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.
|Ling, Hui; Pickard, Karen; Ivan, Cristina et al. (2016) The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis. Gut 65:977-89|
|Kim, Sun-Hee; Hashimoto, Yuuri; Cho, Sung-Nam et al. (2016) Microsomal PGE2 synthase-1 regulates melanoma cell survival and associates with melanoma disease progression. Pigment Cell Melanoma Res 29:297-308|
|Oba, Junna; Wei, Wei; Gershenwald, Jeffrey E et al. (2016) Elevated Serum Leptin Levels are Associated With an Increased Risk of Sentinel Lymph Node Metastasis in Cutaneous Melanoma. Medicine (Baltimore) 95:e3073|
|Van Roosbroeck, Katrien; Fanini, Francesca; Setoyama, Tetsuro et al. (2016) Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clin Cancer Res :|
|Roszik, Jason; Haydu, Lauren E; Hess, Kenneth R et al. (2016) Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set. BMC Med 14:168|
|Paladini, Laura; Fabris, Linda; Bottai, Giulia et al. (2016) Targeting microRNAs as key modulators of tumor immune response. J Exp Clin Cancer Res 35:103|
|Siiskonen, Satu J; Zhang, Mingfeng; Li, Wen-Qing et al. (2016) A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants. Cancer Epidemiol Biomarkers Prev 25:714-20|
|Roszik, Jason; Wu, Chang-Jiun; Siroy, Alan E et al. (2016) Somatic Copy Number Alterations at Oncogenic Loci Show Diverse Correlations with Gene Expression. Sci Rep 6:19649|
|Vaysse, Amaury; Fang, Shenying; Brossard, Myriam et al. (2016) A comprehensive genome-wide analysis of melanoma Breslow thickness identifies interaction between CDC42 and SCIN genetic variants. Int J Cancer 139:2012-20|
|Han, Jun; Walters, James T R; Kirov, George et al. (2016) Gender differences in CNV burden do not confound schizophrenia CNV associations. Sci Rep 6:25986|
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