Research Project
6642563
DESCRIPTION (provided by applicant): Somatostatin receptors are expressed on a number of tumor types including, neuroendocrine tumors, small cell lung carcinoma, and breast cancer. Commercial radiodiagnostic imaging agents targeted to this receptor are currently in clinical use, and corresponding radiotherapeutic agents are in clinical evaluation. While these therapeutic agents show much promise, the high level of radioresistance displayed by many applicable tumor types limits their efficacy. The primary objective of this proposal is to design a new somatostatin receptor targeted radiotherapeutic that includes an RGD peptide element. Preliminary studies show that this molecule is able to induce cellular apoptosis via caspase-3 activation. The apoptosis inducing activity of the RGD-linked radiopeptide is additive to the cytotoxic effects of a solely radiolabeled somatostatin analog. Thus, the therapeutic index of a somatostatin-RGD radiopharmaceutical is expected to be greater than current targeting molecules. The specific aims of this feasibility study are: (1) synthesize a candidate molecule; (2) test its in vitro cell killing potency; and (3) utilize caspase-3 activation assays to confirm the mechanism of action. The lead molecule contains three main components: a DOTA chelator, to allow radiolabeling; a somatostatin peptide for targeting to receptors; and a cyclic-RGD peptide, to activate caspase-3 when internalized into cells.
