Ovarian cancer is associated with a poor overall survival due to the advanced stage of the disease at the time of diagnosis and the high incidence of acquired resistance to standard treatments. Identification of the major determinants of ovarian cancer progression and the development of more efficacious treatments still remain challenging. Lysophosphatidic acid (LPA) has been associated with multiple aspects of ovarian cancer biology including malignant transformation of ovarian epithelium, tumor progression and metastasis. In ovarian tumorigenesis, LPA receptors profiling changes dramatically and the aberrant overexpression of two of those ones, LPA2 and LPA3, is associated to the passage from the benign to the malignant stage of the pathology. LPA induces VEGF upregulation, activation of metalloproteinases (MMP), overexpression of growth factor receptors, and production of both pro-angiogenic and pro-metastatic cytokines such as interleukin-8 (IL-8) and interleukin-6 (IL-6). LPA not only modulates tumor cell responses but also influences cellular and molecular cross- talk among cancer cells, stroma, vascular and extracellular matrix components present in the tumor microenvironment. LPA is elevated in sera and ascites fluid of patients with early and late stage disease. Based on this evidence, LPA and its signaling network represent attractive molecular and cellular targets for rational drug discovery in the treatment of ovarian cancer. We have developed a humanized monoclonal antibody that specifically recognizes LPA, designated as LT3015, and neutralizes biological actions of the lipids on its cognate GPCRs. We hypothesize that our anti-LPA antibody could be used as a molecular sponge to selectively absorb LPA, thus lowering the effective extracellular levels of this tumorigenic, pro-angiogenic and metastatic agent in the tumor microenvironment. It is anticipated that neutralizing LPA would result in the reduction of tumor weights and metastatic potential as well as blocking the neovascularization that would otherwise feed the growing tumor. We also hypothesize that the ability of LPA to protect cells from apoptosis could be reversed by the anti-LPA mAb, thus increasing the efficacy of standard pro-apoptotic chemotherapeutic agents. Preliminary studies with the murine anti-LPA antibody, Lpathomab, have shown efficacy tested in a panel of relevant in vitro assays using the ovarian cell line SKOV3. Lpathomab blocked tumor cell migration and invasion triggered by LPA, reduced cytokines release in tumor conditioned media, and blocked LPA mediated protection from apoptosis triggered by the chemotherapeutic drug, taxol. More importantly, Lpathomab retarded the progression of orthotopically placed SKOV3 tumor cells, reduced neovascularization in two classical angiogenic models (Matrigel plug and choroid neovascularization models) and showed preliminary anti-metastatic activity when tested in the B16-F10 melanoma metastasis model. For this proposal, we intend to demonstrate the efficacy of the humanized anti-LPA mAb, designated as LT3015, alone and in combination with the standard chemotherapeutic agent, Taxol, in a murine model of human ovarian cancer (SKOV3). We will determine the optimal dosing regimen for LT3015 to inhibit ovarian cancer progression as well as ovarian tumor metastasis by using a well established LPA2 receptor overexpressing-SKOV3 metastasis model. In moving towards commercialization of LT3015, we will perform toxicology and pharmacokinetics studies to determine the suitability of LT3015 as a clinical drug candidate. In view of these results, we hypothesize that the anti-LPA antibody-based neutralization of LPA may offer the potential to augment the efficacy of current ovarian cancer therapy by blocking the growth-promoting, angiogenic and metastatic effects of LPA generated either by ovarian cancer cells or the tumor microenvironment.
Public Health Relevance: Cancer is a devastating disease, with the second highest mortality in the US. As described in the Cancer Trends Report update 2007, the incidences of cancers such as liver, pancreas, kidney, thyroid, brain, bladder and skin melanoma as well as new cases of non-Hodgkin lymphoma, leukemia, myeloma, and childhood cancers have continue to rise in past years. Late state of disease at the first diagnosis, resistance to standard treatment, relapsing cases and, finally, tumor metastasis represent the major problems occurring in the treatment of cancer patients. In particular, once the disease becomes metastatic, survival rates drop significantly due to a lack of effective therapy. Thus, urgent needs exist for novel anti-cancer therapies that will improve quality of life as well as offering a potential cure. Discovering the major determinants in cancer progression for the development of more efficacious therapies is therefore extremely important to society.
