Screening for Anti‐cancer Drugs in Drosophila

Abstract

The vinegar fly, Drosophila melanogaster, has been a cornerstone of genetic analysis and cell and developmental biology research for over 100 years. Within the last decade, Drosophila is making its mark in translational research in its utilisation in modelling human diseases and in screens for small molecule inhibitors. In particular, its use in modelling cancer development and in identifying anti‐cancer therapeutics is beginning to make an important contribution to the current drug discovery pipeline, which to date has been only poorly successful in delivering drugs, identified in vitro, into the clinic for anti‐cancer therapy. The primary advantages of the Drosophila system for use in anti‐cancer drug screening are the conservation of cancer genes/pathways between flies and mammals, its suitability for rapid phenotypic screening of chemicals for anti‐cancer effects in vivo in a high‐throughput and cost‐effective manner and its use in identifying drugs that can specifically target tumours in vivo.

Key Concepts

  • The current drug screening pipeline has been only poorly efficient in progressing anti‐cancer drugs to the clinic because of differences between in vitro and in vivo systems
  • Drosophila melanogaster is an excellent model organism for cost‐effective high‐throughput in vivo screening for anti‐cancer compounds relevant to human cancer
  • Drosophila larvae or adults can be readily screened in a high‐throughput manner for the effect of orally administered compounds on a particular phenotype using phenotypic or fluorescent read‐outs
  • Drosophila models of cancer used for chemical screens include those generated by expression of cancer‐causing genes, whole animal synthetic lethality with radiation and specific cancer phenotypes
  • Biological and technical limitations of Drosophila might restrict the discovery of compounds and their translation into the clinic
  • Screening of orally administered drugs in flies has already proven to be successful in identifying new compounds or FDA‐approved compounds for use in cancer therapy

Keywords: Drosophila; chemical screening; anti‐cancer drugs; cancer; signalling pathways; multiple endocrine neoplasia type 2; polypharmachological compounds; glutamate utilisation inhibitors; translational inhibitors; combination therapy

Figure 1. Chemical screening in models of cancer.
Figure 2. Post screen – mechanism, drug refinement and translation to the clinic.
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References

Acharyya S, Oskarsson T, Vanharanta S, et al. (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150: 165–178.

Ahluwalia GS, Grem JL, Hao Z and Cooney DA (1990) Metabolism and action of amino acid analog anti‐cancer agents. Pharmacology and Therapeutics 46: 243–271.

Anuradha A, Annadurai RS and Shashidhara LS (2007) Actin cytoskeleton as a putative target of the neem limonoid Azadirachtin A. Insect Biochemistry and Molecular Biology 37: 627–634.

Barker N and Clevers H (2006) Mining the Wnt pathway for cancer therapeutics. Nature Reviews Drug Discovery 5: 997–1014.

Bell GP and Thompson BJ (2014) Colorectal cancer progression: lessons from Drosophila? Seminars in Cell & Developmental Biology 28: 70–77.

Bernards A and Hariharan IK (2001) Of flies and men‐‐studying human disease in Drosophila. Current Opinion in Genetics & Development 11: 274–278.

Bhandari P and Shashidhara LS (2001) Studies on human colon cancer gene APC by targeted expression in Drosophila. Oncogene 20: 6871–6880.

Bier E (2005) Drosophila, the golden bug, emerges as a tool for human genetics. Nature Reviews Genetics 6: 9–23.

Brumby AM and Richardson HE (2003) scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO Journal 22: 5769–5779.

Brumby AM and Richardson HE (2005) Using Drosophila melanogaster to map human cancer pathways. Nature Reviews Cancer 5: 626–639.

Caponigro G and Sellers WR (2011) Advances in the preclinical testing of cancer therapeutic hypotheses. Nature Reviews Drug Discovery 10: 179–187.

Chang S, Bray SM, Li Z, et al. (2008) Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nature Chemical Biology 4: 256–263.

Cordero JB, Stefanatos RK, Myant K, Vidal M and Sansom OJ (2012a) Non‐autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1‐driven intestinal stem cell hyperplasia in the Drosophila adult midgut. Development 139: 4524–4535.

Cordero JB, Stefanatos RK, Scopelliti A, Vidal M and Sansom OJ (2012b) Inducible progenitor‐derived Wingless regulates adult midgut regeneration in Drosophila. EMBO Journal 31: 3901–3917.

