- Novel highly tractable genetic model organism of human pancreatic ductal
- Platform with ease of handling, short-term experiment and high cost effectiveness
- First candidate therapeutics for 4-gene mutated PDAC with the worst prognosis
Background & Technology
Pancreatic ductal adenocarcinoma (PDAC) is a disease which has one of the highest mortality rate among all major cancers, remaining as the fourth leading cause of cancer-related deaths in developed countries. KRAS, TP53, CDKN2A (p16) and SMAD4 are the most frequently mutated genes in PDAC.
PDAC patients carrying mutations in all of these four genes have the poorest prognosis but animals modeling such ‘4-hit’ mutations were lacking, making researches on PDAC mechanisms and therapeutics problematic.
Inventor and their former affiliate laboratory reported transgenic Drosophila model for medullary thyroid carcinoma (MTC) and discovered a first remedy as well as novel leads of kinase inhibitor drug for treating MTC via whole-body chemical genetics in this model. Inventor has been working in the digestive organ cancer field, and intended to tackle PDAC by their research platform combining Drosophila with mammals. Here, we have developed ‘4-hit flies’, the first animal model for 4-hit PDAC, by targeting the 4 gene alternations to wing disc epithelium in larvae. Exploring therapeutic candidate targets for PDAC, we identified kinase1-5 as the key kinases in a whole-kinome genetic screening and obtained synergetic anti-neoplastic effects of combination therapies targeting these kinases in 4-hit flies. We confirmed similar results also in human PDAC cell line (MIA PaCa-2) as well as in a mouse xenograft model, which can substantiate our progress to clinical trials. Moreover, we will collaborate with partners for exploring novel leads or further mono/combination therapy by using our platform.
*Loss of function
**Expressing Drosophila Cyclin E to model
P16LOF (Datar et al. EMBO J 2000)
Identification of pancreatic cancer-promoting kinase (PPK) and the combination effect between PPK inhibitors
Sonoshita et al. Curr Top Dev Biol 2017 121:287-309.
Sonoshita et al. Nat Chem Biol 2018 14:291-298.
Ung*, Sonoshita* et al. PLoS Comput Biol 2019 15:e1006878. (*co-first authors)
We are looking for partner companies to develop this combination therapy further or to collaborate for exploring new drug candidate via Drosophila platform with us.