Using chemical synthetic lethal screening to identify novel compounds that sensitize acute myeloid leukemia with FLT3-ITD mutations to novel small-molecule FLT3 tyrosine kinase inhibitors, ITRI-260 and overcome microenvironment-mediated drug resistan

Project: A - Government Institutionb - Ministry of Science and Technology

Description

Acute myeloid leukemia (AML) is a heterogenous disease characterized by recurrent genetic changes. Of them, the most common one is FLT3 mutations. AML with FLT3 mutations, especially internal tandem duplications (ITDs) has poor prognosis. In the past few years, we and Industrial Technology Research Institute (ITRI, 工研院生醫所) have been working on developing novel small-molecule tyrosine kinase inhibitors (TKIs) for AML. We identified a compound, called ITRI-260, which is active for AML with FLT3 mutations. Our prior studies have indicated that ITRI-260 inhibits the growth of AML with FLT3-ITD mutations in vitro and, markedly prolongs survival of leukemic mice in vivo. Yet, we also found that this agent, like other FLT3 inhibitors in clinical trials, cannot eradicate leukemia, partly due to microenvironment-mediated drug resistance in vivo. For further development of ITRI-260, we have established an array of cell lines with different FLT3 mutations cloned out from primary AML and cells lines with artificially created mutations that render cells resistant to different FLT3 TKIs, including sorafenib, sunitinib and PKC412. In this proposal, we would like to use this platform to conduct high-throughput strategy to identify agents that can sensitize ITRI-260 and overcome drug resistance. We intend to use a strategy called synthetic lethal screening to screen through chemical libraries, including a kinase library and a compound library containing agents currently used in clinics, to identify compounds that enhance the activity of ITRI-260 not only in vitro but also in vivo in our platform. The reason we choose to use chemical screening, instead of RNAi strategy, is that we might be able to quickly move our findings into clinical practice in the future. To achieve the goals, we will have three specific aims. In specific aim 1, we will use chemical synthetic lethal screening to identify novel agents that sensitize human AML with FLT3-ITD mutations to ITRI-260 and overcome microenvironment-mediated drug resistance and identify the underlying mechanisms. In specific aim 2, we will perform in vitro and in vivo validation of the compounds in our proprietary drug discovery platform. In specific aim 3, we will conduct in vivo validation of novel treatment paradigm in an animal model mimicking real-world human AML. We believe that, through these aims, we will be able to identify agents that further our understanding of drug resistance and increase the odds of eradicating this particular type of AML.
StatusFinished
Effective start/end date8/1/137/31/14

Keywords

  • ITRI-260
  • temsirolimus
  • syngersic effect