# Improving targeted therapy in FLT3-mutated AML

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2021 · $54,000

## Abstract

PROJECT SUMMARY
This is a Supplement for my Mentored Clinical Scientist Development Award (K08-CA230190). K08-CA230190
was funded on 07/01/2020 and details a five-year plan to promote my career as 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 focuses on unanticipated responses 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. I am overjoyed with the birth of my first
child on 11/22/2019; however, this critical life event has reduced my productivity prior to and during Year 1 of
the K08 award period due to childcare demands. This administrative supplement will provide funding for a
research technician to accelerate the pace of experiments and projects to help me continue to move forward in
my path to independence.

## Key facts

- **NIH application ID:** 10277509
- **Project number:** 3K08CA230190-01A1S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Pamela Jeannette Sung
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $54,000
- **Award type:** 3
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10277509

## Citation

> US National Institutes of Health, RePORTER application 10277509, Improving targeted therapy in FLT3-mutated AML (3K08CA230190-01A1S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10277509. Licensed CC0.

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