ABSTRACT Central nervous system (CNS) metastasis and relapse occurs in up to 10% of patients with acute lymphoblastic leukemia (ALL), despite CNS-directed prophylaxis with cytotoxic chemotherapy or craniospinal irradiation. With no uniformly effective treatment options, CNS relapse carries a grim prognosis of less than 6 months. Until now, the molecular mechanism of ALL invasion into the CNS has been poorly understood, preventing targeted drug development. Our lab recently discovered a previously unknown mechanism used by B-ALL cells to enter the CNS. This invasion pathway is dependent on key molecular interactions between ?6 integrin, a surface protein expressed on ALL blasts, and its receptor laminin, expressed on the basement membrane of vessels connecting the calvarial and vertebral bone marrow to the CNS leptomeninges. We further demonstrated that B-ALL ?6 integrin expression is regulated by PI3K signaling, and that PI3K? isoform inhibition in vivo in mouse models of leukemia blocks CNS metastasis. Using in vitro and in vivo mouse models of B-ALL, we now show that treatment with the pan-PI3K isoform inhibitor copanlisib has additional therapeutic effects including cell cycle arrest and chemosensitization of ALL blasts. These translate to decreased CNS metastasis, reduced systemic disease burden and prolonged survival in leukemic mice. Based on these data, we have designed a novel window-of- opportunity (WoO) clinical trial to characterize molecular responses to pan-PI3K inhibition in ALL in humans. We have also designed mouse models to study the impact of PI3Ki on the persistence of minimal residual disease (MRD) following chemotherapy, a key prognostic indicator of disease relapse. In the current research proposal, we aim to: 1) Perform detailed correlative analyses of B-ALL cell molecular responses in patient samples pre- and post-copanlisib dosing in our WoO trial, and 2) Determine whether pan-PI3K inhibition by copanlisib combined with salvage chemotherapy can decrease MRD in our preclinical models of B-ALL. The therapeutic role of PI3K inhibition in ALL has not yet been established; therefore, data gathered from our WoO protocol and the experiments described within this research proposal will critically inform trial design of a potential follow-on phase II study of copanlisib incorporated into existing ALL treatment regimens. If successful, our work will represent a novel breakthrough in CNS prophylactic therapy for ALL, addressing an area of substantial unmet clinical need for patients.

R21CA263908

2021-08-01

2023-07-31