Periodic Reporting for period 4 - PNANOMED (Personalized Nanomedicines for Leukemia Patients)
Período documentado: 2020-01-01 hasta 2020-06-30
We applied cutting-edge technology to mouse models from primary human AML patients to identify the target proteins that sustain leukemia stem cell self-renewal and to develop effective nanomedicines against these targets. We ued primary AML models to study the functional hierarchy of genetic aberrations and to prioritize potential target molecules. A biobank of human transplantable AML xenografts has been established (WP1) and characterized by state-of-the-art genomic approaches (WP2). Genetic aberrations were reversed by knockdown and gene replacement strategies and functional consequences are being assessed in vivo (WP3). Most advanced nanoparticle/siRNA formulations and preparation tools have been employed to develop leukemia-specific nanomedicines (WP4 and 5). This project contributed to a better understanding of AML biology to develop better treatments for leukemia patients.
We established multiple serially transplantable patient derived xenograft (PDX) models from leukemia patients including three serially transplantable CMML-PDX models with disease related gene mutations that recapitulate the disease in vivo. We identified the combination of azacitidine and trametinib as an effective treatment in NRAS-mutated CMML and proposed its clinical development.
We identified novel biologic functions in leukemia and normal cells relating to the function of ETV6, IDH1, its oncometabolite R-2HG and the fusion gene KMT2A-MLLT3.
We identified, patented and characterized the novel mutant IDH1 inhibitor HMS-101 and showed that IDH1 inhibitors strongly synergize with the hypomethylating chemotherapy azacitidine.
We developed siRNAs that specifically inhibit the fusion oncogenes BCR-ABL, TCF3-PBX1, NUP98-NSD1 and CALM-AF10. We packaged the siRNAs in lipid nanoparticles and treated xenograft AML mice. The target siRNA/LNP formulation improved the survival of the mice and was overall well tolerated. This work provides a new, selective approach for targeting fusion oncogenes, which were previously considered undruggable.
We also developed a novel treatments against rare AML subtypes characterized by fusion genes. This treatment is based on lipid nanoparticles that encapsulate small interfering RNAs, that directly target the oncogene. Our proof of efficacy and tolerability in leukemia models provides the basis for the clinical development of this treatment.