# Targeting lung tumors expressing mutant p53 with oncolytic viruses and suicide genes

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $429,763

## Abstract

Mutations of the p53 gene are found in the majority of lung cancers and most of these mutations are single
amino acid changes instilling gain-of-function (GOF) oncogenic phenotypes, making the GOF p53 oncoprotein
an excellent cancer therapeutic target. We propose a radically different approach to current GOF p53 targeting
therapeutic concepts in which instead of inhibiting the protein, we weaponize GOF p53 in promoting lung cancer
cell death, either by suicide, viral lysis, or both, while leaving normal cells unscathed. This innovative strategy
is possible based on our discovery of a unique transactivation mechanism for GOF p53, and from that, our
creation of a GOF p53 inducible promoter. Our GOF p53 inducible promoter directs expression of any gene
cloned downstream only if the cell has a GOF p53 mutation, with wild-type (WT) p53 having no effect on the
promoter and cells with WT p53 or p53 null mutations showing no expression. For our first major goal, we
propose using an exciting new oncolytic virus that only replicates, propagates, and kills cancer cells with GOF
p53 while having no effect on normal cells. We have placed two adenoviral early genes, E1A and E1B, the
genes needed for adenoviral replication, under the control of the GOF p53 inducible promoter within an
adenoviral vector. Initial studies show that this virus has remarkable oncolytic ability and specificity for lung
cancer cells with GOF p53, with no effect or viral growth whatsoever in cells with WT p53. The killing effects in
xenograft tumors with GOF p53 appear as though there is sustained accelerated tumor killing after a short delay
of when the virus is injected. We propose to enhance the oncolytic virus by adding additional lysis abilities and
by combining the suicide strategy with the oncolytic strategy. Preliminary results look very promising for this
combination. For our second goal, we propose devising a means of specifically killing lung cancer cells with
GOF p53 mutations by cloning a suicide gene downstream of our GOF p53 inducible promoter. This construct
will be introduced into an adenoviral vector so that when the virus infects cells, only cells with a GOF p53 mutation
(cancer cells) will die from prodrug treatment. We have created such a virus using the Herpes Thymidine Kinase
suicide gene and show striking killing effects and specificity for lung cancer cells with GOF p53 both in culture
and in xenograft tumors. We aim to further discover how this strategy works and ways to improve it. We propose
the use of the bacterial Cytosine Deaminase suicide gene (bCD) to enhance the bystander effect of our GOF
p53 specific suicide virus. In addition, we propose to improve the inducibility of our GOF p53 inducible promoter
to further enhance the suicide and oncolytic viruses. The potential impact of this work is far-reaching since these
strategies should be applicable for any cancer with GOF p53 mutations, which constitutes over half of all cancers.

## Key facts

- **NIH application ID:** 10052896
- **Project number:** 1R01CA238515-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Sumitra Deb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,763
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052896

## Citation

> US National Institutes of Health, RePORTER application 10052896, Targeting lung tumors expressing mutant p53 with oncolytic viruses and suicide genes (1R01CA238515-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10052896. Licensed CC0.

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