Zebrafish screen identifies novel compound with selective toxicity against leukemia

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Blood (Impact Factor: 10.45). 04/2012; 119(24):5621-31. DOI: 10.1182/blood-2011-12-398818
Source: PubMed


To detect targeted antileukemia agents we have designed a novel, high-content in vivo screen using genetically engineered, T-cell reporting zebrafish. We exploited the developmental similarities between normal and malignant T lymphoblasts to screen a small molecule library for activity against immature T cells with a simple visual readout in zebrafish larvae. After screening 26 400 molecules, we identified Lenaldekar (LDK), a compound that eliminates immature T cells in developing zebrafish without affecting the cell cycle in other cell types. LDK is well tolerated in vertebrates and induces long-term remission in adult zebrafish with cMYC-induced T-cell acute lymphoblastic leukemia (T-ALL). LDK causes dephosphorylation of members of the PI3 kinase/AKT/mTOR pathway and delays sensitive cells in late mitosis. Among human cancers, LDK selectively affects survival of hematopoietic malignancy lines and primary leukemias, including therapy-refractory B-ALL and chronic myelogenous leukemia samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for antineoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. Although our efforts focused on leukemia therapy, this screening approach has broad implications as it can be translated to other cancer types involving malignant degeneration of developmentally arrested cells.

Download full-text


Available from: Lance Batchelor,
  • Source
    • "The prostaglandin derivative dmPGE2, initially identified in zebrafish as a drug that increases the number of HSCs has been approved for phase I clinical trials to enhance engraftment of HSC transplantation in leukemia patients (Goessling et al., 2011; North et al., 2007). Another compound, lenaldekar (LDK), identified in a zebrafish small molecule screen for selective elimination of immature T cells, may be a new drug for treatment of T cell leukemia (Ridges et al., 2012). Interestingly, because multiple sclerosis involves an over-activation of T cells as well, they tested this new drug in an MS mouse model (EAE) showing a reduced disease severity due to prevention of expansion of the T-cell population (Cusick et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A major question in research on immune responses in the brain is how the timing and nature of these responses influence physiology, pathogenesis or recovery from pathogenic processes. Proper understanding of the immune regulation of the human brain requires a detailed description of the function and activities of the immune cells in the brain. Zebrafish larvae allow long-term, noninvasive imaging inside the brain at high-spatiotemporal resolution using fluorescent transgenic reporters labeling specific cell populations. Together with recent additional technical advances this allows an unprecedented versatility and scope of future studies. Modeling of human physiology and pathology in zebrafish has already yielded relevant insights into cellular dynamics and function that can be translated to the human clinical situation. For instance, in vivo studies in the zebrafish have provided new insight into immune cell dynamics in granuloma formation in tuberculosis and the mechanisms involving treatment resistance. In this review, we highlight recent findings and novel tools paving the way for basic neuroimmunology research in the zebrafish. GLIA 2014. © 2014 Wiley Periodicals, Inc.
    Glia 05/2015; 63(5). DOI:10.1002/glia.22780 · 6.03 Impact Factor
  • Source
    • "The authors identified several compounds that influenced the development of the central nervous system, altering its general morphology by significantly increasing the size of the hindbrain ventricle and producing tissue artifacts such as ‘sawtooth-like’ projections within the organ (Peterson et al., 2000). Subsequently a number of studies have demonstrated the utility of chemical screening in zebrafish embryos for identifying and evaluating the efficacy of potential anti-cancer agents (Murphey et al., 2006; Ridges et al., 2012; Yeh et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The current preclinical pipeline for drug discovery can be cumbersome and costly, which limits the number of compounds that can effectively be transitioned to use as therapies. Chemical screens in zebrafish have uncovered new uses for existing drugs and identified promising new compounds from large libraries. Xenotransplantation of human cancer cells into zebrafish embryos builds on this work and enables direct evaluation of patient-derived tumor specimens in vivo in a rapid and cost-effective manner. The short time frame needed for xenotransplantation studies means that the zebrafish can serve as an early preclinical drug screening tool and can also help personalize cancer therapy by providing real-time data on the response of the human cells to treatment. In this Review, we summarize the use of zebrafish embryos in drug screening and highlight the potential for xenotransplantation approaches to be adopted as a preclinical tool to identify and prioritize therapies for further clinical evaluation. We also discuss some of the limitations of using zebrafish xenografts and the benefits of using them in concert with murine xenografts in drug optimization.
    Disease Models and Mechanisms 07/2014; 7(7):745-754. DOI:10.1242/dmm.015784 · 4.97 Impact Factor
  • Source
    • "Zebrafish cancers are responsive to many of the same radiation and chemotherapies used to treat human cancer. Thus, it is not surprising that zebrafish have emerged as an important discovery tool for identifying novel drugs that modulate cancer growth (Yeh et al., 2009; Ridges et al., 2012; Le et al., 2013; Trede et al., 2013; Gutierrez et al., 2014). The most straightforward experiments to assess the effects of clonal heterogeneity on response to therapy will be to generate mosaic transgenic animals that bear tumors with genes of interest overexpressed or knocked out, and to screen for the emergence of therapy-resistant clones. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays.
    Disease Models and Mechanisms 07/2014; 7(7):755-762. DOI:10.1242/dmm.015842 · 4.97 Impact Factor
Show more