Mare Cudic

Cancer: General Cancer Research

A major goal in developing new cancer chemotherapeutics is to identify and target biological processes that distinguish malignant from normal cells. One such target is the glycosylation of proteins, which is known to change with the onset of cancer. Recently, it was demonstrated that a β–galactoside-specific lectin expressed on endothelial cells, galectin-3, interacts with Thomsen-Friedenreich (TF) antigen (core I structure: galactose-β-1,3-N-acetylgalactosamine) of the cancer-associated MUC1 glycoprotein. This interaction promotes cancer cell adhesion to endothelium by revealing epithelial adhesion molecules that are otherwise concealed by MUC1. The goal of our research is to design inhibitors of galectin-3 that can suppress cancer cell adhesion, migration, and invasion, thereby reducing formation of metastases.

A second goal of our research is to design and prepare novel functionalized liposomes to target cancers that use carbohydrate recognition by lectins to metastasize. The use of integrated nanotherapeutic systems (e.g., theranostic nanomedicine) has emerged as a novel and promising therapeutic approach. Most nanomedicine systems have low therapeutic efficacy due to the so-called “passive targeting” concept. To minimize adverse effects, our research efforts are focused on enhancing the nanomedicine’s selectivity by utilizing the “active targeting" approach.

Obesity linked diseases: Diabetes/Heart Disease/Obesity

Adiponectin is an adipocyte-secreted peptide hormone that has demonstrated insulin-sensitizing properties. In addition, adiponectin has many beneficial effects on obesity-related metabolic and cardiovascular dysfunctions. Adiponectin is predominantly present in the circulation as oligomeric complexes; by contrast, the monomeric form of adiponectin has never been detected under native conditions. Evidence from clinical, genetic, and animal studies increasingly suggest that oligomerization represents a key mechanism for regulation of the multiple biological activities of adiponectin. Posttranslational modifications (PTMs) within the collagenous domain of adiponectin, including hydroxylation of proline, and hydroxylation and glycosylation of lysine, have recently been shown to correlate with adiponectin multimerization and secretion. The specific goals of this research project are to elucidate further the role of adiponectin PTMs, particularly glycosylation, in oligomer assembly, and to elucidate the susceptibility of adiponectin to proteolytic cleavage.

Dr. Mare Cudic started her research career at the University of Zagreb, Croatia, where she obtained a Ph.D. in organic chemistry in 1996. The focus of her Ph.D. thesis was the synthesis of glycoconjugates of leucine- and methionine-enkephalins, endogenous opioid peptides in order to gain insights into alterations in receptor selectivity induced by glycosylation. Dr. Cudic was awarded the prestigious European Peptide Society Award for Young Scientists in 1994 to further explore structure activity relationship studies of enkephalin glycopeptides analogs.

Dr. Cudic has held two postdoctoral fellow positions in Paris, France. In the laboratory of Claire Ducrocq at the National Center for Scientific Research, Institute for Natural Compounds, she assessed the reactivity of nitric oxide and its higher oxides (NO2, N2O3, and peroxynitrite) toward biologically active peptides and some currently used drugs. In the laboratory of Prof. Jean-Marie Lehn, 1987 Nobel Prize Laureate, she was engaged in the design and synthesis of novel nonviral gene transfer agents based on amino carbohydrates. Dr. Cudic continued her postdoctoral training in the USA at the Wistar Institute, Philadelphia, in the laboratory of Dr. Laszlo Otvos in cancer glycobiology, glycoimmunology and antimicrobial drug development.

In 2003, she was recruited by Dr. Gregg Fields to the Center of Excellence in Biomedical and Marine Biotechnology at Florida Atlantic University, Boca Raton, Florida. As a part of the Center, Dr. Cudic was engaged in the synthesis of non-proteinogenic amino acid γ-hydroxyvaline (γ-HyVal) found for the first time in the peptide sequence of a novel conopeptide that belongs to the class of valuable therapeutic agents for the treatment of a variety of neurologically related diseases. In addition, Dr. Cudic continued to explore the biological role of glycans in protein structure and function. Under the mentorship of Dr. Fields, she synthesized triple-helical models of collagen containing hydroxylated and monoglycosylated hydroxylysine (Hyl) moieties to study enzymes involved in collagen post-translational modification, the effects of glycosylation on cell recognition and signaling, and collagen fibril formation.

Dr. Cudic joined Torrey Pines Institute for Molecular Studies in July 2010 as an Assistant Member.

