# Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates

> **NIH NIH R01** · NORTHEASTERN UNIVERSITY · 2021 · $374,660

## Abstract

Project Summary/Abstract
 Mutant forms of KRAS are a key driver in human tumors but remains refractory to therapeutic intervention
despite over three decades of research. Clinical attempts to directly or indirectly inhibit KRAS function have
both yielded unsatisfactory results. The difficulty for developing small molecule KRAS inhibitors has heightened
the importance of alternative methods targeting the oncogene. One such strategy involves therapeutic nucleic
acids, which make it possible to deplete target proteins that are intractable to conventional drug modalities. We
have developed a novel form of nucleic acid therapeutics, termed pacDNA, that substantially enhances the
antitumor activity of nucleic acid drugs by elevating in vivo stability, accelerating cellular uptake, and improving
plasma pharmacokinetics and tumor accumulation, allowing a much lower dosage to be used compared to
conventional methods. The pacDNA also suppresses nearly all side effects associated with traditional nucleic
acid drugs by reducing unwanted nucleic acid-protein interactions. In this proposal, we aim to build upon our
promising preliminary results, and gain deeper insights into the cell biology of the pacDNA with respect to cell
uptake mechanism, intracellular trafficking, KRAS depletion and subsequent cell signaling, and demonstrate
efficacy in KRAS-dependent non-small cell lung cancer cell lines and 3D models. In addition, we will study the
primary pharmacology and antitumor activity of pacDNA in advanced preclinical lung cancer models including
an orthotopic tumor model, a patient derived tumor model, and a syngeneic genetically engineered mouse
model (GEMM), and perform initial in vivo safety and tolerability studies. The outcome of this project will be a
safe and potent anti-KRAS agent that can be readily translated into clinical studies for non-small cell lung
cancer and potentially additional cancer classes.

## Key facts

- **NIH application ID:** 10210369
- **Project number:** 5R01CA251730-02
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Ke Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,660
- **Award type:** 5
- **Project period:** 2020-07-06 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210369

## Citation

> US National Institutes of Health, RePORTER application 10210369, Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates (5R01CA251730-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210369. Licensed CC0.

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