Angiogenesis, necessary for tumor growth involves cell proliferation and directed migration. Thus, there is clearly a crucial role of cytoskeletal microtubule (MT) dynamics in angiogenesis;linking perturbations of MT dynamics to inhibition of tumor angiogeneisis. Furthermore, the PI3K/Akt survival pathway regulates HIF-la expression and activity. Our preliminary data strongly suggest that a semisynthetic tubulin-binding anticancer~ agent,(S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo[4,5-g]-isoquinolin-5-yl)-6,7-dimethoxyisobenzofuran-1(3H)-one (EM011), has potent antiangiogenic activity (based upon NCI-DTP antiangiogenic drug screen). We also demonstrated that EM011 inhibits the P13K/Akt pathway through dephosphorylation of Akt. Our hypothesis is that EM011 will serve as an effective anticancer agent since it can target the MT cytoskeleton without causing any gross effects (over- or de- polymerization of MTs) with concomitant antiangiogenic effects.
The specific aims for the mentored phase are:
Aim 1. Evaluation of the antiangiogenic efficacy of EM011. This will be accomplished by a) measuring its ability to prevent invasion and migration of endothelial cells, b) determining its effect on protrusion and proliferation of microvessels by tubular morphogenesis assays, ex vivo explant cultures, and the chick chorloallantoic membrane (CAM) assay, c) evaluating EM011's ability to inhibit cellular proliferation, affect cell-cycle progression, and to induce apoptosis in endothelial cells.
Aim 2. Determination of EM011's effect on the dynamic instability of MTs, HIF-1a expression and transactivation of downstream targets such as VEGF. We will also determine if EM011-medlated inhibition of Pl3KIAkt regulates HIF-1a expression and its transcriptional activation capability. Equally important, our preliminary data show that EM011 does not cause any hematologic, immunologic and neuronal toxicity. Based upon Its non-toxic attributes, we rationalize that combination of EM011 with other angiogenic inhibitors that function through independent mechanisms but show toxicity at their maximum tolerated doses (MTD5), presents a unique opportunity to reduce their doses to maximize therapeutic outcomes with decreased toxicity. The independent phase of the project will thus focus on the following two aims:
Aim 3. Investigation of potential synergistic antiproliferative and antiangiogenic effects of combinations of EM011 and ZD6474 (a tyrosine kinase inhibitor), or thalidomide (endothelial cell proliferation inhibitor) in breast (MDA-MB-231) and prostate (PC-3) cancer cells.
Aim 4. Determination of the in vivo efficacy of EM011 and its synergistic combinations with ZD6474 or thalidomide, as inhibitors of experimental primary and metastatic breast and prostate cancers in real-time using non-invasive bioluminescent imaging, As a practical and translational approach, the long-range goal of these studies would be to define and establish the usefulness of EM011 alone, and its synergistic combinations with other drugs, for remission of human breast and prostate cancers without compromising the quality of life.
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