Novel drugs to inhibit breast cancer metastasis

Institution: University of California, Santa Cruz
Investigator(s): Joseph  Konopelski , Ph.D. -
Award Cycle: 1997 (Cycle III) Grant #: 3CB-0183 Award: $197,064
Award Type: ITaMoCAs
Research Priorities
Innovative Treatments>New drug design: creative science



Initial Award Abstract (1997)
The change from a normal to a cancerous cell is accompanied by changes in the biological molecules at the surface of, and surrounding that cell. Some of these new biomolecules are unique enough to allow their use for diagnostic and treatment purposes. One protein component of the matrix of molecules that both surrounds a cell and forms the basement membrane is called laminin. Breast cancer cells attach to laminin using a specific laminin-binding protein (LBP), a cell surface protein. LBP expression provides an excellent prognostic indicator in breast cancer, and shows a positive correlation with progression in many solid tumors. This correlation likely results from the ability of LBP to enhance tumor cell attachment with the basement membrane as a prerequisite to spread in the body, or metastasis. Although laminin is a large protein, only a small part, called peptide 11, is involved in cell binding. When injected into test animals, peptide 11 can effectively block tumor spread to the lung and tumor angiogenesis (blood vessel growth). Unfortunately, other properties of peptide 11 make it unsuitable for immediate therapeutic applications. Thus, we have initiated a multi-disciplinary collaboration focused on structural analysis of peptide 11 to develop novel drugs for inhibition of breast cancer invasion and metastasis.

Our project pursues a chemical approach to prepare, structurally analyze, and test laminin peptide 11-derived unusual amino acids and related analogs (peptidomimetics). The desired molecular properties include (i) increased hydrolytic stability, (ii) protein inhibition properties, and/or (iii) unique conformational restrictions. These properties are measured by both enhanced protein and cell binding and drug stability when administered by animal injection. Peptide 11 is very attractive as a lead, ‘parent’ compound for developing a novel therapeutic agent. We expect that molecules resembling peptide 11 will not have additional, unwanted biological effects. Thus, our research goal is to block movement of breast cancer cells to spread through the body. Our present inability to address tumor cell spread, or metastasis, is a challenge to develop novel drug treatments based on our current understanding of the molecular processes involved. Finally, our research has added potential application of being able to detect a protein (LBP) present on breast cancer cells, thus offering both a method of early detection and identifying those tumors with a dangerous metastatic potential.


Final Report (2000)
Note: This grant was extended one year to complete the aims.

The goal of our project was to develop novel compounds that would serve to block the attachment and movement of breast cancer cells. These attachment/movement processes occur at a molecular level when proteins at the surface of breast cancer cells bind selectively to other protein constituents of the extracellular matrix. One protein component of the matrix of molecules that surround a cell is called laminin. Breast cancer cells attach to laminin using a specific laminin-binding protein (LBP). LBP expression correlates with progression of many solid tumors. Although laminin is a large protein, only a small part, called peptide 11, is involved in cell binding. This research program has been focused on, (i) the structure of peptide 11 as it is bound to LPB, (ii) analysis of this structure to suggest non-peptide compounds (called ‘mimetics’) that could duplicate the effect of peptide 11, and (iii) the synthesis and testing of one or more of these mimics. The expertise of three different research groups in two universities were combined for this research. Our collaborators are Dr. W. Todd Wipke at UCSC and Dr. Jean Starkey at Montana State University.

Studies of the backbone and side chain requirements for the activity of peptide 11 have been completed to the level necessary for mimic analysis. Further refinement of the solution structure of peptide 11 has been hampered by the important finding that the LBP protein had an unexpected enzyme activity, called sulphydryl oxidase, which served to dimerize the bound peptide. This discovery has led to further research on the possible mechanism of action of invasion. Several thousand possible synthetic targets have been generated by the INVENTON program of the Wipke group, and one of these with a particularly high similarity of structure to peptide 11, a compound known as candidate 16, was chosen for synthesis. That synthesis is underway and should be completed before the end of this year.

Future work will include completion of the synthesis of candidate 16 and full evaluation of this material as a mimic of peptide 11. In addition, continued exploration of the sulphhydryl oxidase activity of LBP and its role in the mechanism of action of cell invasion will likely lead to new insights to metastasis.
Phage display mapping for peptide 11 sensitive sequences binding to laminin-1
Periodical:Journal of Molecular Biology
Index Medicus: J Mol Biol
Authors: Kazmin DA, Hoyt TR, Taubner L, Teintze M, and Starkey JR
Yr: 2000 Vol: 298 Nbr: 3 Abs: Pg:431-445
Sidechain and backbone requirements for anti-invasive activity of laminin peptide 11
Periodical:Biochemica et Biophysica Acta
Index Medicus: Biochem Biophys Acta
Authors: Starkey JR, Dai S, and Dratz EA
Yr: 1998 Vol: 1429 Nbr: 1 Abs: Pg:187-207