A human iPSC derived bone marrow milieu identifies a novel target against niche-conferred leukaemia proliferation and treatment resistance

Detecting how to clinically target the leukaemia microenvironment has remained a substantial hindrance in drug discovery and drug development. To address this clinical challenge, we have developed a human pluripotent stem cell-engineered co-culture system to support the ex vivo propagation of patient-derived leukaemia cells and to explore actionable niche-mediated blood cancer biology. Here we show that both messenchymal and vascular niche cell types impact malignant proliferation, dormancy and treatment resistance. Furthermore, both the niche cell types supported blast proliferation and conferred dexamethasone resistance onto patient-derived leukaemia cells. While vascular cells protected only quiescent blasts against dexamethasone, mesenchymal cells protected both proliferating and dormant blasts. Growth support and treatment protection was dependent on direct cell-cell interaction and was mediated by N-cadherin (CDH2). We show that CDH2 antagonist ADH-1, a compound with a proven low toxicity profile in adult solid tumour Phase l trials showed high in vivo efficacy in a highly aggressive and incurable leukaemia patient-derived xenograft model. Furthermore, we observed superior in vivo efficacy of ADH-1/Dexamethasone combination compared with single agent Dexamethasone therapy. These findings provide a proof-of-concept starting point to begin investigations into novel and potentially safe anti-cancer therapeutics that target actionable niche-mediated cancer cell dependencies in haematological malignancies.