# Mechanisms by which of GPCR Signaling Inhibits Acute Myeloid Leukemia

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $46,036

## Abstract

Project Summary:
Despite recent advances in cancer therapy the 5-year overall survival rate of Acute Myeloid Leukemia (AML)
remains around 30%. The first line standard of care therapy for AML is chemotherapy, which is ineffective in
relapsed patients and often too toxic to be administered to older patients. Targeted therapy such as venetoclax
and decitabine have only shown modest effects in the clinic, calling for different approaches in targeting AML.
Our lab has shown that one such approach is through the activation of the Gs-coupled G-protein coupled
receptor, G-protein Coupled Estrogen Receptor (GPER). Work from our lab has shown that pharmacological
activation of GPER with LNS8801 induces differentiation, promotes growth inhibition, and drives
immunogenicity in melanoma without observable toxicity in animal models. I have shown that primary AML
cells and AML cell lines that are exposed to LNS8801 induce cell death, which is likely through apoptosis
based on positive Annexin V and PI staining, in addition to growth arrest. LNS8801 induced cell death is
accompanied by the depletion of Mcl-1, which is an anti-apoptotic protein that is often overexpressed in cancer
cells. Additionally, I found that death response to GPER activation highly correlates with the mutational status
of FLT3, specifically FLT3-ITD. FLT3-ITD mutants maintain survival through constitutive activation of AKT,
which consequently maintains Mcl-1 expression. Although FLT3 inhibitors are used in clinic, patients inevitably
succumb to disease due to development of resistance. FLT3-ITD vulnerability to GPER activation indicates
that LNS8801 may be able to be used as a novel therapeutic approach for FLT3-ITD mutant patients. Seeing
that activation of GPER may lower the apoptotic threshold in AML, I tested whether LNS8801 can enhance the
efficacy of cytarabine in vitro and showed that combination therapy is more effective than either drug alone.
Based on these preliminary data, I will perform experiments to 1) Define the mechanism by which Gs-coupled
GPCRs induce apoptosis in AML cells and to 2) test efficacy of LNS8801 alone and combination with
cytarabine in vivo AML models. In aim 1, I will first determine whether the depletion of Mcl-1 is responsible for
cell death by genetically manipulating the expression of Mcl-1 in the presence or absence of drug. Next, I will
determine whether Mcl-1 depletion is mediated through AKT depletion. I will then test whether FLT3-ITD
mutation renders cells more vulnerable to GPCR activation by measuring the viability of a panel of FLT3-ITD
and FLT3wt primary samples that are exposed to GPCR agonists. I will also overexpress FLT3-ITD in FLT3wt
and FLT3 null cells to test whether they become more sensitive to GPCR activation. Next, in aim 2, I will test
whether LNS8801 alone can effectively inhibit AML in vivo. I will also determine whether LNS8801 enhances
the efficacy of cytarabine in vivo with limited toxicity. Together, these aims will define t...

## Key facts

- **NIH application ID:** 10315637
- **Project number:** 1F31CA265219-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** In Young Lee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-07-12 → 2023-07-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315637

## Citation

> US National Institutes of Health, RePORTER application 10315637, Mechanisms by which of GPCR Signaling Inhibits Acute Myeloid Leukemia (1F31CA265219-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10315637. Licensed CC0.

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