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Updated: Mar 20, 2026
Screening for Melanoma Modifiers using a Zebrafish Autochthonous Tumor Model
Published on: November 13, 2012
Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics
Laura Fernandez Del Ama1, Mary Jones1, Paul Walker1
1Faculty of Life Sciences, The University of Manchester, Manchester, UK.
Abstract:
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.
Insights
This study introduces a novel zebrafish melanoma model to screen existing drugs for cancer therapy. Researchers identified Rapamycin, Disulfiram, and Tanshinone as promising compounds that synergize with MEK inhibitors to suppress melanoma growth.
Area of Science:
- Oncology
- Pharmacology
- Zebrafish models
Background:
- Phenotype-guided drug re-profiling accelerates anticancer therapeutic development by bypassing target identification.
- Approved drugs offer a faster route to clinical application, with potential for combination therapies.
- An oncogenic-RAS-driven zebrafish melanoma model was developed to study melanocyte hyperplasia.
Purpose of the Study:
- To establish and validate a phenotype-guided screening assay using a zebrafish melanoma model.
- To identify FDA-approved compounds that can synergize with MEK inhibitors (MEKi) or PI3K/mTOR inhibitors (PI3K/mTORi) in suppressing melanoma.
- To evaluate the efficacy of identified compounds in combination therapies for melanoma.
Main Methods:
- Developed a rapid method to quantify melanocyte burden in V12RAS transgenic zebrafish embryos.
- Screened FDA-approved compounds for their ability to potentiate MEKi (PD184352) or PI3K/mTORi (NVPBEZ235) in suppressing V12RAS-driven melanocyte hyperplasia.
- Assessed the synergistic effects of drug combinations (MEKi + PI3K/mTORi) on melanoma suppression and tested efficacy on cultured human melanoma cells.
Main Results:
- Combined MEK inhibitors and PI3K/mTOR inhibitors demonstrated super-additive suppression of melanocyte hyperplasia.
- Rapamycin was confirmed to synergize with MEKi and PI3K/mTORi, suppressing melanoma development and human melanoma cell growth.
- Disulfiram and Tanshinone were identified as compounds that cooperate with MEKi to suppress zebrafish melanocyte growth and showed activity against human melanoma cells.
Conclusions:
- The phenotype-guided screening assay is effective for identifying compounds that impact melanoma development.
- Disulfiram and Tanshinone show potential as combination therapy partners for melanoma treatment.
- Further evaluation of Disulfiram and Tanshinone is warranted for their application in melanoma therapy.
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