Dar AC, Das TK, Shokat KM and Cagan RL (2012) Chemical genetic discovery of targets and anti‐targets for cancer polypharmacology. Nature 486: 80–84.

Dar AC, Lopez MS and Shokat KM (2008) Small molecule recognition of c‐Src via the Imatinib‐binding conformation. Chemistry & Biology 15: 1015–1022.

Das T and Cagan R (2010) Drosophila as a novel therapeutic discovery tool for thyroid cancer. Thyroid 20: 689–695.

Das TK and Cagan RL (2013) A Drosophila approach to thyroid cancer therapeutics. Drug Discovery Today Technologies 10: e65–e71.

DeBerardinis RJ and Cheng T (2010) Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29: 313–324.

Denton JE, Lui MS, Aoki T, Sebolt J and Weber G (1982) Rapid in vivo inactivation by acivicin of CTP synthetase, carbamoyl‐phosphate synthetase II, and amidophosphoribosyltransferase in hepatoma. Life Sciences 30: 1073–1080.

Desai UA, Pallos J, Ma AA, et al. (2006) Biologically active molecules that reduce polyglutamine aggregation and toxicity. Human Molecular Genetics 15: 2114–2124.

Earhart RH and Neil GL (1985) Acivicin in 1985. Advances in Enzyme Regulation 24: 179–205.

Eder J, Sedrani R and Wiesmann C (2014) The discovery of first‐in‐class drugs: origins and evolution. Nature Reviews Drug Discovery 13: 577–587.

Edwards A, Gladstone M, Yoon P, et al. (2011) Combinatorial effect of maytansinol and radiation in Drosophila and human cancer cells. Disease Models & Mechanisms 4: 496–503.

Elf SE and Chen J (2014) Targeting glucose metabolism in patients with cancer. Cancer 120: 774–780.

Elsum I, Yates L, Humbert PO and Richardson HE (2012) The Scribble‐Dlg‐Lgl polarity module in development and cancer: from flies to man. Essays in Biochemistry 53: 141–168.

Galindo RL, Allport JA and Olson EN (2006) A Drosophila model of the rhabdomyosarcoma initiator PAX7‐FKHR. Proceedings of the National Academy of Sciences of the United States of America 103: 13439–13444.

Garcia‐Alcover I, Colonques‐Bellmunt J, Garijo R, et al. (2014) Development of a Drosophila melanogaster spliceosensor system for in vivo high‐throughput screening in myotonic dystrophy type 1. Disease Models & Mechanisms 7: 1297–1306.

Geldenhuys WJ, Allen DD and Bloomquist JR (2012) Novel models for assessing blood–brain barrier drug permeation. Expert Opinion on Drug Metabolism & Toxicology 8: 647–653.

Giovannucci E, Harlan DM, Archer MC, et al. (2010) Diabetes and cancer: a consensus report. CA: A Cancer Journal for Clinicians 60: 207–221.

Gladstone M, Frederick B, Zheng D, et al. (2012) A translation inhibitor identified in a Drosophila screen enhances the effect of ionizing radiation and taxol in mammalian models of cancer. Disease Models & Mechanisms 5: 342–350.

Gladstone M and Su TT (2011) Screening for radiation sensitizers of Drosophila checkpoint mutants. Methods in Molecular Biology 782: 105–117.

Godde NJ, Sheridan JM, Smith LK, et al. (2014) Scribble modulates the MAPK/Fra1 pathway to disrupt luminal and ductal integrity and suppress tumour formation in the mammary gland. PLoS Genetics 10: e1004323.

Gonzalez C (2013) Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nature Reviews Cancer 13: 172–183.

Grzeschik NA, Parsons LM, Allott ML, Harvey KF and Richardson HE (2010) Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Current Biology 20: 573–581.

Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144: 646–674.

Harrison DA, Binari R, Nahreini TS, Gilman M and Perrimon N (1995) Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO Journal 14: 2857–2865.

Hirabayashi S, Baranski TJ and Cagan RL (2013) Transformed Drosophila cells evade diet‐mediated insulin resistance through wingless signaling. Cell 154: 664–675.

Jaklevic BR and Su TT (2004) Relative contribution of DNA repair, cell cycle checkpoints, and cell death to survival after DNA damage in Drosophila larvae. Current Biology 14: 23–32.

Jaklevic B, Uyetake L, Lemstra W, et al. (2006) Contribution of growth and cell cycle checkpoints to radiation survival in Drosophila. Genetics 174: 1963–1972.

