Abstract B216: A soil-to-seeds anticancer strategy: Targeting stroma to kill cancer cells.

Abstract

Abstract Rationale: We propose a dual targeting anticancer theragnostic strategy called OncoCidia, with which we intend to destroy and radioactively contaminate tumor stroma (soil) in order to eradicate all cancer cells (seeds) using vascular disrupting agents (VDAs) followed by radiolabeled necrosis-avid compounds (NACs), both of which are small molecular, naturally or synthetically derivable, systemically injectable, and of unique and complementary targetabilities. Methods: Combretastatin A4 phosphate (CA4P) and Hypericin, as a representative of VDAs and NACs respectively, were tested among liver and subcutaneous tumor models (Ø > 0.8 cm) in rats, mice and rabbits (n > 100). We first injected CA4P intravenously at a dose of 10 mg/kg to cause tumor necrosis that became the next target. Hypericin was labeled with iodine-131 to form 131I-Hypericin (131I-Hyp), which was then iv injected at 300 MBq/kg 24h after administration of CA4P. 131I-Hyp accumulated in necrotic tumor, killing adjacent residual cancer cells by cross-fire irradiation and preventing tumor re-growth. We studied OncoCidia by comparing vehicle-control, single-targeting (either CA4P or 131I-Hyp) and dual-targeting (CA4P plus 131I-Hyp) groups using in vivo MRI and scintiscans, and ex vivo gamma-counting, autoradiography and histology. Results: Eight days after only one dosage of each drug, typically the tumor size in vehicle-controls doubled that in single-targeting groups (p < 0.001), and was 5-times that in dual-targeting group (p < 0.0001), without treatment-related animal death. Tumors in OncoCidia groups appeared as hot-spots on scintiscans even weeks after treatment, corresponding to > 3.34% ID/g of 131I-Hyp and a target-to-liver ratio > 20. Significantly prolonged survival and reduced lung metastases occurred in tumor-bearing mice and rabbits respectively. Such encouraging results with histomorphological proofs were independent of animal species and tumor types. Conclusion: Our preclinical experiments suggest that OncoCidia may present a simple, workable, affordable and general solution for treatment, detection and therapeutic monitoring of diverse solid malignant tumors, and deserve further exploitation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B216.