Despite intense research efforts, therapeutic efficacies in multiple cancer types are sorely lacking. However, early detection of tumor formation can substantially improve patient prognosis via reduced probability of metastasis, improved therapeutic effectiveness, and reduced tumor burden. Our research applies engineering principles to chemistry, biology, and physiology to enhance the limits of disease detection, with a particular focus on in vivo molecular imaging of tumors. Molecular imaging is the non-invasive detection, localization, and quantification of molecules and molecular processes in the body. This approach can yield increased specificity and sensitivity relative to traditional imaging and enable a molecular understanding of disease biology thereby providing utility for diagnostics, therapeutic monitoring, drug development, and scientific research.
Imaging living systems at the molecular and cellular scale necessitates command of molecular recognition, molecular biology of the target, biological transport at the tissue and cellular levels, and detection technology. Our program benefits from focused research on high-throughput engineering of molecular recognition proteins with exceptional affinity, stability, and biological properties. This is coupled with in silico, in vitro, and in vivo studies of the biology and transport of the molecular target to yield efficient, selective delivery. These innovations are merged with multimodality imaging technologies to enhance detection. Tangentially, lessons learned in these endeavors are also directly applicable to (a) engineering proteins for industrial, scientific, and therapeutic applications; (b) in vitro diagnostics; (c) tumor targeting for therapeutic applications; and (d) targeting of other malignancies or molecules of scientific interest.
- American Cancer Society / Canary Foundation Early Detection of Cancer Postdoctoral Fellowship, 2010-2011
- Hackel, B.J., Kimura, R.H., and Gambhir, S.S., Use of 64Cu-labeled Fibronectin Domain with EGFR-Overexpressing Tumor Xenograft: Molecular Imaging. Radiology (2012) 263:179-188.
- Hackel, B.J., Neil, J.R., White, F.M., and Wittrup, K.D., Epidermal growth factor receptor downregulation by small heterodimeric binding proteins. Protein Eng Des Sel. (2012) 25:47-57.
- Kimura, R.H., Teed, R., Hackel, B.J., Pysz, M.A., Chuang, C.Z., Sathirachinda, A., Willmann, J.K., and Gambhir, S.S., Pharmacokinetically Stabilized Cystine Knot Peptides That Bind Alpha-v-Beta-6 Integrin with Single-Digit Nanomolar Affinities for Detection of Pancreatic Cancer. Clin. Cancer Res. (2012) 18:839-849.
- Pirie, C.M., Hackel, B.J., Rosenblum, M.G., and Wittrup, K.D., Convergent potency of internalized gelonin immunotoxins across varied cell lines, antigens, and targeting moieties. J. Biol. Chem. (2011) 286, 4165-4172.
- Hackel, B.J., Ackerman, M., Howland, S., and Wittrup, K.D., Stability and complementarity-determining region biases enrich binder functionality landscapes. J. Mol. Biol. (2010) 401, 84-96.
- Hackel, B.J., and Wittrup, K.D., The full amino acid repertoire is superior to serine/tyrosine for selection of high affinity immunoglobulin G binders from the fibronectin scaffold. Prot. Engr. Des. Sel. (2010) 23, 211-219.
- Ackerman, M., Levary, D., Tobon, G., Hackel, B.J., Orcutt, K.D., and Wittrup, K.D., Highly avid magnetic bead capture: an efficient selection method for de novo protein engineering utilizing yeast surface display. Biotech. Prog. (2009) 25, 774-783.
- Hackel, B.J., and Wittrup, K.D., "Yeast surface display in protein engineering and analysis" in Protein Engineering Handbook (Lutz, S., and Bornscheuer, U.T., eds) (2008) 621-648.
- Hackel, B.J., Kapila, A., and Wittrup, K.D., Picomolar affinity fibronectin domains engineered utilizing loop length diversity, recursive mutagenesis, and loop shuffling. J. Mol. Biol. (2008) 381, 1236-1252.
- Lipovsek, D., Lippow, S.M., Hackel, B.J., Gregson, M.W., Cheng, P., Kapila, A., and Wittrup, K.D., Evolution of an interloop disulfide bond in high-affinity antibody mimics based on fibronectin type III domain and selected by yeast-surface display: Molecular convergence with single-domain camelid and shark antibodies. J. Mol. Biol. (2007) 368, 1024-1041.
- Chao, G., Lau, W.L., Hackel, B.J., Sazinsky, S.L., Lippow, S.M., and Wittrup, K.D., "Isolating and engineering human antibodies using yeast surface display" Nature Protocols 1, 755-768 (2006).
- Hackel, B.J., Huang, D., Bubolz, J.C., Wang, X.X., and Shusta, E.V., "Production of soluble and active transferrin receptor-targeting single-chain antibody using Saccharomyces cerevisiae" Pharm. Res. 23, 790-797 (2006).
- Camarero J.A., Hackel, B.J., DeYoreo, J.J, and Mitchell, A.R., Fmoc-based synthesis of peptide alpha-thioesters using an aryl hydrazine support. J. Org. Chem. (2004) 69, 4145-51.