Dr. Tibes is the principal investigator on more than 15 clinical phase I/II trials in oncology and hematology; and a co-investigator on over 35 trials.
Active projects include:
- RNAi screens with gene sets targeting the human kinome (711 kinases), apoptosis and cell cycle regulators (532 genes) and phosphatome (206 phosphatases) in myeloid cells of heterogenous genetic background. Selective vulnerabilities in specific molecular contexts' were discovered, i.e. novel targets inJak2 mutant vs. wild-type cells. Hits are currently being validated as novel crucial growth regulators in Jak2 mutant cells and for their value as drug-targetable kinase target applying novel inhibitors in combination targeting the identified candidate genes.
- A first-in-class RNAi kinome sensitizer screen with cytarabine in leukemias was conducted. Out of 572 kinases individually silenced with cytarabine in two cell lines, only 1.6 and 1.4 percent were synergistically lethal to leukemia cells. For top kinase hits, novel agents were identified that inhibited growth of myeloid cells in vitro and ex vivo. These preclinical data led to proposals for clinical trials. Underlying mechanism of sensitization are characterized centering round DNA damage repair and cell cycle pathways.
- A top hit sensitizing to the hypomethylating agent 5-Azacytidine has been identified out of screening > 1100 cancer associated genes and kinases in leukemia cells. A clear pattern of targeting a certain group of related cell-cycle and apoptotic regulators emerged. Regulation may be mediated by miRNA's and specific miRNA silenced and re-activated have been identified.
- As the next large experimental approach RNAi libraries specific for genes involved in leukemogenesis have been assembled and will be systematically explored for their role as (haploinsufficient) targets in myeloid cells.