# Project 3: Using RNAi-based Spherical Nucleic Acid (SNA) Nanoconjugates Targeting Bcl2L12 to Promote Therapy-Induced Apoptosis in Glioblastoma

> **NIH NIH P50** · NORTHWESTERN UNIVERSITY · 2020 · $347,798

## Abstract

PROJECT 3: SUMMARY
Glioblastoma (GBM), the most aggressive and prevalent manifestation of malignant glioma, is characterized by
resistance to extant therapeutic modalities, and exhibit a neurologically debilitating course culminating in death,
often within 14 months after diagnosis. Among the critical challenges for improving treatment outcomes for
GBM patients are the identification and characterization of new drug targets to overcome the notorious therapy
resistance of GBM, and the development of 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 wildtype but functionally suppressed 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 GBM.
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 GBM tumor cells upon crossing the blood-brain/blood-tumor barrier in
intracerebral GBM xenografts following systemic administration of the SNAs. SNAs exhibit stability in
physiological environments, provoke robust intratumoral Bcl2L12 mRNA and protein knockdown resulting in
p53 reactivation, and slow tumor growth in GBM patient derived xenograft (PDX) models. Here, we will further
investigate the hypothesis that Bcl2L12 ablation by SNA treatment increases p53 tumor suppression, slows
GBM progression, and can be combined with conventional genotoxic therapies as well as with targeted
therapeutics for improved suppression of tumor growth, and possibly for causing tumor regression. In Aim 1,
we will determine siBcl2L12 treatment effect in patient-derived glioma-initiating cells (GICs) in vitro, and in PDX
models in vivo, as monotherapy and in combination with radiation therapy (RT). In Aim 2, using both PDX
models for newly diagnosed and recurrent tumor, together with syngeneic, immunocompetent mouse models,
we will combine siBcl2L12 with cytotoxic and p53-activating chemotherapeutic drugs, i.e., the DNA alkylator
temozolomide and the MDM2 inhibitor RG7388, respectively. Aim 3 proposes a phase 0 clinical trial of
siBcl2L12-SNAs, to determine SNA pharmacokinetics, biodistribution, and ability to downregulate GBM-
associated Bcl2L12 mRNA and protein. The results of this proposal will provide an in-depth characterization of
the Bcl2L12 oncoprotein as an actionable GBM oncoprotein, and will pave the way to successfully implement
SNA-mediated, multi-modal p53 reactivation as a therapeutic approach to incorporate in clinical practice.

## Key facts

- **NIH application ID:** 9981700
- **Project number:** 5P50CA221747-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Alexander H. Stegh
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,798
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981700

## Citation

> US National Institutes of Health, RePORTER application 9981700, Project 3: Using RNAi-based Spherical Nucleic Acid (SNA) Nanoconjugates Targeting Bcl2L12 to Promote Therapy-Induced Apoptosis in Glioblastoma (5P50CA221747-03). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/9981700. Licensed CC0.

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