Presentation on theme: "2 E Conférence Québécoise Sur La Résistance Thérapeutique du Cancer Q-CROC Montréal, November 5-6, 2010."— Presentation transcript:
2 E Conférence Québécoise Sur La Résistance Thérapeutique du Cancer Q-CROC Montréal, November 5-6, 2010
Potential Conflict of Interest Dr. Thierry Muanza –None
Radiotherapy Along with surgery and chemotherapy, radiotherapy is a mainstay of cancer treatment 75% cancer patients in the course of their disease will undergo radiotherapy
Radiobiology IR local release of large amount of energy ~ 33eV dissipated / ionizing event, enough to break strong chemical bond energy associated C=C bond is 4.9 eV Types: Electromagnetic particulate
Radiation Induced DNA Damage http://www.radiation-scott.org/radsource
Chromosomal Damage ApoptosisReproductive death Necrosis
Radiation Induced DNA Damage ATM G1 arrest Repair G2 arrest G1 arrest Apoptosis G2 arrest pH2XA P53 BAX Cytochrome c Apaf1 Caspase 9 Caspase 6 Caspase 3 Apoptosis P53 Cycline B N Cycline-B-p34 cdc2 p21 WAF1 / CIPI cdK /Cycline D Cycline E pRb E2F pRb E2F Smac/ Diablo Survivin
DNA Repair Mechanisms ATM DSB Rad51 /Rad52 Rad52/MRE11/NBSI BRAC1/BRAC2 Completion of DSB repair DNA-PKcs / Ku80/70 MRE11/Rad51/NBSI DNA ligase IV, XRCC4 RNA Pol II or XPC XPD / XPB ERCC1 / XPG Completion of repair DNA Pol / ligase DNA Pol / DNA ligase III XRCC1 BER NHEJ HR pH2aX NER SSB
EGFR Signaling Pathway TK TGF RAS RAF ERK1/2 BAD Apoptosis Caspase 9 Caspase 3 Survival AKT EGFR P Serine136 Serine112 P PI3K P Over-expression of EGFR associates with activation of the AKT pathway. P HER2 MEK
Conclusions Significant cell killing in cells exposed to combination of ionizing radiation with ZRBA1. Higher G2M arrest in cells exposed to the combined treatment. The most effective schedule for this combination is administration of drug before and / or concurrent with radiation. ZRBA1 potentiates the effect of radiation in MDA-MB-468 cells. The combination of IR and ZRBA1 induces the formation of γH2AX foci.
Future Plans Better understanding of the molecular mechanism induced by this novel therapeutic approach. Evaluate the status of DNA repair proteins. Evaluate the expression levels of antiapoptotic and proapoptotic proteins. Investigation for other possible modes of cell death. In-vivo correlative studies.
Cancer Stem Cells Self-renewing cell Pluripotent cell: recapitulate its tumor in SCID mice
Future directions Clinical models for identification of RT resistance Rectal cancer CNS tumors Zevalin resistant lymphoma
Acknowledgments Dr. Thierry Muanza - Mitra Heravi - Lillian Lee - Azusa Maeda - Ava Schlisser Dr. Danuta Radzioch Dr. Bertrand Jean-Claude (Cancer Drug Research Laboratory) - Dr. Zakaria Rachid - Margarita Todorova