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Novel Therapy Sensitization Strategy for Lung Cancer

Institution: Torrey Pines Institute for Molecular Studies
Investigator(s): Ruth Gjerset, Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18XT-0164 Award: $450,000
Subject Area: Cancer
Award Type: Exploratory/Developmental Award
Abstracts

Initial Award Abstract
Therapy resistance and therapy toxicity pose major challenges for lung cancer treatment. This study will explore a novel molecularly-targeted strategy for therapy sensitization of lung cancer that could reduce therapy toxicity, improve treatment outcome, and reverse therapy resistance for a large fraction of lung cancer patients whose tumors have failed conventional approaches. The approach involves the use of inhibitors of a group of cellular enzymes known as histone acetyltransferases, or HATs. These enzymes regulate DNA function and are attractive targets for novel drug development, but the development of HAT inhibitors has progressed slowly. Importantly, HATs can promote resistance to several important lung cancer therapeutic drugs that act by damaging cellular DNA by contributing to the cellular process of DNA repair. We have recently observed that treatment of lung cancer cells with the synthetic HAT inhibitor, Spermidine-CoA, (abbreviated below as Spd-CoA) or with a truncated analogue of Spd-CoA, prevents DNA repair and enhances lung cancer cell killing by several lung cancer therapeutic drugs and radiation. The therapy sensitization effect is specific for cancer cells, and therefore will not increase toxicity to normal tissue and may allow lower doses of therapy to be used for all treatment regimens. The synergizing drugs include the lung cancer therapeutic cisplatin (Platinol®), which has been used as a first and second-line therapy for lung cancer, and the plant alkaloid, camptothecin, from which an important class of lung cancer therapeutics is derived (Irinotecan [Camptosar®], Topetecan [Hycamtin]). We hypothesize that these and related compounds that inhibit HAT could constitute a novel class of potent therapy sensitizers for lung cancer that could reduce the toxicity of chemotherapy and greatly improve treatment outcome for advanced disease. We are proposing to test this hypothesis by evaluating the activities in lung cancer cells of the two synthetic spermidine-based HAT inhibitors, as well as several plant-derived HAT inhibitors. We will also examine the basis of cancer cell specificity, as this will provide a rationale for further improvements on inhibitor design (Aim 1). To validate the potential of spermidine-based HAT inhibitors in vivo, we will carry out a rigorous pre-clinical evaluation in mouse models for human lung cancer (Aim II). This study represents a new direction in lung cancer research, and could lead to significant improvements in lung cancer patient survival and quality of life. If successful, the project will lead to a better understanding of the biological properties in vitro and in vivo of two first generation Spd-based HAT inhibitors, and to establish a rationale for a larger full-scale study into the development and characterization of improved spermidine-based structures with increased potency.
Publications

Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo- and radiosensitization
Periodical: Cell Cycle Index Medicus:
Authors: Bandyopadhyay K, Banères JL, Martin A, Blonski C, Parello J, Gjerset RA ART
Yr: 2009 Vol: 1 Nbr: 8 (17) Abs: Pg: 2779-88