# Preclinical Validation of Dual-Modal Nanotherapy for Chronic Myeloid Neoplasms and Beyond

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $192,020

## Abstract

PROJECT SUMMARY
Preclinical Validation of Dual-Modal Nanotherapy for Chronic Myeloid Neoplasms and Beyond
 Multiple pathological pathways concomitantly contribute to cancer development and progression.
Single-modal therapies for cancer are ineffective and often lead to resistance against the therapies. To
achieve our long-term goal of developing an effective and safe therapy for hematologic malignancies,
the objective of this study is to pre-clinically validate the targeted therapeutic effects of combination
gene therapy and tyrosine kinase inhibition, which function through simultaneously tackling multiple
pathological pathways associated with cancer. This study hypothesizes that simultaneously
upregulating a pro-apoptotic protein, BIM, and silencing a pro-survival protein, MCL-1, particularly in
combination with a BCR-ABL or JAK1/2 tyrosine kinase inhibitor (TKI), will effectively eradicate BCR-
ABL+ (Philadelphia chromosome-positive [Ph+]) and Ph- JAK2V617F+ leukemia, respectively, in
physiologically-relevant syngeneic and patient-derived xenograft animal models. This approach also
minimizes the chance of developing drug-resistance. Guided by strongly supportive preliminary results
using viral/nonviral chimeric nanoparticles (ChNPs) consisting of a BIM-encoding adeno-associated
virus (AAV) at the core and a MCL-1 siRNA encapsulating, acid-degradable polymeric shell, the central
hypothesis will be tested by pursuing specific aims to demonstrate 1) enhanced imatinib (BCR-ABL
inhibitor) therapy for BCR-ABL+ leukemia by ChNPs, and 2) inhibited JAK2V617F+ MPN in combination
with ruxolitinib (JAK1/2 inhibitor), using preclinical models that closely simulate clinical myeloid
neoplasms. This study is expected to develop highly effective, molecularly targeted, and synergistic
therapies for hematological malignancies using conventional (TKI) and emerging (gene therapy for
multiple pathways) therapeutic modalities. This research is innovative because it will develop a dual-
modal therapy (gene and chemotherapy; two genes simultaneously expressed and silenced) using
virus/polymer hybrid gene carriers in combination with a synthetic drug. The significance of this study
is the development and validation of effective, targeted, and synergistic cancer therapies that
addresses current clinical challenges. The paradigm to be explored in this study can make a prolonged
impact on developing efficient and safe therapies for a broad range of diseases that are often attributed
to multiple abnormal pathways.

## Key facts

- **NIH application ID:** 9848510
- **Project number:** 5R21CA228099-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Young Jik Kwon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,020
- **Award type:** 5
- **Project period:** 2019-01-09 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848510

## Citation

> US National Institutes of Health, RePORTER application 9848510, Preclinical Validation of Dual-Modal Nanotherapy for Chronic Myeloid Neoplasms and Beyond (5R21CA228099-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9848510. Licensed CC0.

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