Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics.
Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics.
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DOI：
10.18632/oncotarget.9613
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Hurlstone AF
中科院分区：
文献类型：
--
作者：
Fernandez Del Ama L;Jones M;Walker P;Chapman A;Braun JA;Mohr J;Hurlstone AF
通过绕过基于靶点的方法的靶点识别瓶颈和通过对已经在临床中的药物进行采样，对已批准的药物分子进行表型引导的重新分析为开发抗癌疗法提供了加速途径。此外，可以筛选掺入靶向疗法的组合的功效和毒性。以前，我们已经开发了一个致癌RAS驱动的斑马鱼黑色素瘤模型，我们现在描述显示黑素细胞增生，而仍然是胚胎。在设计了一种快速定量黑素细胞负荷的方法后，我们表明，这种表型可以通过将V12 RAS转基因胚胎与MEK或PI 3 K/mTOR的有效和选择性小分子抑制剂一起孵育来化学抑制。此外，我们证明了MEK抑制剂（MEKi）与双重PI 3 K/mTOR抑制剂（PI 3 K/mTORi）的组合导致黑素细胞增生的超加性抑制。我们的新型筛选测定的稳健性和简单性启发我们对FDA批准的化合物进行适度筛选，以确定其增强MEKi PD 184352或PI 3 K/mTORi NVPBEZ 235对V12 RAS驱动的黑素细胞增生的抑制的能力。通过这种途径，我们证实雷帕霉素是一种可以与MEKi协同作用的化合物，甚至与PI 3 K/mTORi协同作用，以抑制黑色素瘤的发展，包括抑制培养的人黑色素瘤细胞的生长。此外，我们发现了另外两种化合物-双硫仑和丹参酮-也与MEKi合作抑制转化的斑马鱼黑素细胞的生长，并对培养的人黑色素瘤细胞显示出活性。总之，我们提供了概念验证，我们的表型指导筛选可用于识别影响黑色素瘤发展的化合物，并提示进一步评估双硫仑和丹参酮作为联合治疗的可能合作伙伴。
Phenotype-guided re-profiling of approved drug molecules presents an accelerated route to developing anticancer therapeutics by bypassing the target-identification bottleneck of target-based approaches and by sampling drugs already in the clinic. Further, combinations incorporating targeted therapies can be screened for both efficacy and toxicity. Previously we have developed an oncogenic-RAS-driven zebrafish melanoma model that we now describe display melanocyte hyperplasia while still embryos. Having devised a rapid method for quantifying melanocyte burden, we show that this phenotype can be chemically suppressed by incubating V12RAS transgenic embryos with potent and selective small molecule inhibitors of either MEK or PI3K/mTOR. Moreover, we demonstrate that combining MEK inhibitors (MEKi) with dual PI3K/mTOR inhibitors (PI3K/mTORi) resulted in a super-additive suppression of melanocyte hyperplasia. The robustness and simplicity of our novel screening assay inspired us to perform a modest screen of FDA approved compounds for their ability to potentiate MEKi PD184352 or PI3K/mTORi NVPBEZ235 suppression of V12RAS-driven melanocyte hyperplasia. Through this route, we confirmed Rapamycin as a compound that could synergize with MEKi and even more so with PI3K/mTORi to suppress melanoma development, including suppressing the growth of cultured human melanoma cells. Further, we discovered two additional compounds—Disulfiram and Tanshinone—that also co-operate with MEKi to suppress the growth of transformed zebrafish melanocytes and showed activity toward cultured human melanoma cells. In conclusion, we provide proof-of-concept that our phenotype-guided screen could be used to identify compounds that affect melanoma development and prompt further evaluation of Disulfiram and Tanshinone as possible partners for combination therapy.
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Tanshinones：来源，药代动力学和抗癌活动。
影响因子：
5.6
作者：
Zhang Y;Jiang P;Ye M;Kim SH;Jiang C;Lü J
通讯作者：
Lü J
影响因子：
46.9
作者：
Lehar, Joseph;Krueger, Andrew S.;Avery, William;Heilbut, Adrian M.;Johansen, Lisa M.;Price, E. Roydon;Rickles, Richard J.;Short, Glenn F., III;Staunton, Jane E.;Jin, Xiaowei;Lee, Margaret S.;Zimmermann, Grant R.;Borisy, Alexis A.
通讯作者：
Borisy, Alexis A.
影响因子：
50.3
作者：
Herrero, Ana;Pinto, Adan;Crespo, Piero
通讯作者：
Crespo, Piero
影响因子：
10.3
作者：
Meier, F.;Busch, S.;Schittek, B.
通讯作者：
Schittek, B.
MTOR抑制剂在肝细胞癌中的回归，基因表达的逆转和自噬协同。
影响因子：
17.1
作者：
Thomas HE;Mercer CA;Carnevalli LS;Park J;Andersen JB;Conner EA;Tanaka K;Matsutani T;Iwanami A;Aronow BJ;Manway L;Maira SM;Thorgeirsson SS;Mischel PS;Thomas G;Kozma SC
通讯作者：
Kozma SC