# Novel use of PI3K inhibition to prevent recurrence of B-cell acute lymphoblastic leukemia

> **NIH NIH R21** · DUKE UNIVERSITY · 2022 · $221,286

## Abstract

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.

## Key facts

- **NIH application ID:** 10455633
- **Project number:** 5R21CA263908-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Dorothy A Sipkins
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $221,286
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455633

## Citation

> US National Institutes of Health, RePORTER application 10455633, Novel use of PI3K inhibition to prevent recurrence of B-cell acute lymphoblastic leukemia (5R21CA263908-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10455633. Licensed CC0.

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