# Improving targeted therapy in FLT3-mutated AML

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2020 · $194,670

## Abstract

PROJECT SUMMARY
This application describes my research on cell signaling in acute myeloid leukemia (AML) to be performed within
the context of a 5-year mentored career development plan. My ultimate goal is to become an independent
physician-scientist in the area of laboratory-based academic Hematology/Oncology. Under the guidance of my
primary research mentor, Dr. Martin Carroll, at the University of Pennsylvania (UPENN), I have developed a
structured training plan consisting of intensive laboratory research, didactics, and oversight by an experienced
faculty advisory committee. The proposed research will focus on mechanisms of resistance to FLT3 targeted
therapy in AML based on key insights from the clinical trials of these agents conducted at UPENN. Early
generation FLT3 inhibitors (FLT3i) were met with lukewarm enthusiasm due to poor target specificity and limited
bioavailability. Newer agents have recently been developed with improved activity against FLT3 and clinical
efficacy as evidenced by clearance of leukemic blast cells. However, these agents are not curative and many
patients respond with differentiation rather than eradication of the leukemic clone. This raises important
questions about how FLT3 regulates the differentiation state of leukemia cells. In preliminary studies, I identified
a novel pathway downstream of FLT3 inhibition that leads to rapid downregulation of the histone
methyltransferase, EZH2. EZH2 is the catalytic component of the PRC2 transcriptional repressor. This research
represents the first demonstration of FLT3 regulation of an epigenetic modifier. Loss of EZH2 activity has been
linked to increased myeloid differentiation and decreased leukemogenicity, making it an attractive target to study
as a potential mechanism for FLT3i-induced differentiation. This proposal aims to demonstrate that PRC2 is
necessary for FLT3-ITD leukemogenesis (Aim 1), demonstrate that FLT3i functionally inhibit PRC2 activity (Aim
2), and determine the mechanism of EZH2 downregulation after FLT3 inhibition (Aim 3). These findings will
provide insight into the biology of FLT3 signaling and identify improved approaches to induce terminal
differentiation of FLT3-ITD leukemia cells. In undertaking the proposed studies and training plan, I will develop
the skills and expertise necessary to establish an independent career in translational research.

## Key facts

- **NIH application ID:** 9892570
- **Project number:** 1K08CA230190-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Pamela Jeannette Sung
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,670
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892570

## Citation

> US National Institutes of Health, RePORTER application 9892570, Improving targeted therapy in FLT3-mutated AML (1K08CA230190-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892570. Licensed CC0.

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