Drosophila as a novel therapeutic discovery tool for thyroid cancer.
BACKGROUND
Multiple endocrine neoplasia type II (MEN2) is a rare but aggressive cancer for which no effective treatment currently exists. A Drosophila model was developed to identify novel genetic modifier loci of oncogenic RET, as well as to provide a whole animal system to rapidly identify compounds that suppressed RET-dependent MEN2. ZD6474 (Vandetanib), currently in phase III trials, suppressed tumorigenesis in MEN2 model flies, demonstrating for the first time the effectiveness of a Drosophila-based whole animal model for identifying therapeutically useful compounds.


CONCLUSIONS
Clinical data suggest that drug mono-therapy for MEN2 and other cancers typically yield only moderate benefits as patients develop drug resistance and suffer from drug-induced pathway feedback. Combinations of drugs that target different nodes of the oncogenic pathway are an effective way to prevent resistance as well as feedback. Identifying the optimal drug-dose combinations for therapy poses a significant challenge in existing mouse models. Fly models offer a means to quickly and effectively identify drug combinations that are well tolerated and potently suppress the MEN2 phenotype. This approach may also identify differences in therapeutic responses between the two subtypes of MEN2--MEN2A and MEN2B--providing additional therapeutic insights.


CONCLUSIONS
Fly models have proven useful for identifying known drugs as well as novel compounds that, as single agents or in combinations, effectively suppress the MEN2 syndrome. These findings validate the use of fly models for both drug discovery as well as identification of useful drug combinations. In the future, rapid pairing of new genomic information with increasingly complex fly models will aid us in efforts to further tailor drug treatments toward personalized medicine.
Das
Tirtha
T
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Cagan
Ross
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D004195:Disease Models, Animal; D004330:Drosophila / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D018813:Multiple Endocrine Neoplasia Type 2a / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018814:Multiple Endocrine Neoplasia Type 2b / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D057285:Precision Medicine / Q000379:methods; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016606:Thyroid Nodule / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051096:Proto-Oncogene Proteins c-ret