The Rosenzweig Lab

 

Welcome to the Rosenzweig Laboratory Web page.

The Overall theme of research in the lab is the study of growth factor dysregulation in disease. In particular, we are focused on the Insulin-like Growth Factor (IGF) System and its role in Head and Neck Cancer. The IGF system is comprised of two ligands, IGF-1 and IGF-2, two receptors, the IGF-1 receptor (IGF1R) and the insulin receptor (IR), and a family of six binding proteins IGFBP 1-6, which function to bind IGF-1 and IGF-2 in the circulation in order to block their access to the IGF-1R (1-3).

These studies led to the discovery of a novel signaling paradigm in which IGF1Rs were found to stimulate the expression and secretion of vascular endothelial growth factor (VEGF). VEGF, inturn, was found to initiate an autocrine/paracrine signaling pathway (4). Signaling by the VEGFR (Flk-1/KDR), also a receptor tyrosine kinase like the IGF-1R (6), was found to result in the tyrosine phosphorylation of neural precursor cell expressed developmentally downregulated 9 (NEDD9), a scaffold protein that has been shown to be a part of the metastatic signature of melanoma, breast, lung, glioblastoma and head and neck cancer (7, 8). This signaling pathway is currently under investigation in order to define the signaling proteins participating in cell invasion and metastasis.

In studying IGF dysregulation in cancer, the Rosenzweig laboratory has had a long-standing interest in developing inhibitors of IGF1R signaling in a variety of tumors, as a means of reducing the burden of cancer. To that end, we developed IGFBP2 as an inhibitor of IGF-1 and IGF-2 signaling. During the course of characterizing IGFBP2 truncation structure and function (9-11) along with our Nuclear Magnetic Resonance expert collaborators at the Indian Institute of Science in Bangalore, we discovered that the C-terminal peptide of IGFBP2 comprised of residues 249-289 spontaneously assemble into nanotubes (12, 13). We are currently evaluating these nanotubes for their suitability in drug delivery to different tissue sites and disease. For a more detailed description, please visit the Somatoceutics, LLC website.

References:

1. Horney, M.J. Evangelista, C. A. and Rosenzweig, S.A. Synthesis and characterization of insulin-like growth factor-1 (IGF-1) photoprobes selective for the IGF binding proteins (IGFBPs): Photoaffinity labeling of the IGF-binding domain on IGFBP-2. J. Biol. Chem. 276, 2880-2889, 2001.

2. Rosenzweig, S.A. What's new in the IGF binding proteins? (Review), Growth Hormone & IGF Research 14, 329-336, 2004.

3. Robinson, S.A. and Rosenzweig. S.A. Synthesis and characterization of biotinylated forms of insulin-like growth factor-1: topographical evaluation of the IGF-1:IGFBP-2 and IGFBP-3 interface. Biochemistry 43, 11533-11545, 2004.

4. Slomiany, M.G. and Rosenzweig, S.A. Hypoxia inducible factor-1 (HIF-1) dependent and independent regulation of insulin-like growth factor-1 (IGF-1) stimulated vascular endothelial growth factor (VEGF) secretion. J. Pharmacol. Exp. Ther. 318, 666-675, 2006.

5. Slomiany M.G., Black, L.A., Kibbey, M.M., Tingler, M.A., Day, T.A. and Rosenzweig S.A. Insulin-like growth factor-1 receptor and ligand targeting in head and neck squamous cell carcinoma. Cancer Lett. 248, 269-279, 2007.

6. Rosenzweig, S.A. Acquired Resistance to Drugs Targeting Receptor Tyrosine Kinases. Biochem. Pharmacol. 83, 1041-1048, 2012.

7. Lucas, J.T., Jr., Slomiany, M.G., Salimath, B.P. and Rosenzweig, S.A. Regulation of invasive behavior by vascular endothelial growth factor is HEF1-dependent. Oncogene. 29, 4449-4459, 2010.

8. Grauzam, S., Brock, A.M., Holmes, C.O., Tiedeken, J.A., Boniface, S.G., Pierson, B.N., Patterson, D.G., Coaxum, S.D., Neskey, D.M. and Rosenzweig, S.A. NEDD9 stimulated MMP9 secretion is required for invadopodia formation in oral squamous cell carcinoma. Oncotarget, 9, 25503-16, 2018.

9. Kibbey, M.M., Jameson, M.J., Eaton E.M. and Rosenzweig, S.A. Insulin-like growth factor binding protein-2: contributions of the C-terminal domain to IGF-1 binding. Mol. Pharmacol. 69, 833-845, 2006.

10. Swain, M., Slomiany, M.G., Rosenzweig, S.A. and Atreya, H.S. High-yield expression and structural characterization of recombinant human insulin-like growth factor binding protein-2. Arch. Biochem. Biophys. 501, 195-200, 2010.

11. Rosenzweig, S.A. and Atreya, H.S. Commentary: Defining the pathway to insulin-like growth factor system targeting in cancer. Biochem. Pharmacol. 80, 1115-1124, 2010.

12. Swain, M., Thirupati, R., Krishnarjuna, B., Eaton, E.M., Kibbey, M.M., Rosenzweig, S.A. and Atreya, H.S. Spontaneous and reversible self-assembly of a polypeptide fragment of insulin-like growth factor binding protein-2 into nanotubular structures. Chem. Commun. (Cambridge) 46, 216-218, 2010.

13. Asampille, G., Verma, B.K., Swain, M., Shettar, A., Rosenzweig, S.A., Kondaiah, P. and Atreya, H.S. An ultra-stable self-assembling polypeptide nanotube for targeted imaging and therapy in cancer. Journal of Nanobiotechnology, In Press. 2018 Dec 8;16(1):101. doi: 10.1186/s12951-018-0427-1