Targeting Non-Small Cell Lung Tumors Expressing Mutant p53 with Suicide Genes and Immune Activation
Abstract
Area of Emphasis: Identify innovative strategies for the treatment of lung cancer. Lung cancer is the deadliest of all the cancers in the USA. The ultimate goal of this research is to cure lung cancer. The Cancer Genome Atlas (TCGA) shows that 69% of lung cancers have p53 mutations, most of which are single amino acid changes instilling gain-of-function (GOF) oncogenic properties. It has been demonstrated that lung cancers expressing GOF mutant p53 (GOF p53) lose oncogenicity once the cancer cells lose GOF p53 or when functions of GOF p53 are inhibited. These make GOF p53 a highly desirable cancer therapeutic target. The immediate goal of this project is to develop, for future use, a therapeutic strategy that proposes to use GOF p53 to induce lung cancer cell death in either of two ways: 1. GOF p53 will induce expression of an immune signaling molecule, IL2, to elicit an immune response and kill tumor cells expressing GOF p53. In addition, replication of an otherwise replication-defective adenovirus that can only replicate in the presence of GOF p53 and lyse the cell will be used in combination. As a result of the replication and lysis, more virus is produced, infecting more cells, and killing more cancer cells. 2. GOF p53 will induce suicide gene expression in an adenovirus vector, forcing expression of a killer gene in lung cancer cells expressing GOF p53 only while leaving normal cells with wild-type (WT) p53 unharmed. The suicide gene will be used in combination with a GOF p53-inducible IL2 adenovirus to enhance the tumor-killing effects. The above strategies will be tested using tumors in mouse model systems; tumors will be from both human and mouse sources. If the strategy is successful with animal models, clinical trials will be needed in the foreseeable future (beyond the scope of this proposal) for successful application to human lung cancers that have GOF p53 mutations. Within the grant period of 3 years, a good impression will be obtained regarding how successful the approach is. Successful completion of the work may impact a large percentage of lung cancers that express mutant p53 with amino acid substitutions. Since military Service Members, Veterans, and their families are equally (if not slightly more) affected by lung cancer than the general population is, the therapeutic improvement planned above will have a positive effect on them as well.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210286
Entities
People
- Sumitra Deb
Organizations
- United States Army
- Virginia Commonwealth University