Education

• 1986-1990 Bachelor of Science, University of Zagreb, Faculty of Science, Zagreb, Croatia
• 1990-1993 M.S. in Organic Chemistry, University of Zagreb, Rudjer Boskovic Institute, Zagreb, Croatia
• 1993-1996 Ph.D. in Organic Chemistry, University of Zagreb, Rudjer Boskovic Institute, Zagreb, Croatia

Positions

• 1995 Ph.D. Internship, National Institute of Chemistry, Ljubljana, Slovenia
• 1995 Ph.D. Internship, Institute of Technology, Chemistry Center, University of Lund, Lund, Sweden
• 1990-1996 Associate Scientist, Rudjer Boskovic Institute, Department of Chemistry and Biochemistry, Zagreb, Croatia
• 1997-1998 Postdoctoral Fellow, National Center for Scientific Research, Institute for Natural Compounds, Gif-sur-Yvette, France
• 1998 Postdoctoral Fellow, College of France, Paris, France (Laboratory of Prof. Jean-Marie Lehn, 1987 Nobel Laureate in Chemistry)
• 1998-2000 Postdoctoral Fellow, The Wistar Institute, Philadelphia, PA
• 2000-2003 Staff Scientist, The Wistar Institute, Philadelphia, PA
• 2003-2003 Research Director, Chaperone Technologies, Audubon, PA
• 2003-2007 Research Associate, Florida Atlantic University, Boca Raton, FL
• 2007-2009 Research Assistant Professor, Florida Atlantic University, Boca Raton, FL
• 2009 Adjunct Faculty, Farquhar College of Arts and Sciences, Nova Southeastern University,FL
• 2010-present Assistant Member, Torrey Pines Institute for Molecular Studies, FL

Professional Affiliations

• Member of the American Peptide Society
• Member of the American Chemical Society
• Reviewer for the International Journal of Peptide Research and Therapeutics

Honors & Awards

• 1990-1996 Rudjer Boskovic Institute Scholarship, University of Zagreb, Croatia
• 1997-1998 Postdoctoral fellowship award, National Center for Scientific Research, Institute for Natural Compounds, Gif-sur-Yvette, France
• 1994 European Peptide Society, Young Scientist Award
• 2001 American Peptide Society, Bachem Travel Award

Selected Publications (10 of 40)

1. M. Cudic, J. Horvat, M. Elofsson, K. E. Bergquist, J. Kihlberg and S. Horvat (1998) “Synthesis and cis-trans isomerism in novel Leu-enkephalin-related peptidomimetics containing N-glycated glycine residue.” J. Chem. Soc. Perk. Trans. 1: 1789-1795
2. M. Cudic, P. Bulet, R. Hoffmann, D. J. Craik, and L. Otvos Jr. (1999) “Chemical synthesis, antibacterial activity and conformation of diptericin, an 82-mer peptide originally isolated from insects.” Eur. J. Biochem. 266: 549-558. PMID: 10561597
3. M. Cudic, J. D. Wade, and L. Otvos, Jr. (2000) “Convenient synthesis of a head-to-tail cyclic peptide containing an expanded ring.” Tetrahedron Lett. 41: 4527-4531
4. M. Cudic, H.C.J. Ertl, and L. Otvos, Jr. (2002) “Synthesis, conformation, and T-helper cell stimulation of an O-linked glycopeptide epitope containing extended carbohydrate side-chains.” Bioorg. Med. Chem. 10: 3859-3870. PMID: 12413838
5. M. Cudic, C.V. Lockatell, D.E. Johnson and L. Otvos, Jr. (2003) “In vitro and in vivo activity of an antibacterial peptide analog against uropathogens.” Peptides 24: 807-820. PMID: 12948832
6. M. Cudic, J. L. Lauer-Fields, and G. B. Fields (2005) “Improved synthesis of 5-hydroxylysine (Hyl) derivatives.” J. Peptide Res. 65: 272-283. PMID: 15705169
7. M. Cudic, D. Patel, J. L. Lauer-Fields, K. Brew, and G. B. Fields (2008) “Development of a convenient peptide-based assay for lysyl hydroxylase.” Biopolymers (Pept. Sci.), 90: 330-338. PMID: 17610258
8. M. Cudic, Frank Marí, and Gregg B. Fields (2007) “Synthesis and solid-phase application of suitably protected γ-hydroxyvaline building blocks.” J. Org. Chem. 72: 5581-5586. PMID: 19400295
9. M. Cudic, and G. B. Fields (2009) ”Extracellular proteases as targets for drug development.” Curr. Protein Pept. Sci. 10: 297-307.
10. M. Cudic, G.D. Burstein, G.B. Fields & J. Lauer-Fields. (2010) “Analysis of flavonoid-based pharmacophores that inhibit aggrecanases (ADAMTS-4 and ADAMTS-5) and matrix metalloproteinases through the use of topologically constrained peptide substrates.” Chem. Biol. Drug Design, 74: 473-482. PMC2782546