Janssens DH and Lee CY (2014) It takes two to tango, a dance between the cells of origin and cancer stem cells in the Drosophila larval brain. Seminars in Cell & Developmental Biology 28: 63–69.

Jeibmann A, Eikmeier K, Linge A, et al. (2014) Identification of genes involved in the biology of atypical teratoid/rhabdoid tumours using Drosophila melanogaster. Nature Communications 5: 4005.

Joost HG (2014) Diabetes and cancer: epidemiology and potential mechanisms. Diabetes & Vascular Disease Research 11: 390–394.

Kasai Y and Cagan R (2010) Drosophila as a tool for personalized medicine: a primer. Personalized medicine 7: 621–632.

Kimura T, Takabatake Y, Takahashi A and Isaka Y (2013) Chloroquine in cancer therapy: a double‐edged sword of autophagy. Cancer Research 73: 3–7.

King EG, Kislukhin G, Walters KN and Long AD (2014) Using Drosophila melanogaster to identify chemotherapy toxicity genes. Genetics 198: 31–43.

Kobia F, Duchi S, Deflorian G and Vaccari T (2014) Pharmacologic inhibition of vacuolar H+ ATPase reduces physiologic and oncogenic Notch signaling. Molecular Oncology 8: 207–220.

Kola I and Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery 3: 711–715.

Lee WC, Beebe K, Sudmeier L and Micchelli CA (2009) Adenomatous polyposis coli regulates Drosophila intestinal stem cell proliferation. Development 136: 2255–2264.

Markstein M, Dettorre S, Cho J, et al. (2014) Systematic screen of chemotherapeutics in Drosophila stem cell tumors. Proceedings of the National Academy of Sciences of the United States of America 111: 4530–4535.

Moreadith RW and Lehninger AL (1984) The pathways of glutamate and glutamine oxidation by tumor cell mitochondria. Role of mitochondrial NAD(P)+−dependent malic enzyme. Journal of Biological Chemistry 259: 6215–6221.

Muller PA and Vousden KH (2014) Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25: 304–317.

Mummery‐Widmer JL, Yamazaki M, Stoeger T, et al. (2009) Genome‐wide analysis of Notch signalling in Drosophila by transgenic RNAi. Nature 458: 987–992.

Munos B (2009) Lessons from 60 years of pharmaceutical innovation. Nature Reviews Drug Discovery 8: 959–968.

Muyrers‐Chen I, Rozovskaia T, Lee N, et al. (2004) Expression of leukemic MLL fusion proteins in Drosophila affects cell cycle control and chromosome morphology. Oncogene 23: 8639–8648.

Nam KH, Smith AS, Lone S, Kwon S and Kim DH (2014) Biomimetic 3D tissue models for advanced high‐throughput drug screening. Journal of Laboratory Automation. pii: 2211068214557813 [Epub ahead of print]

Ocana A, Pandiella A, Siu LL and Tannock IF (2011) Preclinical development of molecular‐targeted agents for cancer. Nature Reviews Clinical Oncology 8: 200–209.

Osman D, Gobert V, Ponthan F, et al. (2009) A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1‐ETO. Proceedings of the National Academy of Sciences of the United States of America 106: 12043–12048.

Pandey UB and Nichols CD (2011) Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacological Reviews 63: 411–436.

Parsons LM, Portela M, Grzeschik NA and Richardson HE (2014) Lgl regulates notch signaling via endocytosis, independently of the apical aPKC‐Par6‐Baz polarity complex. Current Biology 24: 2073–2084.

Pearson HB, Perez‐Mancera PA, Dow LE, et al. (2011) SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. Journal of Clinical Investigation 121: 4257–4267.

Perrimon N, Ni JQ and Perkins L (2010) In vivo RNAi: today and tomorrow. Cold Spring Harbor Perspectives in Biology 2: a003640.

Petzoldt AG, Gleixner EM, Fumagalli A, Vaccari T and Simons M (2013) Elevated expression of the V‐ATPase C subunit triggers JNK‐dependent cell invasion and overgrowth in a Drosophila epithelium. Disease Models & Mechanisms 6: 689–700.

Radimerski T, Montagne J, Hemmings‐Mieszczak M and Thomas G (2002) Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes and Development 16: 2627–2632.

Read RD (2011) Drosophila melanogaster as a model system for human brain cancers. Glia 59: 1364–1376.

Read RD, Cavenee WK, Furnari FB and Thomas JB (2009) A drosophila model for EGFR‐Ras and PI3K‐dependent human glioma. PLoS Genetics 5: e1000374.

