Lpath Inc. has developed a novel cancer therapeutic agent, ASONEPTM, a humanized monoclonal antibody, which neutralizes the tumorigenic and angiogenic growth factor, sphingosine-1-phosphate (S1P). S1P is an unusual target as it is a bioactive lipid. Thus ASONEP potentially represents a first-in-class anti-cancer agent. ASONEP is currently in Phase 1 trials for cancer. For this grant, we are requesting matching funds for clinical development and commercialization of ASONEP. Lpath has performed a comprehensive series of pre-clinical efficacy and pharmacokinetic studies to confirm the potential anti-cancer utility of the anti-S1P antibody. The neutralization of extracellular S1P mediated by the anti-S1P mAb could result in a marked decrease in cancer progression in humans as a result of inhibition of tumor proliferation and the growing vasculature needed to support tumor growth. Furthermore, recent research suggests that many angiogenesis inhibitors may also act as anti-invasive and anti-metastatic compounds which could also mitigate the spread of cancer to sites distant from the initial tumor. Up-regulation of the oncogene, sphingosine kinase 1 (sphk1) and the resulting release of S1P into the tumor microenvironment represents an important mechanism by which cancer cells acquire resistance to treatment as the cancer progresses. We hypothesize that overexpression of the SphK1 enzyme and the increased production and release of its product, S1P, could be responsible for resistance to cytotoxics and other treatments in a wide variety of cancer lineages. Using S1P as a biomarker and SphK1 as a surrogate marker, we believe that it may be possible to identify patients whose resistance can be attributed to an up-regulation of the S1P system. We will investigate whether sensitivity to therapy can be promoted in these patients with ASONEP in combination with standard treatments against which the patient has developed resistance as a consequence of S1P up-regulation. In moving towards commercialization, we will conduct one Phase 1b safety trial and one Phase 2a clinical trial in selected cancer types based on potential efficacy in the Phase 1 study and/or those demonstrating a promise of efficacy from preclinical and clinical biomarker studies. As requested by the FDA, a 13-week safety study in nonhuman primates will be completed prior to initiation of these Phase 2a studies. In support of the Phase 1b and 2a studies, we will also conduct a biomarker study designed to provide validation of sphingolipid-specific biomarkers (i.e. plasma S1P) and surrogate markers (e.g., tissue SphK1) to help aid in the selection of patients and cancer disease types where resistance to standard treatment may be attributed to an up-regulation of the S1P signaling system. Multivariate analysis will also be performed to assess the correlation of S1P-specific biomarkers/surrogate markers with other relevant signals that will be obtained from genomic and proteomic arrays of patient samples.
This aim will be used to support future Phase 0 biomarker studies not supported by the SBIR Bridge grant. As an additional specific aim of the project, we will conduct preclinical studies using animal xenografts and transgenic mouse models intending to demonstrate that acquired resistance to cytotoxics and other treatments could be reversed by anti-S1P treatment. Efficacy studies will determine whether the anti-S1P mAb treatment can re-establish sensitivity to treatment. These studies will be used in conjunction with the biomarker/surrogate marker studies to select primary indications for future Phase 2 efficacy trials.

Public Health Relevance

Cancer is a devastating disease and is the second leading cause of death in the US. This has resulted in an unprecedented R&D effort to discover, develop and market cancer therapeutics for the US government and pharmaceutical companies. Unfortunately the enormous amount of cancer research has not been enough to ameliorate the significant damage caused by cancer. There are still estimated to be 1.5 million new cases of cancer diagnosed in 2008 and over 565,000 deaths in the year 2008 in the US alone.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZCA1-SRRB-3 (J1))
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Andalibi, Ali
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Lpath Therapeutics, Inc.
San Diego
United States
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Zhang, Liang; Wang, Xiaoen; Bullock, Andrea J et al. (2015) Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer. Clin Cancer Res 21:1925-1934
Oskeritzian, Carole A; Hait, Nitai C; Wedman, Piper et al. (2015) The sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 axis regulates early airway T-cell infiltration in murine mast cell-dependent acute allergic responses. J Allergy Clin Immunol 135:1008-18.e1
Ader, Isabelle; Gstalder, Cécile; Bouquerel, Pierre et al. (2015) Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer. Oncotarget 6:13803-21
Sabbadini, Roger A (2011) Sphingosine-1-phosphate antibodies as potential agents in the treatment of cancer and age-related macular degeneration. Br J Pharmacol 162:1225-38
O'Brien, Nicole; Jones, S Tarran; Williams, David G et al. (2009) Production and characterization of monoclonal anti-sphingosine-1-phosphate antibodies. J Lipid Res 50:2245-57