Abstract 1491: Targeting radiation-inducible cell surface TIP-1 using HVGGSSV peptide as a novel imaging and therapeutic strategy for tumors

Abstract

Abstract The greatest challenge in radiotherapy is to maximize radiation doses to tumors while sparing the normal tissues. Ionizing radiation has been shown to induce expression of proteins on surface of tumor cells. Using this strategy, drug delivery can be targeted specifically to cancer and guided by use of a beam of radiation. We used phage-displayed peptide libraries to discover radiation-inducible antigens in different cancer models. One such inducible-antigen is Tax interacting protein-1 (Tip-1) which was shown to bind the hexapeptide HVGGSSV. TIP-1 is an atypical PDZ protein consisting of only a single PDZ domain that is predominantly cytosolic protein and expressed in all types of cells. Overall TIP-1 expression levels in tumor cells and non-tumor cells are similar; however it is over-expressed on the tumor cell surface following irradiation. In this study, we evaluated the affinity of binding of HVGGSSV and a scrambled peptide to TIP-1 using surface plasmon resonance (SPR) technology. A KD (dissociation constant) of 3.3e-8M for HVGGSSV and 1.37e-3M for the scrambled peptide was obtained. We next determined the specificity of HVGGSSV to bind tumors in vivo using nano SPECT technology. HVGGSSV was conjugated to a 40KDa PEG (for longer circulation time) and radiolabelled with 111Indium (111In) using diethylene triamine pentaacetic acid (DTPA) as the chelator. The A549 tumor bearing nude mice were irradiated (3Gy x 3 times) or sham irradiated prior to tail vein injections of 111In labeled HVGGSSV. The mice were imaged 48h and 96h post injection using nano CT-SPECT imager. The SPECT images revealed that HVGGSSV specifically bound to the irradiated A549 tumors while little or no binding was seen in the sham irradiated tumors. The post-SPECT imaging bio-distrubution also revealed maximum uptake in irradiated tumors. We further evaluated tumor binding of HVGGSSV in Glioma (D54), esophageal cancer (OE33), cervical cancer (HT3), and pancreatic cancer (BxPC3). The nano-SPECT imaging showed that HVGGSSV specifically bound to all the irradiated tumors tested. Phosphor images of the tumor sections showed that HVGGSSV specifically bound to the tumors and not to normal tissues. In conclusion, HVGGSSV peptide has high affinity to TIP-1 in vitro and in vivo. Radiolabeled HVGGSSV is a novel tool for imaging tumors and may be developed further as a therapeutic agent to deliver cancer specific drugs or therapeutic radioisotopes. Citation Format: Vaishali Kapoor, David Dadey, Kim Nguyen, Hua Li, Buck Rogers, Dinesh Thotala, Dennis Hallahan. Targeting radiation-inducible cell surface TIP-1 using HVGGSSV peptide as a novel imaging and therapeutic strategy for tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1491. doi:10.1158/1538-7445.AM2015-1491