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p53 and p14ARF: Multiple pathways of lung cancer suppression

Institution: Sidney Kimmel Cancer Center
Investigator(s): Ruth Gjerset, Ph.D.
Award Cycle: 2002 (Cycle 11) Grant #: 11RT-0074 Award: $821,050
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
This study will investigate a novel biological strategy to lung cancer treatment based on two central tumor suppressor genes, p53 and p14ARF, whose function is frequently abrogated in lung cancer. This project examines a novel treatment strategy for lung cancer that could have significance for a broad range of lung cancers that fail to be cured by conventional therapy alone. The rationale for the study comes from observations that these two tumor suppressor genes collaborate to trigger an important cellular pathway known as apoptosis, which leads to cell death. Each gene also contributes independently to cell death or arrest of cell growth through separate pathways. We hypothesize that therapies that exploit the two tumor suppressors together will provide a tumor cell-specific treatment strategy with minimal toxicity and superior tumor suppression than those based on p53 alone. We also hypothesize that a better understanding of how ARF contributes to tumor suppression alone and in combination with p53 will provide a basis for the development of more effective tumor suppressor-based therapies applicable to a broader range of lung cancers. ARF + p53-based therapies would be particularly relevant to lung cancer, which is a prime candidate for gene therapy applications in practice today, and which frequently is observed to lose ARF and/or p53. Such therapies could have a major impact for lung cancer treatment, a disease that frequently fails conventional therapy and for which new therapeutic options are urgently needed, by providing a highly effective biological alternative to conventional treatments, and possibly improving tumor responses to conventional therapy. In order to further our understanding of this central pathway in lung cancer so as to fully exploit its potential for therapy, we are proposing a research study to (1) evaluate in both cultured tumor cell lines and in a mouse model for lung cancer the efficacy of ARF-mediated suppression, alone and in combination with p53 and chemotherapeutic drugs, and (2) investigate the biological mechanism by which ARF achieves tumor suppression and identify other components of the pathway that might also be exploited for therapy.
Publications

Enhanced tumor suppression by a p14ARF/p53 bicistronic adenovirus through increased p53 protein translation and stability.
Periodical: Cancer Research Index Medicus:
Authors: Huang Y, Tyler T, Saadatmandi N, Lee C, Borgstrom P, Gjerset R ART
Yr: 2003 Vol: 63 Nbr: Abs: Pg: 3646-3653

Role in the cellular stress response and applications to cancer.
Periodical: Cancer Therapy Index Medicus:
Authors: Huang Y, Gjerset RA ART
Yr: 2003 Vol: 1 Nbr: Abs: Pg: 343-351

Novel stragegies for lung cancer treatment based on p53 and p14ARF
Periodical: TRDRP Annual Report to the State of California Legislature Index Medicus:
Authors: Gjeset R, Huang Y, Lee C, Tyler T, Borgstrom P ABS
Yr: 2003 Vol: Nbr: Abs: Pg:

Antitumor activity and bystander killing by p14ARF
Periodical: American Association for Cancer Research Index Medicus:
Authors: Huang Y, Borgsrom P, Gjerset R ABS
Yr: 2004 Vol: Nbr: Abs: Pg:

DNA damage disrupts the p14 ARF/B23(NPM) interaction and tiggers a transient subnuclear redistribution of p14 ARF (submitted 2005)
Periodical: Cancer Research Index Medicus:
Authors: lee C, Smith BA, Gjerset RA. ART
Yr: 2005 Vol: 65 Nbr: Abs: Pg: 9834-9842

DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer.
Periodical: Journal Molecular Histol Index Medicus:
Authors: Gjerset R, ART
Yr: 2006 Vol: Nbr: Abs: Pg:

Regulation of p14ARF through subnuclear compartmentalization
Periodical: Cell Cycle Index Medicus:
Authors: Gjerset R, Bandyopadhyay K. ART
Yr: 2006 Vol: 5 Nbr: 7 Abs: Pg: 686-690

A bystander effect triggered by p53-mediated apoptosis and mediated by cytotoxic macrophages
Periodical: American Association for Cancer Research Index Medicus:
Authors: Gjerset, R. ABS
Yr: 2006 Vol: Nbr: Abs: Pg:

Novel mechanism of p14ART gene silencing in esophageal cancer
Periodical: American Association for Cancer Research Index Medicus:
Authors: Gjerset, R ABS
Yr: 2005 Vol: Nbr: Abs: Pg:

Tumor suppression by a p14ARF/p53 adenovirus
Periodical: American Association for Cancer Research Index Medicus:
Authors: Gjerset, R ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Anti-tumor activities of p53 and p14ARF in breast and prostate cancer
Periodical: American Association for Cancer Research Index Medicus:
Authors: Gjerset, R ABS
Yr: 0 Vol: Nbr: Abs: Pg: