# Unlocking the Potential of PI3K Inhibition in CLL

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $571,051

## Abstract

Project Summary
CLL is the most common leukemia of adults in North America and remains incurable. Recent discovery of
targeted oral kinase inhibitors of the B cell receptor signaling pathway is transforming the therapy of CLL, but
challenges remain. Individually none of these drugs is curative, and approximately 30% of patients discontinue
for toxicity despite good disease response. The PI3K p110δ inhibitors include the first generation FDA
approved drug idelalisib, as well as duvelisib, a PI3K γ and δ inhibitor currently in registration trials. The PI3Kδ
inhibitors have a pattern of toxicity that includes hepatitis, colitis and pneumonitis. We have two ongoing
clinical trials in CLL patients, one idelalisib based and one duvelisib based, in which we have described these
toxicities to be immune-mediated. We have further shown that this toxicity associates with a decrease in T
regulatory cells, which could also enhance efficacy and decrease risk of solid tumors in these patients. In this
grant in Specific Aim 1 we propose to deepen these observations, characterizing the T regulatory and T
effector landscape of CLL during therapy with PI3Kδ inhibitors in relation to observed toxicities, with the goal of
identifying clinical and immunologic predictors of toxicity and efficacy. We will further perform in vitro functional
assays to assess the impact of PI3Kδ inhibition on the suppressive function of T regulatory cells, the activation
capacity of T effector cells and the in vitro differentiation potential of naïve CD4+ T cells. In Specific Aim 2 we
will assess the impact of PI3Kδ knockdown on the Eμ-TCL1 mouse model of CLL in terms of disease
development, autoimmune toxicity and T cell milieu. These experiments will focus on the mouse kinase dead
genetic model but will also assess pharmacologic inhibitors. Aims 1 and 2 will therefore elucidate the
fundamental biology of PI3Kδ selective inhibition in humans and mice and enable us to identify predictors of
toxicity and efficacy that will optimize patient selection for these drugs. In Specific Aim 3, we will characterize
the mechanisms of sensitivity and resistance to PI3Kδ inhibition. Our preliminary data implicate genetic and/or
biochemical upregulation of the ERK pathway in patients who are or become resistant to PI3Kδ inhibition. We
therefore propose to perform direct mechanistic studies of the impact of ERK pathway activation on PI3Kδ
resistance in vitro. We will also perform additional discovery by studying patients enrolled on these two
prospective clinical trials at baseline, during remission and at time of acquired resistance, including genomic,
transcriptomic and signaling evaluation. This previously untreated uniform patient population represents an
ideal homogeneous cohort that will allow us to understand these mechanisms much more effectively than a
heterogeneous relapsed cohort. This project will therefore represent a major advance in the understanding of
the biology of PI3Kδ inhibition in h...

## Key facts

- **NIH application ID:** 10143197
- **Project number:** 5R01CA213442-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Jennifer R Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $571,051
- **Award type:** 5
- **Project period:** 2017-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143197

## Citation

> US National Institutes of Health, RePORTER application 10143197, Unlocking the Potential of PI3K Inhibition in CLL (5R01CA213442-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143197. Licensed CC0.

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