that can enhance their potency as cancer cell killing agents or their ability to be converted into imaging probes. The main challenge for aptamers has traditionally been the generation of versions that are resistant to degradation in serum without compromising affinity or specificity. Within the last three years, a new concept has emerged for the generation of stable aptamers: Spiegelmers (mirror images). Spiegelmers are the mirror images of aptamers, aimed at the same target region without loss of affinity. However their mirror-image nature makes them a non-substrate for the RNases that normally degrade aptamers. As a starting point in the exploitation of this new class of compounds, we propose to build on our existing aptamers, identify the target regions on the receptor for those aptamers with the most promising properties and generate the corresponding Spiegelmer versions. We will test these Spiegelmers for their ability to inhibit ErbB2/ErbB3 signaling in cell culture as well as tumor progression in mice. Our long-range goal is to establish a family of Spiegelmers that can complement other therapies in the treatment of ErbB overexpressing cancers and furthermore, to use them as a chemical platform for targeted drug delivery as well as imaging tools to classify tumors and track the progression of therapy by non-invasive means.