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. 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]-iso-quinolin-5-yl)-6,7-dimethoxylsobenzofuran-1(3H)-one (EM011), has potent antiangiogenic activity
(based upon NCI-DTP antiangiogenic drug screen). 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 depolymerization
of MTs) with concomitant antiangiogenic effects. The specific aims for the mentored phase
were: Aim 1. Evaluation of the antiangiogenic efficacy of EM011. Aim 2. Determination of EM011's effect on
the dynamic instability of MTs, HIF-1alpha expression and transactivation of downstream targets such as
VEGF. We have successfully accomplished the proposed research in the K99 phase. Based upon the nontoxic
attributes of EM011, we rationalize that combination of EM011 with other angiogenic inhibitors that
function through independent mechanisms but show toxicity at their maximum tolerated doses (MTDs),
presents a unique opportunity to reduce their doses to maximize therapeutic outcomes with decreased
toxicity. The ROO phase of the project will focus on 2 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. |