# Systemic RNA interference to reactivate p53 tumor suppression

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $353,176

## Abstract

Glioblastoma multiforme (GBM), the most aggressive and prevalent manifestation of malignant glioma, are
characterized by resistance to extant therapeutic modalities, and exhibit a neurologically debilitating course
culminating in death often within 14 months after diagnosis. With this dismal prognosis and a near 100% failure
rate of GBM drug development, the critical challenges facing the glioma field are to identify and characterize
new drug targets to overcome the notorious therapy resistance of GBM, and to develop drug delivery platforms
to target undruggable genetic lesions. Restoration of p53 activity represents an attractive therapeutic strategy
for the treatment of GBM, as ~65% of primary GBM patients express functionally defective wildtype p53.
Amplification and overexpression of the atypical Bcl2 family protein Bcl2L12 (Bcl2-Like-12) compromises p53
function by blocking the transcriptional activity of p53. To inhibit Bcl2L12 function, we propose to use novel
RNAi-based nanoconjugates, termed Spherical Nucleic Acids (SNAs) to neutralize Bcl2L12 expression in
established glioma. We have found that Bcl2L12-targeting SNAs (siBcl2L12-SNAs) are able to traverse cellular
membranes including the blood-brain-barrier. We established that siBcl2L12-SNAs do not require the use of
toxic auxiliary reagents and accumulate effectively in cells and upon crossing of the blood-brain/blood-tumor
barrier in intracerebral gliomas upon systemic delivery. They exhibit stability in physiological environments,
provoke robust intratumoral Bcl2L12 mRNA and protein knockdown and p53 reactivation, and reduce tumor
burden in GBM PDX models. To establish the SNA platform as a p53 activating therapeutic modality applicable
to the treatment of other highly malignant and lethal solid cancers, we elected cutaneous melanoma as a
second cancer type for the evaluation of siBcl2L12-SNAs. Similar to GBM, cutaneous melanoma are
characterized by infrequent p53 mutation and elevated Bcl2L12 expression, which correlates with the degree
of melanoma drug resistance and progression. Here, we will test the hypothesis that Bcl2L12 ablation by a
high activity SNA conjugate increases p53 tumor suppression, reduces GBM and melanoma progression, and
thus represent a novel, broadly applicable therapeutic strategy for the activation of wild-type p53 in solid
cancers. In Aim 1, we will determine the mechanism and identify surrogate markers of p53 reactivation by
siBcl2L12-SNAs. In Aim 2, we will optimize SNA surface chemistry for optimized delivery of siBcl2L12
oligonucleotides to GBM and melanoma tumors. Aim 3 will evaluate siBcl2L12-SNAs in genetically engineered
melanoma (Aim 3a) and GBM mouse models (Aim 3b), as monotherapies, and in combination with the DNA
alkylator temozolomide (Aim 3c). The results of this proposal will provide an in-depth characterization of the
Bcl2L12 oncoprotein at cellular and biological levels, and will pave the way to successfully implement multi-
modal p53 reac...

## Key facts

- **NIH application ID:** 9858303
- **Project number:** 5R01CA208783-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** CHAD A. MIRKIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,176
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858303

## Citation

> US National Institutes of Health, RePORTER application 9858303, Systemic RNA interference to reactivate p53 tumor suppression (5R01CA208783-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858303. Licensed CC0.

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