# Project 1 Targeting the PI3K Pathway to Overcome Resistance to Immunotherapy in Melanomas with Loss of PTEN

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $387,285

## Abstract

Project 1: Project Summary/Abstract
Cutaneous melanomas (CM) have a very high rate of somatic mutations, and oncogenic drivers are identified
in the majority of patients. PTEN, a tumor suppressor that regulates the oncogenic PI3K-AKT signaling
pathway, demonstrates complete loss of expression in up to 30% of these tumors. Our previous studies
showed that loss of PTEN is associated with shorter overall survival in stage III melanoma patients, and with
inferior outcomes with targeted therapies in patients with stage IV disease. Building upon these studies,
recently we investigated the impact of PTEN loss on the anti-tumor immune response and immunotherapy.
Initial preclinical studies demonstrated that loss of PTEN in melanomas increases the expression of
immunosuppressive cytokines, decreases the intratumoral infiltration of critical effector T cells, and causes
resistance to T-cell mediated immunotherapy in vitro and in vivo. Analyses of cohorts of advanced melanoma
patients showed that loss of PTEN was associated with decreased CD8+ T cell infiltration in stage III melanoma
patients, and significantly decreased response rates to FDA approved anti-PD-1 antibodies in stage IV disease.
Treatment with GSK2636771, an isoform-specific inhibitor of PI3Kβ, decreased AKT activation, increased T
cell infiltration, and increased the efficacy of anti-PD-1 checkpoint inhibitor therapy in vivo in an
immunocompetent model of PTEN-null, PD-1-resistant melanoma. Notably, GSK2636771 did not harm the
viability or function of immune cells, consistent with the selective dependence on PI3Kβ in cells with PTEN
loss. Based on these studies, we hypothesize that inhibition of the PI3K-AKT pathway will overcome resistance
to anti-PD-1 immunotherapy in melanomas with loss of PTEN. To test this hypothesis, and address the unmet
need for effective therapies for PD-1-refractory patients, we are conducting a phase I/II clinical trial of
GSK2636771 in combination with the anti-PD-1 antibody pembrolizumab in metastatic melanoma patients
with PTEN loss that failed to respond to anti-PD-1. Blood and tumor samples will be collected prior to and
during treatment as well as at progression to improve our understanding of the effects of this regimen and the
results of the trial. In Aim 1 we will determine the effects of this treatment on the activation of the PI3K-AKT
pathway, and the relationship between pathway inhibition, GSK2636771 steady-state levels, and treatment
outcomes. In Aim 2 we will evaluate the immune effects of the combination treatment by evaluating tumor and
blood samples for the presence and changes in immune cell subsets and immunoregulatory cytokines, which
will also be compared to clinical responsiveness. In Aim 3 we will use preclinical models to evaluate intermittent
dosing and combinatorial approaches with additional isoform-selective PI3K inhibitors as strategies to further
improve the efficacy of GSK2636771 with anti-PD-1. These studies will improve our unders...

## Key facts

- **NIH application ID:** 10208808
- **Project number:** 5P50CA221703-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Michael Davies
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,285
- **Award type:** 5
- **Project period:** 2019-07-16 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208808

## Citation

> US National Institutes of Health, RePORTER application 10208808, Project 1 Targeting the PI3K Pathway to Overcome Resistance to Immunotherapy in Melanomas with Loss of PTEN (5P50CA221703-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10208808. Licensed CC0.

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