ZIA BC 010789 (ZIA) | |||
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Title | Pathophysiologic Consequences of Neurotrophin Activation of Trk in Neuroblastoma | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Thiele, Carol | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $310,725 | Project Dates | 10/01/2006 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Childhood Cancers (100.0%) Taxol (10.0%) |
Central Nervous System - Not Including Brain (10.0%) Nervous System (100.0%) Neuroblastoma (90.0%) |
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Research Type | |||
Cancer Progression and Metastasis Localized Therapies - Discovery and Development |
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Abstract | |||
Aim 1. To investigate biologic consequences of PI-3Kinase/AKT activation on NB tumor biology Inhibition of AKT pathway in neuroblastoma inhibits tumor cell growth in vitro and in vivo. Our previous studies have identified activation of the PI3Kinase/Akt/GSK3 pathway mediates resistance to chemotherapy in neuroblastoma cells. Moreover our genetic and pharmacologic studies indicated that activation of AKT alone attenuated the effects of chemotherapy in neuroblastoma cells. Since activated AKT is more highly expressed in tumors of Neuroblastoma patients with a poor prognosis, we screened a number of inhibitors of the AKT that could enhance the efficacy of chemotherapy in our pre-clinical in vitro models. We focused on the AKT inhibitor, Perifosine, because it is Phase I/II trials in adult cancers, with a toxicity profile that is controllable with systemic therapy. Perifosine was tested in a number of our pre-clinical in vitro models as well as our in vivo murine heterotypic and orthotopic xenograft models. Perifosine inhibits activation of AKT and more impressively inhibits tumor cell growth in all 4 cell line models tested in vitro and in vivo. In the AS neuroblastoma model system there was complete tumor regression. In the least sensitive model, the addition of chemotherapy with Perifosine caused dramatic tumor regressions. Moreover Perifosine inhibited the growth of NB tumors containing ALK mutations, even those with the ALKF1174L mutation, which are less sensitive to some small molecule inhibitors of ALK. While studies from the Brodeur lab have shown that it is reasonable to pursue inhibition of the TrkB receptor as an adjunct to therapy, the use of an Akt inhibitor would be valuable in combination or following receptor targeted therapy since targeting receptors may cause activation of AKT due to feedback suppression. Moreover, targeting AKT inhibits a key survival signaling node used not only by TrkB but by other membrane receptors shown to enhance NB cell survival such as IGF1R, IL-6 receptors and VEGFR. By targeting a common downstream signal intermediary, one covers a broader spectrum of signaling pathways that use this common intermediary to affect biologic function. While we initiated studies using Perifosine as an AKT inhibitor, we knew Akt was not its only target. To more directly assess the contribution of AKT to our models, we established an MTA with Merck to study their AKT inhibitor MK2206. This is an allosteric AKT inhibitor which acts by specifically binding to the PH domain of AKT thus preventing its binding to phosphatidylinositol-3,4,5-trisphosphate. There is differential inhibition of AKTisoforms; IC50-Akt1=5.3nM, -Akt2=12nM and -Akt3=65nM. We find MK2206 inhibits AKT activity as assessed by inhibition of phosphorylation of downstream target S6 kinase in the pharmacologic range but the growth of only 3/9 NB cell lines tested is inhibited within this range. In this study, we investigated whether a novel allosteric Akt inhibitor MK-2206 increased the sensitivity of NB to etoposide or rapamycin. Here we showed that in vitro, a synergistic effect was detected in combination of MK-2206 with etoposide through apoptosis, and MK-2206 enhanced the sensitivity to rapamycin via reactive oxygen species; in vivo, a significant increased anti-tumor growth effect and murine survival advantage were observed in the combination of MK-2206 with etoposide or rapamycin. This study provides the basis for the combination use of molecular targeted drug of Akt with other treatment regimens in NB or other cancers with aberrant Akt activation and has important clinical implications. These studies provide proof of principle that targeting Akt alone will inhibit neuroblastoma cell growth and will synergize with cytotoxics such as etoposide or mTOR inhibitors. Recently the Pediatric Phase I study of Perifosine showed activity in neuroblastoma. Based on our pre-clinical study and the Phase I results the FDA approved Perifosine for Orphan " |