Repurposing in personalized leukemia therapy

Repurposing of medicines includes development of well-known and safe medicines for use in other diseases than originally established. Acute myeloid leukemia is an aggressive blood cancer with a median age at diagnosis of 71 years old. Approximately 20% of patients survive longer than three years following diagnosis and as such there is a great need for improved therapy. We have selected combinations of two medicines that each have reported to give exceptionally rare suppression of normal bone marrow function (<1:10 000 individuals dosed). These observations and preliminary laboratory experiments have given us the hypothesis that in combination these otherwise well tolerated medicines may have strong effect against blood cancer. Laboratory experiments have revealed that specific drug combinations are highly effective against acute myeloid leukemia. Similarly, mouse models of leukemia seem to be effectively treated by these combinations without unexpected side effects. Furthermore, we have treated single patients with off-label use of these drug combinations, and experience well tolerated treatment and occasionally stable disease. This project will treat 8+16 patients with relapsed or therapy refractory leukemia to determine the optimal dose of our drug combination. If 1 or more of the 8 first patients experience clinical benefit, we will proceed with 16 more patients. If 5 or more of the 24 patients experience clinical benefit, we will plan a new study to document the therapeutic effect. Along with the therapy we will perform blood and bone marrow sampling to molecularly map how the leukemia cells and immune cells respond to the therapy. Our preliminary data shows treated patients experience blood cell responses within a few hours, and we question if these molecular responses translate into clinical benefit for our patients. Such specific cancer cell protein modulation may reveal features of responder and non-responder patients. We will use clinical and molecular data from patient cancer cells, including functional tests like longitudinal cellular signaling responses and in vitro drug sensitivity. These data will be analyzed in machine learning algorithms 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. We hypothesize that functional tests of cancer cell signaling within hours or days may identify responders. Some of the medicine combinations are well accepted in leukemia patients with severe infections, and the beneficial effect on both infection and leukemia is explored. Together, the project aims to develop new clinical trials for patients with aggressive blood cancer.

This phase I clinical trial will examine the repurposed medicine combination with 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.