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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Repurposing in personalized leukemia therapy

Alternative title: Bruk av kjente medisiner til nye sykdommer: Malaria- og epilepsimedisin til bruk mot leukemi

Awarded: NOK 12.0 mill.

Repurposing of medicines is an established approach to develop safe and well-known medicines for use in other diseases that the medicine originally was developed for. Acute myeloid leukaemia is an aggressive blood cancer with a median age at diagnosis of 71 years old. Less than 20% of patients survive longer than three years following diagnosis and as such there is a great need for improved medicines. Two medicines, an anti-convulsive agent and an anti-malaria agent were both chosen from a list of medicines that in rare cases may suppress growth of healthy bone marrow. The hypothesis being that leukaemia cells will be more sensitive for such agents than the cells of a healthy bone marrow and combined may form an effective anti-leukaemic therapy. Our laboratory experiments have revealed that this drug combination is highly effective in causing acute myeloid leukaemia cells to enter cell death whilst healthy cells are mostly unaffected. Similarly, mouse models of leukaemia seems to be effectively treated by this combination without unexpected side effects. We have treated five separate patients with off-lable use of this drug combination. The combination was well tolerated and one patient experienced stable disease. This project will treat 8+16 patients with relapsed or therapy refractory leukaemia to determine the optimal dose of our drug combination. If ?1 of the 8 first patients experience clinical benefit, we will proceed with 16 more patients. If ?5 of 24 experience clinical benefit we will plan a study expansion to document the therapeutic effect. Along with the therapy we will perform blood and bone marrow sampling to molecularly map how the leukaemia cells and immune cells respond to the therapy. Our preliminary data shows treated patients experience blood cell responses within a few hours. Such specific protein modulation in cancer cells under therapy may reveal features of responder and non-responder patients. Together with mutational analysis of the patients, we will use artificial intelligence computing to search for diagnostics that allow a simple identification of patients who will benefit from the therapy, providing this information in a useful report for both for patient and treating physician.

This phase I clinical trial will examine the repurposed medicine combination quinacrine and valproic acid in the treatment of unfit elderly patients with acute myeloid leukaemia (AML) considered unfit for standard chemotherapy. Complex clinical and OMICS data longitudinally sampled in patients will be analysed to determine responders and non-responders. Furthermore, the data will be scrutinized in search for mechanistic clues that allow therapy enhancement, and if possible, provide the non-responding patients with alternative therapies available through off-label or compassionate therapy programs. This trial challenges the research frontier of personalized medicine beyond current genomics and towards functional assays and systems medicine analytical approaches. Instead of treating our patient’s disease as stationary and unchanging, we will monitor the disease using single cell immune and signalling profiling along with targeted DNA sequencing of single cells. We will use this profiling of phenotype and genotype to depict the dynamics of acute myeloid leukaemia in response to combination therapy. Building on our participation in the Centre of Excellence Centre of Cancer Biomarkers CCBIO, Digital Life and ELIXIR the scientific questions will be approached in a truly transdisciplinary fashion. The project will integrate state-of-art biomedical science and bioinformatics with the humanities in a single research team. Sophisticated computational modelling and visualization packages developed in this project may be employed beyond this trial to provide personalized medicine in an affordable and effective way.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering