# Engineering ERK-specificity for cancer suicide gene therapy

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2020 · $415,245

## Abstract

PROJECT SUMMARY
Dys-regulated signaling through the Ras/ERK pathway, initiated by receptors including EGFR and MET, is a
common driver of resistance to therapy in glioblastoma multiforme (GBM), and other cancers. Despite
intensive efforts to develop robust inhibitors of this pathway, Ras/ERK signaling remains an elusive target
across oncology. Here, we propose a new way to target Ras/ERK signaling in GBM through an ERK-
dependent “suicide gene” approach. The aim is to introduce exogenous genes that drive the selective
conversion of non-toxic prodrugs to lethal substances. The HSVtk/GCV (Herpes simplex virus thymidine
kinase/ganciclovir) prodrug system is one such strategy. Integration of the HSVtk gene into the host (cancer)
cell genome enables phosphorylation of GCV, an acyclic analog of the 2’-deoxyguanosine nucleotide, which
competes with guanine during DNA synthesis. We recently developed a new strategy in which HSVtk
expression is regulated by ERK activity. Specifically, we engineered a viral vector that expresses a fusion of
HSVtk with a domain from the transcription factor fos-related antigen 1 (FRA1) and a nuclear localization
sequence. ERK phosphorylation of the FRA1 fragment slows the turnover of the HSVtk fusion, which becomes
lethal at sufficient expression levels in the presence of GCV. Preliminary data demonstrate that the GBM cell
expression of the new suicide gene construct can indeed drive DNA damage-dependent death in an ERK
activity-dependent manner. Here, we propose to advance this preliminary work through two complementary
specific aims. In our first aim, we will demonstrate the ability of the suicide gene product (termed HSVtk-FIRE)
to selectively kill specific GBM tumor cell types (versus other cell types found in GBM tumors) based on high
Ras activity and to test its ability to cooperate with approved or investigational therapeutics. In our second aim,
we will determine whether HSVtk-FIRE can be used as an effective therapy in mouse models of GBM. The
second aim will feature the application of convection-enhanced delivery to promote delivery of viral vectors that
will transduce tumor cells with the suicide gene either with or without focused ultrasound, which has been
shown in preliminary studies to promote convection-enhanced delivery in the brain. Ultimately, these studies
will advance the possibility of adding a powerful new approach for targeting elevated Ras activity in
glioblastoma and other cancers. Such approaches are desperately needed—particularly in GBM, where new
improvements in patient survival have not occurred in many years despite knowledge of targetable molecular
processes such as Ras/ERK signaling that should provide opportunities for improved patient outcomes.

## Key facts

- **NIH application ID:** 10044569
- **Project number:** 1R21CA252576-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Matthew J Lazzara
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $415,245
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044569

## Citation

> US National Institutes of Health, RePORTER application 10044569, Engineering ERK-specificity for cancer suicide gene therapy (1R21CA252576-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10044569. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*