Alpha-fetoprotein (AFP), a protein produced by the fetal liver, is one of the agents of pregnancy that affords significant reduction in risk of acquiring breast cancer to women who experience term pregnancy. AFP stops the growth of estrogen-dependent human breast cancer xenografts. It is non-toxic, and its mechanism of action is different from that of agents currently used in the clinic to treat breast cancer. We have designed a novel cyclic synthetic peptide, AFPep, which mimics the anti-oncotic active site of AFP. AFPep inhibits the growth of T47D breast cancer cells in culture and inhibits the growth of MCF-7 human breast cancer growing as xenografts in mice. AFPep has a novel mechanism (i.e., is different from tamoxifen and does not bind to the estrogen receptor), and it blocks tamoxifen-stimulated uterine growth. Proof-of-principle data exist to suggest that AFPep can prevent breast cancer in a rat model. The Iong-term objective of the research program is to develop AFPep (or peptidomimetic analogs of AFPep) for use in the treatment and prevention of breast cancer in women. The hypothesis of this proposal is that administration of AFPep (or peptidomimetic analogs) in combination with tamoxifen to carcinogen (NMU) treated rats will augment cancer chemoprevention efficacy and reduce host toxicity compared to that of tamoxifen alone.
The specific aims are: 1.) To compare the ability of AFPep, and that of tamoxifen, to prevent NMU-induced breast cancer in the rat model; 2.) To develop orally active analogs of AFPep (peptidomimetics) and test prevention capability in the rat model; and 3.) To assess safety of the peptide and analogs by obtaining preliminary toxicity measurements. The research design is to use a well-documented assay in which carcinogen-induced rats are treated with vehicle, AFPep, tamoxifen, or AFPep plus tamoxifen. Endpoints will include tumor latency (increased time to first tumors) and tumor burden (decreased incidence) for efficacy, and decreased uterotrophic response to tamoxifen for host toxicity. Health related aspects of the proposal include the observation that there is need for additional agents, with novel mechanisms of action, for the prevention of estrogen-receptor positive breast cancer. The need is emphasized by the observation that currently used chemopreventives for breast cancer are not without adverse side effects. AFPep has the potential to be used in combination with tamoxifen or as a stand-alone preventive agent. Its development and introduction to the clinic could prevent as many as 50,000 cases of breast cancer every year.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102540-04
Application #
7065992
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Perloff, Marjorie
Project Start
2003-06-13
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$308,960
Indirect Cost
Name
Albany Medical College
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
Bryan, Alberto; Joseph, Leroy; Bennett, James A et al. (2011) Design and synthesis of biologically active peptides: a 'tail' of amino acids can modulate activity of synthetic cyclic peptides. Peptides 32:2504-10
Shields, George C (2009) Computational approaches for the design of peptides with anti-breast cancer properties. Future Med Chem 1:201-12
Tower, Amanda M; Trinward, Andrea; Lee, Katie et al. (2009) AFPep, a novel drug for the prevention and treatment of breast cancer, does not disrupt the estrous cycle or fertility in rats. Oncol Rep 22:49-56
Joseph, Leroy C; Bennett, James A; Kirschner, Karl N et al. (2009) Antiestrogenic and anticancer activities of peptides derived from the active site of alpha-fetoprotein. J Pept Sci 15:319-25
Andersen, T T; Georgekutty, J; Defreest, L A et al. (2007) An alpha-fetoprotein-derived peptide reduces the uterine hyperplasia and increases the antitumour effect of tamoxifen. Br J Cancer 97:327-33
Kirschner, Karl N; Lexa, Katrina W; Salisburg, Amanda M et al. (2007) Computational design and experimental discovery of an antiestrogenic peptide derived from alpha-fetoprotein. J Am Chem Soc 129:6263-8
Bennett, James A; DeFreest, Lori; Anaka, Ikenna et al. (2006) AFPep: an anti-breast cancer peptide that is orally active. Breast Cancer Res Treat 98:133-41
Parikh, Rahul R; Gildener-Leapman, Neil; Narendran, Amithi et al. (2005) Prevention of N-methyl-N-nitrosourea-induced breast cancer by alpha-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP. Clin Cancer Res 11:8512-20
DeFreest, L A; Mesfin, F B; Joseph, L et al. (2004) Synthetic peptide derived from alpha-fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization. J Pept Res 63:409-19