Tumor-cell-specific targets for combined hyperthermia and radiation effects. The inability of radiotherapy to control tumor growth is still a daunting clinical problem that leads to the failure of many treatment regimens. The fundamental question is: can tumor cells be specifically sensitized to ionizing radiations (IR) by heat by targeting essential molecules or structures exclusively expressed (present) in tumor cells? One such factor, expressed in most tumors and silent in somatic cells, is telomerase. Moreover, differences in telomerase activity and cell kinetics between normal and tumor tissues suggest that targeting telomerase would be relatively safe. In this grant application we propose to understanding how inactivation of ataxia-telangiectasia mutated (ATM) and telomerase could enhance heat mediated and IR-induced tumor cell killing. Our preliminary data suggest that: (1) Heat shock activates ATM signaling pathways that overlap with those activated by IR;(2) Hyperthermia transiently enhanced telomerase activity and;(3) The specific inhibition of telomerase activity by GRN163L (a lipid conjugated synthetic DNA analogue complementary to the template region of telomerase RNA "hTR") increased hyperthermia-mediated IR-induced cell killing. The latter result suggests that telomerase inactivation with GRN163L prior to combined hyperthermia and radiotherapy could improve tumor cell killing, specifically inhibiting tumor growth. Clinical trials are ongoing with telomerase inhibitor (GRN163L), the prospect of adding telomerase-based therapies to the growing list of target-specific radiosensitizing products is therefore promising, but the advantages or limitations of combining telomerase inhibition with altered DNA damage sensing needs to be determined. Therefore, we will determine the mechanistic basis of enhancing heat-mediated radiosensitization (HIR) by inhibiting telomerase and radiation signaling pathways, which result in the tumor growth control. Specifically, we propose to ask the following questions: (1) Does telomerase inhibition by GRN163L enhance heat-mediated IR-induced tumor control with little toxicity to normal tissue? (2) Does simultaneous inactivation of telomerase and ATM, or its recently identified effector hSSB1 (a single-strand DNA binding protein essential for DNA damage detection and repair), synergize heat-mediated IR-induced tumor control? (3) Does heat influence DNA damage sensing and the recruitment of repair proteins to DNA double strand break sites in the presence and absence of telomerase activity? Thus, determining the influence of heat and/or IR on ATM function and telomere metabolism will not only add to our understanding of the mechanisms of HIR but will aid in the development of new tumor treatment strategies.
We propose to investigate the mechanistic basis of enhancing cell killing by inhibiting telomerase prior heat and radiation treatment that could result in the suppression of tumor growth. Our preliminary studies suggest that hyperthermia activates ATM signaling pathways and enhances telomerase activity, thus inactivating telomerase prior heat and radiation treatment would result in increased cell killing. If the proposed research is successfully carried out, the novel information generated from the proposed studies will be useful in designing tumor specific therapies.
|Gupta, Arun; Hunt, Clayton R; Chakraborty, Sharmistha et al. (2014) Role of 53BP1 in the regulation of DNA double-strand break repair pathway choice. Radiat Res 181:1-8|
|Pushpavalli, Sreerangam N C V L; Sarkar, Arpita; Bag, Indira et al. (2014) Argonaute-1 functions as a mitotic regulator by controlling Cyclin B during Drosophila early embryogenesis. FASEB J 28:655-66|
|Bolderson, Emma; Petermann, Eva; Croft, Laura et al. (2014) Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks. Nucleic Acids Res 42:6326-36|
|Gupta, Arun; Hunt, Clayton R; Hegde, Muralidhar L et al. (2014) MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice. Cell Rep 8:177-89|
|Yadav, Vinod Kumar; Thakur, Ram Krishna; Eckloff, Bruce et al. (2014) Promoter-proximal transcription factor binding is transcriptionally active when coupled with nucleosome repositioning in immediate vicinity. Nucleic Acids Res 42:9602-11|
|Pandita, Tej K (2014) Unraveling the novel function of the DNA repair enzyme 8-oxoguanine-DNA glycosylase in activating key signaling pathways. Free Radic Biol Med 73:439-40|
|Sun, Chong-kui; Zhang, Fan; Xiang, Tao et al. (2014) Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers. Oncotarget 5:3375-85|
|Singh, Mayank; Hunt, Clayton R; Pandita, Raj K et al. (2013) Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. Mol Cell Biol 33:1210-22|
|Horikoshi, Nobuo; Kumar, Pankaj; Sharma, Girdhar G et al. (2013) Genome-wide distribution of histone H4 Lysine 16 acetylation sites and their relationship to gene expression. Genome Integr 4:3|
|Gupta, Arun; Hunt, Clayton R; Pandita, Raj K et al. (2013) T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice. Mutagenesis 28:263-70|
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