Abstract 2195: Small molecule drug conjugates targeted to cholecystokinin 2 receptors

Abstract Cholecystokinin 2 receptor (CCK2R) is over expressed on many cancers of lungs, pancreas, liver and GI tract (esophagus, colon and GIST), whereas its expression in normal tissues is limited to epithelial cells of the GI tract and brain. This restricted expression pattern renders CCK2R an excellent candidate for use in tumor-targeted drug delivery. Here we used a high affinity, low molecular weight CCK2R antagonist (CRL) to deliver imaging agents and cytotoxic drugs specifically to CCK2R positive tumors. We demonstrated that in vitro CRL conjugated to either NIR dye or radioactive imaging agent binds selectively to CCK2R positive cancer cells and exhibits low nano molar affinity for the receptor. We further showed that In vivo NIR dye and radiolabeled conjugate localizes primarily to the CCK2R positive murine tumor xenografts. Both of these conjugates also exhibited low serum protein binding and cleared rapidly from blood. Thus CRL-NIR dye conjugate have a potential application in fluorescence guided surgery where as CRL-radioactive conjugate seems promising for radioimaging in the clinic. Encouraged by the results of the imaging agents, CRL was conjugated to two potent microtubule inhibitors (tubulysin B hydrazide and desacetyl vinblastine). In vitro these two conjugates demonstrated high affinity and specificity for CCK2R. In vivo CRL conjugated to tubulysin B hydrazide was found to be more effective in eliminating tumor compared to desacetyl vinblastine conjugate. Neither of the CRL-cytotoxic drug conjugates showed any toxicity associated with the base drug nor any weight loss was observed in the mice treated with these conjugates. Results suggest that CRL has the proficiency to delivery drug specifically to tumors over expressing CCK2R receptor and lower the toxicities associated with conventional ways of treating cancer. Citation Format: Jyoti Roy, Charity Wayua, Philip S. Low. Small molecule drug conjugates targeted to cholecystokinin 2 receptors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2195.