The Evaluation of Dual PI3K/mTOR Inhibitors as a Superior Alternative to mTOR Inhibitors in Pre-B Acute Lymphoblastic Leukaemia

Abstract

Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in children. Poor long term survival in adults as well as the bleak outlook for relapsed patients highlights the need for new therapeutic strategies for the treatment of ALL. The major regulators of ALL cell proliferation and survival mediate their effects through the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin. It has been previously shown that the mTOR inhibitor RAD001 extended survival in a non-obese diabetic/severe combined immune deficient (NOD/SCID) mouse xenograft model of ALL. The work presented in this thesis examines the effect of the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in ALL. In summary, dual PI3K/mTOR inhibitors demonstrate primarily superior cytostatic effects in vitro but a mixed level of cytotoxicity when compared to RAD001. In addition, the dual PI3K/mTOR inhibitors extended survival in NOD/SCID mice engrafted with ALL xenografts but failed to demonstrate overall superiority over mTOR inhibition alone. This work contributed to the publication of a paper, presented in two separate chapters. Subsequent unpublished work presented in this thesis examined the effects of the dual PI3K/mTOR inhibitors in combination with conventional chemotherapeutic agents. However, the results presented in this thesis indicate that the dual PI3K/mTOR inhibitors do not cooperate well with the tested agents. Furthermore, the cooperation observed with the dual PI3K/mTOR inhibitors in combination with a MEK inhibitor highlights the need to explore strategies to target multiple signalling pathways.