Clinically relevant mini-organs to identify optimal ‘chemo’-free treatments for childhood cancer Phase I trials

Abstract

Treatment toxicity, treatment resistance and cancer dormancy are key unmet clinical needs in childhood acute lymphoblastic leukaemia (ALL). Biology-driven therapeutics are urgently needed, which further highlights the need for human cell-based, precision oncology preclinical models. The leukaemic bone marrow (BM) microenvironment, specifically the mesenchymal niche, comprising mesenchymal stem cells (MSC) and osteoblasts (OB), is dynamic and evolves to preferentially aid survival of leukaemia over haematopoietic cells. However, mechanisms driving leukaemia biology and means to clinically exploit these remain unstudied.

This project has developed a 3D in vitro human cell-based model, to enable ex vivo survival and growth of patient-derived ALL cells. Furthermore, this project explores mechanisms to clinically exploit leukaemia cross-talk with BM cells. Cancer dormancy and proliferation patterns have been studied to reveal key differences between OB-primed versus MSC-primed ALL. This project finds that unlike MSC, OB cells, which largely constitute the endosteal niche, support a non-cycling, potentially dormant population of ALL. Furthermore treatment-induced ALL dormancy, which occurs under dexamethasone treatment pressure, is a key characteristic of OB-primed ALL. We discover that MSC-ALL co-cultures show TNT formation, however these are absent in OB-ALL co-cultures. In contrary OB-ALL co-cultures upregulate collagen production, and FDA-approved CDH2 antagonist ADH-1, decreases secreted collagen levels in OB-ALL co-cultures. Moreover, a reduction in ALL, including non-cycling OB-primed ALL could be achieved in vitro following treatment with ADH-1. ADH-1 treatment in vivo, both as a single and combinatorial agent was confirmed to reduce Ki67+ ALL tumour burden. Ultimately, inclusion of human macrophage cells in vitro revealed ADH-1-dexamethasone combination in an immune-responsive context to be highly efficacious in eliminating OB-primed dormant ALL populations.

In summary, this paper provides proof-of-concept data to discover clinically exploitable, microenvironment-mediated cancer dormancy. This will enable the beginning of investigations into niche-driven therapeutics within an immune-responsive, precision oncology context.

Date of Award	24 Oct 2024
Original language	English
Awarding Institution	Northumbria University
Supervisor	Deepali Pal (Supervisor), Helen J. Blair (Supervisor) & Stephen Todryk (Supervisor)