Cancer is a leading health problem for United States Veterans. While most cancers are treatable in their earliest forms, gender-related cancers including those of the ovary, breast, and prostate are often fatal when diagnosed at advanced and/or metastatic stages. It is estimated that in 2015, these cancers will account for over 80,000 annual deaths in the general population, with morbidity rates significantly higher in the Veteran population. Many patients initially respon to treatment, but often relapse. Relapse may be due to the heterogeneous nature of the tumor, dysregulation of various signaling pathways, aberrant lectin- carbohydrates, or development of aggressive and drug resistant tumors. The best was to identify and treat these cancers may be through implementation of a more personally tailored diagnostic and/or therapeutic approach in which agents that target multiple biomarkers on cancer cells are employed. However, surprisingly few tumor-associated antigens or biomarkers have been shown to associate with cancer type or stage. Our laboratory has previously utilized bacteriophage (phage) display technology to identify biomarkers and isolate peptide-based targeting molecules that recognize ovarian, breast, and prostate carcinomas. Peptides that target the ErbB-2 and ErbB-3 receptors, carbohydrates (Thomsen-Friedenreich antigen, TF), lectins (galectin- 3, gal-3), and the CD44 splice variant CD44v6, have been obtained. These biomarkers are involved in cell adhesion, angiogenesis, and signaling. TF is expressed in over 90% of all adenocarcinomas, gal-3 is a marker of invasiveness and metastatic potential, ErbB-2 is a marker of aggressive metastasis, ErbB-3 often associates with poor prognosis and treatment resistance, and CD44v6 associates with aggressive cancer initiating (stem) cells (CIC). The ability to detect such biomarkers in vivo will help discern various stages of tumor progression and may help monitor response to therapy. The targeting and imaging of cancer biomarkers has generally relied on the use of radiolabeled antibodies (Abs). Unfortunately, Abs are very large and often cause immunogenic related toxicity and drug resistance. Small peptides are well tolerated in humans but suffer from low tumor uptake, instability, and high kidney retention. Peptides displayed in the context of small scaffolds or single chain Ab fragments (scFv) may provide ideal platforms for development of efficacious tumor targeting agents due to their high affinity, stability, and favorable in vivo pharmacokinetics. It is hypothesized that the phage display selected gal-3/TF, ErbB- 2/ErbB-3, and CD44v6 peptides can be engineered into high affinity, stable, targeting scaffolds to be used in the imaging and response to therapy of ovary, breast, and prostate cancer. The goal of these studies is to develop ErbB-2/ErbB-3 and gal-3/TF-targeting peptides and newly identified CD44v6-targeting peptides into personalized cancer detection or therapy agents. The objectives of this proposed research are to: 1) functionally characterize the peptides for the interruption of signaling pathways and proliferation in vitro and within human breast, ovary, or prostate carcinomas; 2) develop new generation of peptides tailored to radioimaging/therapy applications by: i) synthesis of retro-inverso and multiple antigen peptide constructs, ii) engineering peptides into novel scFv scaffolds, and iii) generating phage display scFv libraries for affinity maturation 3) simultaneous target multiple biomarkers using fluorescence imaging for streamlining the development of cancer detection probes, and 4) perform in vivo biodistribution and positron emission tomography (PET) imaging with 64Cu (or 68Ga)-labeled scaffolds to evaluate as in vivo radiodiagnostic and/or response to therapy agents. Our work will positively impact healthcare in that we are developing targeted agents for the detection and treatment of cancer. The peptide-based agents will be well tolerated in vivo and help improve the lives of our Veterans. This research coincides with BLR&D special interests of Women's Health and Genomic Medicine.
This work is relevant to the VA mission in that we are developing new ways to target and detect ovarian, breast, and prostate cancer. Our studies employ genomics and women's health issues. We have obtained peptides that bind with high affinity and specificity to the ErbB-2/ErbB-3 receptors, the lectin gal-3 and its carbohydrate ligand TF, and CD44v6 on cancer initiating cells. These antigens are overexpressed on many cancer cells and function in key steps in tumorigenesis. The peptides will form the basis of development of scaffolds that can function in optical and diagnostic radioimaging or therapy. In terms of human health, radiolabeled versions of the peptides may translate into safe and specific imaging probes for ovary, breast, and prostate cancer diagnosis as well as response to therapy. The peptide constructs will improve the standard of care of patients in that the peptides will be well tolerated in humans and radiolabeled versions will specifically target cancer cells not normal cells so as to minimize undesirable radiation side-effects.
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