Ocular melanoma is the most common primary eye cancer. Although the primary tumor in the eye can be controlled, frequent cancer spread to the liver results in significant mortality. There are currently no effective treatments for metastastic ocular melanoma in the liver. In the early/pre-metastatic stage of the disease, hypoxia induces the focal expression of chemokine/growth factor receptors in the eye tumor, rendering single melanoma cells responsive to activation by their respective paracrine ligands, stromal derived factor (SDF) and hepatocyte growth factor (HGF) produced in the liver. After extravasation into the circulation these cells home to the liver where they initially form micrometastatic foci that progress to dormant avascular colonies. In the late disease stage, an angiogenic switch leads to the formation of large hepatic macrometastases, which cause patient demise. We have discovered and characterized the anti-tumor properties of novel small molecule arylsulfonamides (ASAs), and obtained exciting preliminary data demonstrating that KCN1, our lead molecule, can potently decrease primary tumor growth, and the establishment and progression of hepatic metastases of uveal melanoma in an orthotopic mouse model we developed. We hypothesize that KCN1 alters the pro-tumorigenic signaling mediated by CXCR4/SDF and cMet/HGF that initiates metastasis, blocks STAT3 signaling involved in early progression in the liver and VEGF pro-angiogenic signaling that leads to macrometastasis, because Hypoxia Inducible Factor (HIF) can regulate these processes and KCN1 blocks HIF transcription. The goal of our proposal is to define the mechanism(s) underlying the anti-tumor effect of KCN1 at the different stages of disease progression. We will determine whether KCN1 inhibits i) the extravasation and survival of primary uveal melanoma cells into the circulation, and their homing to the liver (Aim 1), ii) the progression of micrometastatic foci to avascular melanoma cell colonies in the liver (Aim 2), and iii) the progression of avascular melanoma micrometastatic colonies to macrometastases in the liver by blocking micrometastases-induced angiogenesis (Aim 3). Our preliminary findings support our working hypothesis, as we demonstrate that KCN1 inhibits cMet cell surface receptor activation, STAT3 phosphorylation, and VEGF-mediated tumor angiogenesis in vivo. This work is important as it will better define the mechanisms of uveal melanoma metastases, identify therapeutic targeting points, and help the translation of the small molecules we identified towards becoming novel therapeutic agents for the control of metastasis of uveal melanoma.
In this study we will determine the molecular mechanisms responsible for the potent anti-tumor effects of arylsulfonamide KCN1 against uveal melanoma metastasis to the liver. This knowledge is important to improve our basic understanding of this disease in humans and use it to devise new targeted therapies, including furthering the development of the identified arylsulfonamides toward clinical testing.
|Osuka, Satoru; Van Meir, Erwin G (2017) Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Invest 127:415-426|
|Dai, Xin; Kaluz, Stefan; Jiang, Ying et al. (2017) A novel small-molecule arylsulfonamide causes energetic stress and suppresses breast and lung tumor growth and metastasis. Oncotarget 8:99245-99260|
|Ferguson, Jalisa; De Los Santos, Zeus; Devi, Narra et al. (2017) Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway. Bioorg Med Chem Lett 27:1731-1736|
|Kim, Yong Joon; Kaluz, Stefan; Mehta, Anil et al. (2017) Purifying Properly Folded Cysteine-rich, Zinc Finger Containing Recombinant Proteins for Structural Drug Targeting Studies: the CH1 Domain of p300 as a Case Example. Bio Protoc 7:|
|Yang, Hua; Brackett, Craig M; Morales-Tirado, Vanessa Marie et al. (2016) The Toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism. Oncotarget 7:2936-50|
|Grossniklaus, Hans E; Zhang, Qing; You, Shuo et al. (2016) Metastatic ocular melanoma to the liver exhibits infiltrative and nodular growth patterns. Hum Pathol 57:165-175|
|Halenda, Kevin M; Kudchadkar, Ragini R; Lawson, David H et al. (2016) Reduction of Nodular Growth Pattern of Metastatic Uveal Melanoma after Radioembolization of Hepatic Metastases. Ocul Oncol Pathol 2:160-5|
|Grossniklaus, Hans E; Geisert, Eldon E; Nickerson, John M (2015) Introduction to the Retina. Prog Mol Biol Transl Sci 134:383-96|
|Yang, Hua; Cao, Jinfeng; Grossniklaus, Hans E (2015) Uveal Melanoma Metastasis Models. Ocul Oncol Pathol 1:151-60|
|Luke, Jason J; Triozzi, Pierre L; McKenna, Kyle C et al. (2015) Biology of advanced uveal melanoma and next steps for clinical therapeutics. Pigment Cell Melanoma Res 28:135-47|
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