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Targeting Hypoxia-inducible Factor to Treat Lung Cancer

Institution: The Burnham Institute for Medical Research
Investigator(s): Siva Kolluri, Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12KT-0111 Award: $509,490
Subject Area: Cancer
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
A major strategy in developing new cancer chemotherapeutics is to identify and target biological processes that differ between normal and malignant cells. Hypoxia, a reduction in the normal level of oxygen in tissue, occurs during lung cancer progression. Tumors become hypoxic because their new blood vessels are abnormal and this results in the tumor cells having an inadequate blood supply. In response, the cancer cells undergo genetic and adaptive changes that allow them to survive and proliferate in a hypoxic environment. These processes contribute to malignancy and aggressive tumor behavior. From the clinical perspective, hypoxia is associated with a resistance to radiation therapy and chemotherapy, because the cancer cells have adapted to environmental conditions that favor survival over programmed cell death (apoptosis).

Hypoxia inducible factor 1 (Hif-1) is a key protein factor activated by hypoxia and is involved in regulating the levels of many protein factors in cancer cells. Vascular endothelial growth factor (VEGF), which promotes new blood vessel growth in tumors, is one of the important genes induced by Hif-1. Other genes regulated by Hif-1 activation are expressed at higher levels in cancer cells than in their normal tissue counterparts, and have roles in lung cancer progression. Hif-1 activity is also correlated with poor response of patients to treatment.

Hif-1 consists of and subunits. Dimerization of and subunits is essential for the ability of Hif-1 to regulate expression of many protein factors contributing to the progression of lung cancer. In this project we will study the association of the two Hif-1 subunits, and screen “libraries” of small chemical compounds to identify molecules that have the ability to interfere with the dimerization between Hif-1 and subunits. Alternatively, we will employ peptides derived from the partner proteins of Hif-1 / to block the association between the two subunits of Hif-1. In this effort we are guided by existing information on the aryl hydrocarbon (Ah) receptor, which is a binding partner for Hif-1 and inhibitory PAS domain protein, which is a binding partner for Hif-1. Thus, there exists good background information on the Hif-1 subunits and their partner proteins to suggest that a comprehensive screening effort will yield good candidate inhibitors of Hif-1 for evaluation. In the first phase of this study, we will be evaluating the ability of the identified inhibitors to abrogate Hif-1 subunit dimerization, DNA binding and transcriptional activity. The biological effect of Hif-1 inhibitors to block hypoxia signaling including the effect on growth and invasiveness of lung cancer cells will also be tested. Our proposed studies have the potential to identify novel agents to prevent and treat tobacco-associated lung cancer.
Publications

Nuclear orphan receptor TR3 targets mitochondria and induces apoptosis through interaction with Bcl-2.
Periodical: Cell Index Medicus:
Authors: Lin B, Kolluri SK, Lin F, Liu W, Cao X, Han Y-h, Dawson M, Reed JC, Zhang X-k ART
Yr: 2004 Vol: 116 Nbr: Abs: Pg: 527-540

The R-enantiomer of the Non-Steroidal Anti-inflammatory Drug Etodolac Binds Retinoid X Receptor and Induces Tumor-selective Apoptosis.
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Kolluri, S.K., Maripat Corr, Sharon James, Michele Berasconi Wen Liu, Desheng Lu ART
Yr: 2005 Vol: 102 Nbr: Abs: Pg: 2525 - 2530

Retinoid x receptor regulates Nur 77/TR3-dependent apoptosis by modulating its nuclear export and mitochondrial targeting.
Periodical: Molecular and Cellular Biology Index Medicus:
Authors: Cao, X., liu, W., Lin, F., Li, H., Kolluri, S.k., ART
Yr: 2004 Vol: 24 Nbr: Abs: Pg: 9705 - 9725

Determinants of retinoid X receptor transciptional antagonism.
Periodical: Journal Medical Chemistry Index Medicus:
Authors: Cavasotto CN, Liu G, James SY Hobbs PD, Peterson VJ, Kolluri, SK. ART
Yr: 2004 Vol: 47 Nbr: Abs: Pg: 4360 - 4372