Melanoma is a potentially lethal neoplasm with, a propensity for acquiring the metastatic phenotype. The molecular basis for this acquisition is not very well defined and few treatment modalities are available for this neoplasm at advanced stages. Recently, we reported that one of the genes that stands out as differentially expressed in highly, metastatic melanoma cells as compared to non-metastatic cells, is the thrombin receptor PAR-1, which promotes metastases through multiple mechanisms including angiogenesis, cell signaling, and adhesion, in large part via upregulation of IL-8. Our preliminary data indicated that PAR-1 silencing by short hairpin'RNA (shRNA) in.metastatic melanoma cells inhibited their growth and metastatic potential in vivo. In this proposed study, we will advance this work to the translational phase by pursuing inhibition of PAR-1 as well as the presumed less toxic IL-8 via siRNA encapsulated in neutral liposomes to induce tumor regression in model systems. In addition, results from oUr laboratory have demonstrated that expression of the angiogenic factor interieukin 8 (IL-8), which is itself upregulated through PAR-1 signaling, correlates with the metastatic potential of melanoma cells. Moreover, using a fully human neutralizing antibody against IL-8 (ABX-IL8 which is not available for clinical use), we were able to inhibit tumor growth and metastasis of melanoma in vivo. Our hypothesis is that intravenous administration of IL-8 small interfering RNA (siRNA) packaged in neutral liposomes will cause downregulation of IL-8 /'nwVo, thereby inhibiting melanoma growth and metastasis. We will also evaluate the therapeutic strategy in melanoma patients. To these ends, we propose the following Specific Aims:
Specific Aim 1 : To evaluate the iri vivo effects of PAR-1 siRNA pacltaged in neutral liposomes as a possible therapeutic modality for advanced melanoma alone and/or in combination with chemotherapy.
Specific Aim 2 : To evaluate the in vivo effects of IL-8 siRNA packaged in neutral liposomes as a new therapeutic modality for advanced melanoma alone and/or in combination with chemotherapy.
Specific Aim 3 : To evaluate the safety and efficacy of IL-8 siRNA packaged in neutral liposomes (IL-8 siRNA-DOPC) in a Phase I clinical trial. This is the first attempt at using nanotechnology as a therapeutic modality for advanced melanoma.
Current therapeutic modalities for melanoma are limited and have been disappointing. We propose to perform preclinical studies employing |L-8 siRNA encapsulated in 1,2-dioleoyl-sn-glycero-3- phosphatidylcholine (DOPC) liposomes. Our aim is to translate the preclinical findings into a Phase I clinical trial in year 3 to test the safety and clinical activity, as well as to evaluate surrogate markers of treatment effect in patients with metastatic melanoma. This research will rapidly develop a new treatment for metastatic melanoma by using siRNA-encapsulated nanoparticles alone and/or in combination with chemotherapy.
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