Read RD, Goodfellow PJ, Mardis ER, et al. (2005) A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171: 1057–1081.

Rosales‐Nieves AE and Gonzalez‐Reyes A (2014) Genetics and mechanisms of ovarian cancer: parallels between Drosophila and humans. Seminars in Cell & Developmental Biology 28: 104–109.

Roy M, Pear WS and Aster JC (2007) The multifaceted role of Notch in cancer. Current Opinion in Genetics & Development 17: 52–59.

Rudrapatna VA, Cagan RL and Das TK (2012) Drosophila cancer models. Developmental Dynamics 241: 107–118.

Settle M, Gordon MD, Nadella M, et al. (2003) Genetic identification of effectors downstream of Neu (ErbB‐2) autophosphorylation sites in a Drosophila model. Oncogene 22: 1916–1926.

Sharma SV, Haber DA and Settleman J (2010) Cell line‐based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nature Reviews Cancer 10: 241–253.

Sinenko SA, Hung T, Moroz T, et al. (2010) Genetic manipulation of AML1‐ETO‐induced expansion of hematopoietic precursors in a Drosophila model. Blood 116: 4612–4620.

Siolas D and Hannon GJ (2013) Patient‐derived tumor xenografts: transforming clinical samples into mouse models. Cancer Research 73: 5315–5319.

Stratton MR (2011) Exploring the genomes of cancer cells: progress and promise. Science 331: 1553–1558.

Tipping M and Perrimon N (2014) Drosophila as a model for context‐dependent tumorigenesis. Journal of Cellular Physiology 229: 27–33.

Vaccari T, Duchi S, Cortese K, Tacchetti C and Bilder D (2010) The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor. Development 137: 1825–1832.

Vidal M, Wells S, Ryan A and Cagan R (2005) ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Research 65: 3538–3541.

Willecke M, Toggweiler J and Basler K (2011) Loss of PI3K blocks cell‐cycle progression in a Drosophila tumor model. Oncogene 30: 4067–4074.

Willoughby LF, Schlosser T, Manning SA, et al. (2013) An in vivo large‐scale chemical screening platform using Drosophila for anti‐cancer drug discovery. Disease Models & Mechanisms 6: 521–529.

Wong GT, Manfra D, Poulet FM, et al. (2004) Chronic treatment with the gamma‐secretase inhibitor LY‐411,575 inhibits beta‐amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. Journal of Biological Chemistry 279: 12876–12882.

Zeng X, Singh SR, Hou D and Hou SX (2010) Tumor suppressors Sav/Scrib and oncogene Ras regulate stem‐cell transformation in adult Drosophila malpighian tubules. Journal of Cellular Physiology 224: 766–774.

Zhang Y and Hunter T (2014) Roles of Chk1 in cell biology and cancer therapy. International Journal of Cancer 134: 1013–1023.

Cross‐references to other eLS articles

Barault L (2013) Ras mutations in cancer. DOI: 10.1002/9780470015902.a0025010.

Cheng LY, Parsons LM and Richardson HE (2013) Modelling cancer in Drosophila: the next generation. DOI: 10.1002/9780470015902.a0020862.pub2.

Cobaleda C, Vicente C, Romero‐Camarero I and Sánchez‐García I (2012) Cancer stem cells. DOI: 10.1002/9780470015902.a0020860.pub2.

Colombo MI (2009) Autophagy. DOI: 10.1002/9780470015902.a0021581.

Cruz‐Migoni SB and Borycki A‐G (2014) Hedgehog signalling. DOI: 10.1002/9780470015902.a0000806.pub2.

Danen EHJ (2013) Integrins: signalling and disease. DOI: 10.1002/9780470015902.a0004022.pub3.

Davidovic L, Tournier B and Khandjian EW (2007) The fragile X syndrome. DOI: 10.1002/9780470015902.a0005533.

Dutta P and Li WX (2013) Role of the JAK‐STAT signalling pathway in cancer. DOI: 10.1002/9780470015902.a0025214.

Frayling IM (2006) Colorectal cancer: genetics. DOI: 10.1038/npg.els.0005555.

Funk JO (2006) Cell cycle checkpoint genes and cancer. DOI: 10.1038/npg.els.0006046.

Greenwood D (2009) History of antimalarial agents. DOI: 10.1002/9780470015902.a0003624.pub2.

