# Improving targeted therapy in KRAS mutant lung cancers

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $45,520

## Abstract

SUMMARY/ABSTRACT
Lung cancer is the leading cause of mortality in the US, affecting 160,000 patients annually with a five-year
survival of 17%. The majority of lung cancers harbor KRAS mutations that overactivate the RAS kinase in the
in the MAPK signaling pathway, RAS-RAF-MEK-ERK. Kinase inhibitors (KIs), which target key effectors of
cancer signaling pathways, constitute a major strategy to treat KRAS-driven lung cancers. Potent MEK
inhibitors exist that inhibit downstream ERK signaling in many tumors, but these also suppress signaling in
normal cells so that their dosing is limited by toxicity, resulting in a narrow therapeutic index. The anti-tumor
effects of MEK inhibitors are also diminished by the activation of the compensatory or parallel FGFR1 pathway,
resulting in drug resistance and tumor resurgence. The co-administration of a second KI of the FGFR1
pathway can mitigate this resistance, but many such combinations of KI are highly toxic. Nanoscale drug
delivery is a promising strategy to overcome the limitations of applying combination KI therapy to KRAS mutant
lung cancer. We have discovered that interactions between charged dyes can stabilize diverse drug cargoes to
form nanoparticles. These dyes have a sulfated surface that exhibits selective uptake by cell types with high
CAV1 expression – such as KRAS lung tumor endothelium. In Aim 1, we propose to investigate the
mechanism of this CAV1 targeting and assess its potential to alter the pharmacokinetic and biodistribution of
packaged drugs versus free drugs. We plan to use pharmacological inhibitors of various endocytosis pathways
in endothelial cells in vitro to confirm that the primary mechanism of nanoparticle uptake is caveolin-mediated
endocytosis. We will also use transwell assays to understand how CAV1 knock out in lung endothelial cells
would alter the ability of nanoparticles to transcytose into the tumor environment. We will then conduct in vivo
time lapse intravital microscopy of the lung tumor microenvironment in mice treated with nanoparticles to see in
real-time how the nanoparticles target, interact, and cross the tumor endothelium. In Aim 2, we will assess the
pharmacodynamics of nanoparticle delivered KIs versus free KIs as well as assess improvements to
therapeutic index of nanoparticle-mediated RAS and FGFR pathway inhibition. Previously, we have found that
nanoparticles resulted in long-term inhibition of pERK in tumors and significantly attenuated inhibition in the
skin, demonstrating that this strategy may obviate a major side-effect of MEK inhibitors – skin toxicities. Upon
completion, this project will result in new findings that may produce novel therapies for the treatment of KRAS
lung cancers. This project would establish that combination therapies could be delivered in nanoparticles that
selectively target only the tumor microenvironment. This selective delivery would alter the dose limiting
toxicities seen by these drugs upon systemic administration. Long ...

## Key facts

- **NIH application ID:** 9980172
- **Project number:** 5F31CA232665-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Ramya Sridharan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-07-11 → 2021-07-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980172

## Citation

> US National Institutes of Health, RePORTER application 9980172, Improving targeted therapy in KRAS mutant lung cancers (5F31CA232665-02). Retrieved via AI Analytics 2026-07-01 from https://api.ai-analytics.org/grant/nih/9980172. Licensed CC0.

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