Interferons (IFNs) and retinoids are powerful biological response modifiers. Although they are effective growth inhibitors of certain transformed cells, both these agents have limited efficacy as single agents against many tumors. However, they strongly inhibit the growth of several tumor cells when used in combination. We have shown that the IFN-beta+retinoic acid (IFN/RA) combination synergistically inhibits the growth of a variety of breast and other tumors both in vitro and in vivo. More importantly, IFN/RA is cytotoxic to several breast tumor cell lines. Clinical studies also demonstrated potent tumor inhibitory effects of IFN/RA. In the light of this data, it becomes important to understand the changes in gene expression that lead to tumor growth suppression. Previous studies did not suggest a role for known growth inhibitory gene products in IFN/RA induced cell death. Therefore, we hypothesize that IFN/RA combination employs either novel or hitherto unimplicated gene products for inducing cell death. During the last funding period the principal investigator's laboratory identified several candidate genes, Genes associated with Retinoid-IFN induced Mortality (GRIM) that participate in cell death, using a Suppression of Mortality by Antisense Rescue Technique (SMART). SMART permits the isolation of cell death associated genes on the basis of their function within tumor cells. In this proposal we will characterize the mechanism of GRIM action and their relationship to terminal tumor cell death regulators. The proposal will also examine the relevance of GRIMs for cancer therapy in an animal model. These studies are important because GRIMs may: i) represent novel tumor suppressors, ii) serve as markers for disease status and therapeutic response, iii) play a role in death of other cancer types, and iv) be useful in gene therapy. Our understanding of cancer cell death and growth pathways is far from complete. Although discovered by virtue of their role in IFN/RA induced tumor cell death, GRIMs may participate in other physiologic or therapeutic-induced death pathways. Characterization of GRIMs may permit a rational drug design for cancer therapy. Identifying the mechanisms of GRIM inactivation may help understand the therapeutic resistance. Thus, the proposed studies will contribute novel information to the understanding of cancer cell biology and therapy. This proposal is a translational study that provides a basis and the necessary reagents for future phase II trials with IFN/RA or other drug combinations for cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA071401-04
Application #
2898550
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Mccarthy, Susan A
Project Start
1996-08-06
Project End
2002-07-31
Budget Start
1999-08-06
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Zhang, Jun; Yang, Jinbo; Roy, Sanjit K et al. (2003) The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3. Proc Natl Acad Sci U S A 100:9342-7
Kalvakolanu, Dhananjaya V (2003) Alternate interferon signaling pathways. Pharmacol Ther 100:1-29
Hu, Jiadi; Angell, Jon E; Zhang, Jun et al. (2002) Characterization of monoclonal antibodies against GRIM-19, a novel IFN-beta and retinoic acid-activated regulator of cell death. J Interferon Cytokine Res 22:1017-26
Morrison, Bei H; Bauer, Joseph A; Hu, Jiadi et al. (2002) Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics. Oncogene 21:1882-9
Lindner, Daniel J; Ma, Xinrong; Hu, Jiadi et al. (2002) Thioredoxin reductase plays a critical role in IFN retinoid-mediated tumor-growth control in vivo. Clin Cancer Res 8:3210-8
Roy, Sanjit K; Hu, Junbo; Meng, Qingjun et al. (2002) MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma. Proc Natl Acad Sci U S A 99:7945-50
Fang, Yu-Yan; Song, Zan-Min; Wu, Tao et al. (2002) Defective NF-kappaB activation in virus-infected neuronal cells is restored by genetic complementation. J Neurovirol 8:459-63
Joshi, Vishwas D; Kalvakolanu, Dhananjaya V; Hasday, Jeffrey D et al. (2002) IL-18 levels and the outcome of innate immune response to lipopolysaccharide: importance of a positive feedback loop with caspase-1 in IL-18 expression. J Immunol 169:2536-44
Hu, Junbo; Meng, Qingjun; Roy, Sanjit K et al. (2002) A novel transactivating factor that regulates interferon-gamma-dependent gene expression. J Biol Chem 277:30253-63
Ma, Xinrong; Hu, Junbo; Lindner, Daniel J et al. (2002) Mutational analysis of human thioredoxin reductase 1. Effects on p53-mediated gene expression and interferon and retinoic acid-induced cell death. J Biol Chem 277:22460-8

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