Hatina J, Fernandes MI, Hoffmann MJ and Zeimet AG (2013) Cancer stem cells – basic biological properties and experimental approaches. DOI: 10.1002/9780470015902.a0021164.pub2.

Hoppler S and Nakamura Y (2014) Cell‐to‐cell signalling in development: Wnt signalling. DOI: 10.1002/9780470015902.a0002331.pub2.

Jeibmann A, Kim SN, Paulus W and Klämbt C (2010) Glioblastoma models in Drosophila melanogaster. DOI: 10.1002/9780470015902.a0022540.

Lane MD (2009) Energy balance, obesity and type‐2 diabetes. DOI: 10.1002/9780470015902.a0021317.

Link W, Madureira PA and Hill R (2013) Identifying new targets for personalised cancer therapy. DOI: 10.1002/9780470015902.a0024865.

Look TA and Ferrando AA (2006) Leukemias and lymphomas: genetics. DOI: 10.1038/npg.els.0005553.

Malaquias AC (2014) Developmental syndromes of Ras/MAPK pathway dysregulation. DOI: 10.1002/9780470015902.a0021426.

Marsh M (2001) Clathrin‐coated vesicles and receptor‐mediated endocytosis. DOI: 10.1038/npg.els.0000555.

Najjar S (2003) Insulin action: molecular basis of diabetes. DOI: 10.1038/npg.els.0001402.

Patrick GL (2013) History of drug discovery. DOI: 10.1002/9780470015902.a0003090.pub2.

Pennuto M and Sambataro F (2010) Pathogenesis of polyglutamine diseases. DOI: 10.1002/9780470015902.a0021486.

Peterson DR (2012) Blood–brain barrier. DOI: 10.1002/9780470015902.a0000023.pub3.

Raue F and Frank‐Raue K (2010) Multiple endocrine neoplasia type 2. DOI: 10.1002/9780470015902.a0006061.

Saha V and Jones LK (2006) Fusion proteins and diseases. DOI: 10.1038/npg.els.0005543.

Schur PH (2009) Systemic lupus erythematosus. DOI: 10.1002/9780470015902.a0002147.pub2.

Shaik S, Liu P, Fukushima H, Wang Z and Wei W (2014) Protein degradation in cell cycle. DOI: 10.1002/9780470015902.a0023158.

Turnpenny PD (2014) Syndromes and diseases associated with the Notch signalling pathway. DOI: 10.1002/9780470015902.a0024870.

Wei D and Weissman BE (2014) Genetics and genomics of malignant rhabdoid tumours. DOI: 10.1002/9780470015902.a0025012.

Wordsworth P (2006) Rheumatoid arthritis. DOI: 10.1038/npg.els.0004113.

Yu J (2010) Tuberous sclerosis complex and the mammalian target of rapamycin pathways. DOI: 10.1002/9780470015902.a0022388.

Further Reading

Amoyel M, Anderson AM and Bach EA (2014) JAK/STAT pathway dysregulation in tumors: a Drosophila perspective. Seminars in Cell & Developmental Biology 28: 96–103.

Bell GP and Thompson BJ (2014) Colorectal cancer progression: lessons from Drosophila? Seminars in Cell & Developmental Biology 28: 70–77.

Carney TJ and Ingham PW (2013) Drugging Hedgehog: signaling the pathway to translation. BMC Biology 11: 37 DOI: 10.1186/1741-7007-11-37.

Gladstone M and Su TT (2011) Chemical genetics and drug screening in Drosophila cancer models. Journal of Genetics and Genomics 38: 497–504.

Hanahan D and Weinburg RA (2011) Hallmarks of cancer: the next generation. Cell 144: 646–74.

Markstein M (2013) Modeling colorectal cancer as a 3‐dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies. Drug Discovery Today Technologies 10: e73–81.

Mo JS, Park HW and Guan KL (2014) The Hippo signaling pathway in stem cell biology and cancer. EMBO Reports 15: 642–56.

Ntziachristos P, Lim JS, Sage J and Aifantis I (2014) From fly wings to targeted cancer therapies: a centennial for Notch signaling. Cancer Cell 25: 318–334.

Patel PH and Edgar BA (2014) Tissue design: how Drosophila tumors remodel their neighborhood. Seminars in Cell & Developmental Biology 28: 86–95.

Zhang J, Yang PL and Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nature Reviews Cancer 9: 28–39.

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Richardson, Helena E, Willoughby, Lee, and Humbert, Patrick O(Mar 2015) Screening for Anti‐cancer Drugs in Drosophila. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022535]