# P-selectin-Mediated Targeting of PI3K Nanomedicines to the Tumor Microenvironment

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $639,270

## Abstract

SUMMARY
Personalized medicine, based on the genomic context of a patient’s disease, has become a leading strategy to
treat cancer. However, despite the promising results from customized treatments, targeted therapies affect the
same signaling pathways in non-cancerous cells, often leading to dose-limiting, “on-target” toxicities. One such
example involves PI3K inhibitors. In head and neck squamous cell carcinoma (HNSCC), the 6th most common
cancer worldwide, 34%-56% of tumors harbor mutations or amplifications in PIK3CA, the gene coding for the
p110α subunit of PI3K. PI3Kα inhibitors carry a significant toxicity profile, however, that limits their therapeutic
window, specifically in patients who develop intractable hyperglycemia. Using a targeted drug delivery
approach, we have identified a strategy to address this need. The PI developed a new class of nanoparticles
targeted to P-selectin which allows the incorporation of a wide variety of therapeutic molecules, including
targeted therapies (Shamay, Sci Transl Med 2016). We built a collaborative research team that employed this
technology to target tumors expressing endothelial P-selectin, either at baseline or radiation-induced (Mizrachi,
Nat Commun 2017). The strategy effected a significantly improved therapeutic index and survival, while
minimizing the side effects of targeted therapeutics. Notably, we found that PI3K inhibitors, targeted using our
nanoparticle vehicle, resulted in prolonged pS6 inhibition and anti-tumor efficacy, while minimizing acute and
chronic effects of hyperglycemia. The objective of this project is to investigate, in the context of HNSCC, the
nanoparticle-mediated delivery of PI3K therapies via P-selectin, expressed spontaneously or induced by
radiation. This proposal’s goals are to understand the modulation of drug pharmacology, efficacy, toxicities,
interactions with HNSCC tumor microenvironment, and the impact of ionizing radiation on these parameters.
We plan to pursue the following specific aims: 1) Assess P-selectin-mediated targeting to the tumor
microenvironment. We will measure the localization of the nanoparticle and encapsulated drug in the tumor
microenvironment from the organ to cellular levels. 2) Enhance nanoparticle localization via radiation-induced
endothelial activation. Based on our understanding of radiation-induced expression of P-selectin, we
hypothesize that external beam radiation can increase localization of a P-selectin-targeted PI3K inhibitor in
disseminated tumors due to the increased availability of the target. 3) Assess efficacy of P-selectin-mediated
targeting of PI3K inhibitors. We will assess the relationship between drug delivery mechanism and treatment
response. We hypothesize: (i) that the P-selectin-based targeting will improve PI3K inhibitor-mediated efficacy
and apoptosis in tumors, (ii) that radiation may increase the relative efficacy of the inhibitor, (iii) that
nanoparticle-mediated P-selectin targeting will mitigate PI3K-med...

## Key facts

- **NIH application ID:** 10061563
- **Project number:** 5R01CA215719-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Daniel Alan Heller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $639,270
- **Award type:** 5
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061563

## Citation

> US National Institutes of Health, RePORTER application 10061563, P-selectin-Mediated Targeting of PI3K Nanomedicines to the Tumor Microenvironment (5R01CA215719-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10061563. Licensed CC0.

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