Oral Presentation 31st Lorne Cancer Conference 2019

Safe targeting of T‐cell acute lymphoblastic leukemia by subunit selective gamma‐secretase inhibition (#20)

Charles E de Bock 1 2 , Roger A Habets 3 4 , Lutgarde Serneels 3 4 , Inge Lodewijckx 1 , Rajeshwar Narlawar 3 , Sofie Demeyer 1 , James Dooley 4 , Adrian Liston 4 , Tom Taghon 5 , Jan Cools 1 6 , Bart de Strooper 3 4 7
  1. VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium
  2. Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
  3. Department of Neurosciences, Leuven Institute for Neuroscience and Disease, (LIND), KU Leuven, Leuven, Belgium
  4. VIB Center for Brain and Disease Research, KU Leuven, Leuven, Belgium
  5. Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium
  6. Center for Human Genetics, KU Leuven, Leuven, Belgium
  7. Dementia Research Institute, University College London, London, United Kingdom

Activating NOTCH1 mutations are present in approximately 60% of T-cell acute lymphoblastic leukemia (T-ALL) cases. Mutant NOTCH1 is strictly dependent on γ‐secretase processing for activation thereby providing a strong rationale for the use of γ‐secretase inhibitors (GSIs) as a therapeutic approach for T-ALL. However, available GSI's lead to severe “on‐target” gastrointestinal tract, skin and thymus toxicity, limiting their therapeutic application and clinical translation. What is less appreciated is that the enzymatic activity of the γ-secretase complex reflects the combined activity of at least four different complexes. These complexes broadly differ by the inclusion of one of two Presenilin (PSEN) proteins: PSEN1 or PSEN2. Here we show PSEN1 is expressed significantly higher than PSEN2 in human T-ALL cell lines and primary T-ALL samples. Genetically, the conditional deletion of Psen1 in mice significantly decreased mutant NOTCH1 receptor processing but did not impair normal T-cell development. Furthermore, specific inducible deletion of Psen1 in a mutant NOTCH1-driven leukemia significantly reduced leukemia burden and increased overall survival in vivo. The significant decrease in leukemic burden identified through genetic loss of Psen1 then prompted us to investigate whether selective pharmacological PSEN1 inhibition would be a viable strategy for T‐ALL treatment. To this end, we tested the PSEN1 selective inhibitor MRK‐560, which has ~100‐fold selectivity over PSEN2, on four different T-ALL patient-derived xenograft samples with varying NOTCH pathway mutations. MRK‐560 monotherapy treatment significantly decreased leukemia burden as measured by in vivo bioluminescence and human CD45 in the peripheral blood and significantly increased overall survival. Moreover, treatment with MRK‐560 did not cause any pathological changes in the gastrointestinal architecture nor increased numbers of secretory goblet cells, assessed by Periodic Acid‐Schiff (PAS) staining, even after 4 weeks of treatment. Collectively, these results demonstrate that inhibition of Presenilin‐1 is highly effective in decreasing leukemia whilst avoiding dose‐limiting toxicities and that Presenilin‐1 selective compounds provide a new therapeutic strategy for safe and effective targeting of T‐ALL.