Importance of ATM in Radiotherapy
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1 Importance of ATM in Radiotherapy Radiology and Physical Medicine María Trinidad Rueda Cáceres
2 Radiotherapy Importance of ATM in Radiotherapy One of the standard treatment options for various malignant cancers Multidisciplinary treatment of cancer: Systemic treatment: Chemotherapy Local treatments: Surgery Radiotherapy RT systemic effects than chemotherapy severe local adverse effects Thecniques to improve RT: Stereotactic RT Fractionated RT Radiosensitizing agents ( cytotoxic effects on cancer cells) Radioprotective agents ( adverse effects on normal cells)
3 Importance of ATM in Radiotherapy Radiosensitizers Hypoxia Hyperthermia Chemotherapeutic agents 5-FU, Cisplatin, Gemcitabine Molecularly targeted therapy Promising therapy in treatment of cancer: In cancer cells: effectiveness of RT In normal cells: harmfulness of RT
4 Importance of ATM in Radiotherapy Radiosensitizers Interest in Molecularly targeted therapy Understanding of DNA repair and cell cycle checkpoints signaling pathways ATM central function Mutations in ATM gene telangiectasia (AT) Investigation of AT Ataxia ATM functions (1)
5 Importance of ATM in Radiotherapy ATM (Ataxia-Telangiectasia Mutated) ATM activation: several mechanisms One important DNA DSBs ATM in normal cells: inactive multimer ATM in cells with DSBs: MRN complex recruits ATM to DSB site autophosphorylation and monomerisation activate monomer
6 Importance of ATM in Radiotherapy ATM activated Kinase: phosphorylation of multiple targets ATM activacion effects and some ATM targets implicated: Cell cycle checkpoints G1-S (p53) Intra-S (Nbs1) G2-M (Chk2) DNA repair (RH and NHEJ) ATM directly or indirectly MRN directly or indirectly Dysfunction of MRN complex or ATM Hypersensitivity to DNA-damaging agents ATM and the MRN complex: targets for radiosensitization (2) (3)
7 Importance of ATM in Radiotherapy ATM inhibitors and MRN complex inhibitors Recent specific inhibitors with great potencial in preclinical studies ATM inhibitors KU Inhibit ATM (Blocks phosphorylation of H2AX, NBS1 and Chk1) CGK733 Inhibit ATM and ATR (Blocks checkpoints pathways) CP Inhibit ATM and its targets MRN complex inhibitors Mirin Inhibit MRN complex-dependent ATM activation
8 About ATM inhibition Importance of ATM in Radiotherapy RECENT STUDIES: Murine model of sarcoma: Result: Deletion of ATM gene: much less radiosensitizing effect on normal cardiac endothelia than on tumor endothelia: Hypothesis: PROLIFERATION differences? After inhibition of proliferation (via SCH72765 treatment) + irradiation: ATM deficiency in endothelial cells was irrelevant if cell cycle block was present in the moment of irradiation CONCLUSIONS Different tissues different response to ATM inhibition this is only due to proliferation or there are other additional factors? SOLUTIONS / ALTERNATIVES: Development in drug delivery: Nanomedicine Carriers with tumor-targeting potencial Telomelysin (oncolytic adenovirotherapy) (1) (4)
9 Telomelysin / OBP-301 Adenoviral E1B55kDa protein inhibit MRN complex Inhibition of ATM activation Inhibition of DNA repair Importance of ATM in Radiotherapy
10 Telomelysin / OBP-301 Importance of ATM in Radiotherapy PROBLEMS: 1. Liver trap % of adenoviruses in blood 2. Adenoviruses are very common cold viruses we have Igs Telomelysin is removed Not effective levels at tumor Limited to cancers confined within locoregional areas CONSECUENCE: only administration by LOCAL INJECTION Neccesity to improve systemic delivery to treat distant metastases (1)
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