Abstract P3-10-09: Peptide-based molecular targeting of inflammatory breast cancer.
Authors: BL Eckhardt, RY Miao, Y Cao, WH Driessen, S Krishnamurthy, W Arap, N Ueno, RL Anderson, R Pasqualini
Journal: Cancer Research (2012)

Abstract Inflammatory breast cancer (IBC) is a subtype of breast cancer that has a frequent association with metastatic disease and a poorer prognosis than comparative non-inflammatory breast cancers. While IBC is now considered a distinct subclass of breast cancer, the lack of molecular characterization, both at the genomic and proteomic levels, has hampered the development of rationalized and targeted therapies. Inherent receptor/ligand interactions that can occur on the surface of tumor cells can act as a dynamic molecular address that can enable targeted delivery of drugs and imaging agents to tumors. We hypothesize that such molecular addresses within IBC can be exploited for ligand-based imaging and early detection of disease sites. To this end, it is our goal to generate targeted imaging and therapeutic agents by combining ligand-directed targeting with efficient transduction of IBC cells by hybrid gene delivery vectors. Our strategy utilizes a hybrid vector with genomic elements from adeno-associated virus (AAV) and an M13-derived phage. Ligand-targeted, AAV/phage (AAVP) chimeras can display tumor-homing peptides that mediate selective internalization of viral particles through specific ligand-receptor interactions in vitro and in vivo. Such targeted vehicles are suited for the delivery of different reporter genes that can be used for imaging, diagnosis and therapy of breast cancer As a part of our ongoing studies we have identified, characterized and evaluated a peptide (WIFPWIQL, amino acid sequence) that can target GRP78, a stress-response protein that is expressed in IBC tumors and elevated during metastatic progression. Indeed, we found that this GRP78-targeting peptide can bind to, and internalize within IBC cells. As a result, we sought to characterize the ability of this peptide to mediate the delivery of fluorescent-based compounds and toxic moieties in preclinical models of IBC and breast cancer metastasis. Using amine-based chemical coupling, we conjugated near-infrared dyes on both WIFPWIQL-phage and on a WIFPWIQL-peptide engrafted antibody. When these fluorescent construct were administered into mice bearing IBC or IBC-like tumors, we could visualize tumor-specific targeting of the vectors in vivo. To demonstrate efficacy of GRP78-targeted therapeutics, we conjugated the tumor-homing, GRP78 ligand to a cell-death inducing domain (creating a compound called BMTP-78, βone metastasis targeting peptide-78), which can selectively kill cells upon internalization. We show here that BMTP78 therapy in mice with established GRP78-positive tumors, but not matched GRP78-negative tumors, could effectively reduce tumor growth and metastatic burden. Finally, we demonstrate a WIFPWIQL-AAVP construct that expresses a suicide gene (HSVtk) under the control of either CMV or GRP78 promoter, could sensitize IBC tumor xenografts to the pro-drug ganciclovir. Collectively, our results demonstrate an in vivo receptor/ligand system that has the potential for imaging and therapeutic targeting of IBC and aggressive breast tumors. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-10-09.