The identification of signaling components that promote tumor growth is a critical step toward discovering therapeutic interventions for reducing cancer's morbidity and mortality and generally improving patient outcomes. Research has demonstrated the sphingosine kinase (SPHK) is a recently validated oncogene that produces an extracellular sphingolipid signaling molecule, sphingosine-l-phosphate (S1P), that promotes tumor growth. Tumor growth is promoted both directly and indirectly by S1P's growth factor actions related to tumor cell proliferation and metastasis, as well as S1P's pro-angiogenic effects. Medlyte has produced a monoclonal anti-SiP antibody (anti-SIP mAb) that could be used as a therapeutic molecular sponge to selectively neutralize S 1P, thus lowering extracellular concentrations of this tumor growth factor with the anticipated reduction in tumor volume and metastatic potential as well as simultaneously blocking new blood vessel formation that would, otherwise, feed the growing tumor. Accordingly in Phase I of the proposed work, our project goal is to evaluate the therapeutic potential of our anti-S 1P monoclonal antibodies. In accomplishing this goal, we will test Medlyte's anti-S1P mAb's ability to reduce SIP dependent cell proliferation and metastatic potential in several tumor-derived cell lines. We also intend to test ability of anti-S1P mAbs to reduce S1P-dependent angiogenesis in a Matrigel angiogenesiss assay using HUVECs in vitro as well as an in vivo plug assay. Importantly, we will us the Xenograft SCID model for in vivo testing of anti-S 1P mAb's ability to reduce tumor growth. Accomplishing these aims will demonstrate that the Medltye's anti-S 1P mAb is an effective therapeutic in the treatment of cancer in animal models. The anticipated success of the proposed initial pre-clinical work will lead to more intensive pre-clinical testing for safety and efficacy planned for Phase 2. The ultimate goal of the Phase 2 research is to develop humanized anti-S1P mAbs that can be taken to Phase 1 Clinical Trials for comparison with the anthracycline anti-neoplastic agents. Further, the anti-S1P mAb will be developed as an in vitro diagnostic tool to define the minimum dosage for optimum therapeutic efficacy. While therapeutic antibodies are not generally regarded as toxic, the theranostics approach will improve patient safety in our planned clinical trials. Importantly, the pathway of getting our putative therapeutic antibody to market will be much shorter than the conventional small molecule drug discovery approach.
| Visentin, Barbara; Vekich, John A; Sibbald, Bradley J et al. (2006) Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9:225-38 |
