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Cristel V Camacho, PhD Sandeep Burma, PhD Department of Radiation Oncology June 27, 2013 Genetic Events Underlying Radiation-Induced Gliomagenesis.

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Presentation on theme: "Cristel V Camacho, PhD Sandeep Burma, PhD Department of Radiation Oncology June 27, 2013 Genetic Events Underlying Radiation-Induced Gliomagenesis."— Presentation transcript:

1 Cristel V Camacho, PhD Sandeep Burma, PhD Department of Radiation Oncology June 27, 2013 Genetic Events Underlying Radiation-Induced Gliomagenesis

2 The Space Radiation Problem Galactic Cosmic Rays (GCR) Protons (85%) Alpha particles (14%) High atomic number and high energy (HZE) particles (1%) science1.nasa.gov Solar Energetic Particles Galactic Cosmic Rays Solar Energetic Particles Solar particle events Coronal mass ejections NASA needs to close the knowledge gap on a broad range of biological questions

3 X-rays 1 GeV/n Fe γ science1.nasa.gov Ionizing Radiation and Carcinogenesis

4 NASA Space Radiation Laboratory (NSRL) I.DNA damage responses to gamma- versus particle- irradiation II.Cellular transformation by gamma- versus particle- irradiation III.Mouse models of radiation-induced gliomagenesis science1.nasa.gov

5 Mukherjee B, Camacho CV, et al., DNA Repair 2008 I. DNA damage responses to HZE particles versus gamma-rays Gamma 1 GeV/n Fe Fe ions produce more complex DNA damage Fe ion-induced damage is incompletely repaired - persistent DNA damage signaling - damage-induced senescence - reduced cell survival What are the long term carcinogenic consequences of persistent DSBs such as those induced by Fe ions? Survival Dose (Gy) 1 GeV/n Fe Gamma Mock ~3% ~84% ~24% 1 GeV/n Fe Gamma p53 actin p21 p16/ Ink4a p53 (ser15) 0.5 h 24 h 1 GeV/n Fe γ H2AX 53BP1 γ H2AX 1 GeV/n Fe Gamma % foci remaining Time (hrs)

6 NSCs Astrocytes II. Ink4a/Arf-null astrocytes: A sensitive paradigm for rapidly evaluating the tumorigenic potential of HZE particles IR Tumor suppressor loss Ink4a/Arf-/- Oncogene activation Tumorigenesis McEllin B, Camacho CV, et al., Cancer Research 2010 Mukherjee B, McEllin B, Camacho CV, et al., Cancer Research 2009 p19/Arf Exon 1β Exon 1αExon 2Exon 3 p16/Ink4a Cyclin D CDK 4/6 pRB MDM2p53 IR

7 Gamma 4Gy Fe 1 Gy Mock IR Ink4a/Arf-/- astrocytes irradiated with Fe ions are potently tumorigenic Vol mm 3 Exon 1β Exon 1αExon 2Exon 3 p16/Ink4a p19/Arf Exon 2Exon 1 p15/Ink4b #2 #1 Tumor Ch 4 Ctrlp15

8 Fe 1 Gy (acute) 3 months post-IR Mock Fe Days Post-IR III. Transgenic mouse models of radiation-induced gliomagenesis Ink4a/Arf f/fInk4a-/-;Ink4b-/-;Arf f/f PTEN f/+ Ink4a+/+;Arf+/+ Rapid induction of high-grade gliomas by DNA double-strand breaks

9 Genomic amplification of Met is a frequent event in radiation- induced gliomas Met Amp Non-Amp Met FISH Amp Non-Amp Met pMet Sox2 Actin Par βGal Met V5-tagged Met V5 βGal Met Sox2 Merge βGalMet NSC Soft-agar βGalMet

10 Project Overview Nestin-Cre Ink4a/Arf f/f Nestin-Cre Ink4ab-/-;Arf f/f Nestin-Cre Ink4ab-/-;Arf f/f PTEN f/+ Nestin-Cre Ink4a+/+;Arf +/+ Mock-IR 1Gy Fe (600 MeV/n) 4Gy Gamma-rays 40 HZE particles vs Gamma-rays Molecular Profiling and Validation RNA Expression Profiling Whole Genome aCGH Copy Number Analysis Radiation Protection/Mitigation

11 Acknowledgements Sandeep Burma, PhD Bipasha Mukherjee, PhD Nozomi Tomimatsu, PhD Xiaohuan Gao, PhD Brian McEllin, PhD Mariya Ilcheva Carlos Gil del Alcazar Pavlina Todorova Molly Gillam UTSW Michael D Story, PhD Liang-Hao Ding, PhD Debabrata Saha, PhD Amyn A Habib, MD Xian-Jin Xie, PhD Kimmo Hatanpaa, MD, PhD Adayabalam S Balajee, PhD (Columbia U.) Funding CBP Training Grant (PI: Jerry Shay, PhD) NASA BNL/ NSRL Peter Guida, PhD Adam Rusek, PhD Thesis Committee Robert M Bachoo, MD, PhD David A Boothman, PhD Chaitanya S Nirodi, PhD Past Members Brandon Hahm, MD Nandini Pichamoorthy Kaushik Amancherla Katherine Deland


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