G protein-coupled receptors (GPCRs) represent a diverse family of cell surface receptors that mediate important biological responses in nearly all cells. These responses include proliferation, migration, tissue invasion, and cell survival. As such, this large, ~700 member family represents the most attractive single family of drug targets for a variety of diseases including cancer. A great deal of work has been performed in an effort to generate specific pharmacologic antagonists for individual family members, but the success of this approach has been limited by their structural similarity. This has made it difficult to produce suitably selective compounds that are not complicated by off-target effects. One approach that offers the potential for unparalleled specificity is the development of monoclonal antibodies. However, GPCRs have historically been considered intractable to antibody antagonism due to poor antigenicity of critical, exposed, extracellular motifs that must be targeted to block receptor activation. Breast cancer is a physically and emotionally devastating diagnosis affecting over 2.3 million Americans living with the disease and killing over 100 women each day. Although the prognosis for this disease is gradually improving with the continued development of antineoplastic drugs, hormonal therapies, and targeted therapies, many aggressive forms of breast cancer are resistant to chemotherapy and result in a 10% mortality rate within 5 years of diagnosis. A compound known as sphingosine 1-phosphate (S1P) may be a major determinant of the aggressiveness and drug resistance of breast cancer. S1P is a small molecule normally present in high concentrations in the blood that accelerates the progression of breast cancer. It does this by promoting the growth and spreading of cancer cells and by stimulating the formation of new blood vessels, thereby increasing the supply of oxygen and nutrients to the tumor. Evidence suggests that these actions are largely the result of the stimulation of a cognate GPCR for S1P called S1P3. Since S1P has been shown to promote growth of breast cancer cells, and since it causes blood vessels to grow uncontrollably in tumors, it is likely that blocking S1P3 will inhibit the growth of most forms of breast cancer. Animal studies suggest that loss of this receptor is not associated with undesirable effects, providing evidence for the safety of this approach. Until recently, however, there were no reports of any specific antagonists for S1P3. Our previous work (1R43CA132400) resulted in the development of a monoclonal antibody that specifically recognizes S1P3 and blocks its activation. Since this is the first-reported antibody to block a non-cytokine GPCR, it represents a breakthrough in antibody drug development. The goals of this project are to 1) quantitatively validate the functional efficacy of this antibody, and 2) demonstrate its activity and bioavailability in vivo.
Breast cancer is the second most common form of cancer in women causing the death of over 35,000 Americans each year. The proposed research will characterize a new drug developed at Expression Drug Designs that interrupts cellular processes known to promote growth of breast tumors, thus limiting cancer growth. Completion of the proposed project will determine if this new drug is likely to be effective in treating breast tumors.
| Harris, Greg L; Creason, Michael B; Brulte, Greg B et al. (2012) In vitro and in vivo antagonism of a G protein-coupled receptor (S1P3) with a novel blocking monoclonal antibody. PLoS One 7:e35129 |
| Herr, Deron R (2012) Potential use of G protein-coupled receptor-blocking monoclonal antibodies as therapeutic agents for cancers. Int Rev Cell Mol Biol 297:45-81 |
