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.
|Valerio, Daria G; Xu, Haiming; Eisold, Meghan E et al. (2017) Histone acetyltransferase activity of MOF is required for adult but not early fetal hematopoiesis in mice. Blood 129:48-59|
|Shi, Wei; Vu, Therese; Boucher, Didier et al. (2017) Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress. Blood 129:2479-2492|
|Mujoo, Kalpana; Hunt, Clayton R; Horikoshi, Nobuo et al. (2017) A multifaceted role for MOF histone modifying factor in genome maintenance. Mech Ageing Dev 161:177-180|
|Horikoshi, Nobuo; Pandita, Raj K; Mujoo, Kalpana et al. (2016) ?2-spectrin depletion impairs DNA damage repair. Oncotarget 7:33557-70|
|Jacquet, Karine; Fradet-Turcotte, Amélie; Avvakumov, Nikita et al. (2016) The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 through Direct H4K20me Binding and H2AK15 Acetylation. Mol Cell 62:409-421|
|Horikoshi, N; Hunt, C R; Pandita, T K (2016) More complex transcriptional regulation and stress response by MOF. Oncogene 35:2681-3|
|Farooq, Zeenat; Banday, Shahid; Pandita, Tej K et al. (2016) The many faces of histone H3K79 methylation. Mutat Res Rev Mutat Res 768:46-52|
|Mujoo, Kalpana; Butler, E Brian; Pandita, Raj K et al. (2016) Pluripotent Stem Cells and DNA Damage Response to Ionizing Radiations. Radiat Res 186:17-26|
|Gaur, Puja; Hunt, Clayton R; Pandita, Tej K (2016) Emerging therapeutic targets in esophageal adenocarcinoma. Oncotarget 7:48644-48655|
|Sadik, Helen; Korangath, Preethi; Nguyen, Nguyen K et al. (2016) HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells. Cancer Res 76:4443-56|
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