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Cristel V Camacho, PhD Sandeep Burma, PhD Department of Radiation Oncology June 27, 2013

Genetic Events Underlying Radiation-Induced Gliomagenesis. Cristel V Camacho, PhD Sandeep Burma, PhD Department of Radiation Oncology June 27, 2013. The Space Radiation Problem. Solar Energetic Particles Solar particle e vents Coronal mass ejections.

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Cristel V Camacho, PhD Sandeep Burma, PhD Department of Radiation Oncology June 27, 2013

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

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

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

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

  5. I. DNA damage responses to HZE particles versus gamma-rays 1 GeV/n Fe Gamma 1 GeV/n Fe γH2AX p53 (ser15) Gamma p53 0.5 h p21 % foci remaining p16/ Ink4a 1 GeV/n Fe 1 GeV/n Fe actin Gamma 24 h Mock Gamma 1 GeV/n Fe γH2AX Time (hrs) 53BP1 ~3% ~24% ~84% • Fe ions produce more complex DNA damage • Fe ion-induced damage is incompletely repaired • persistent DNA damage signaling • damage-induced senescence • reduced cell survival Survival Dose (Gy) • What are the long term carcinogenic consequences of persistent DSBs such as those induced by Fe ions? Mukherjee B, Camacho CV, et al., DNA Repair 2008

  6. IR IR Tumor suppressor loss Ink4a/Arf-/- Oncogene activation Tumorigenesis II. Ink4a/Arf-null astrocytes: A sensitive paradigm for rapidly evaluating the tumorigenic potential of HZE particles Cyclin D CDK 4/6 p16/Ink4a pRB Exon 1β Exon 1α Exon 2 Exon 3 p19/Arf MDM2 p53 NSCs Astrocytes McEllin B, Camacho CV, et al., Cancer Research 2010 Mukherjee B, McEllin B, Camacho CV, et al., Cancer Research 2009

  7. Mock (0/8) g 1Gy (0/8) 250 Fe g 4Gy (2/8) Gamma Fe 1 Gy (12/12) 200 150 p15/Ink4b 100 Exon 1 Exon 2 50 0 0 20 40 60 DAY Ink4a/Arf-/- astrocytes irradiated with Fe ions are potently tumorigenic Mock IR Fe 1 Gy Vol mm3 Gamma 4Gy Ch 4 Ctrl p15 Tumor #1 #2 p16/Ink4a Exon 1α Exon 2 Exon 3 Exon 1β p19/Arf

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

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

  10. Project Overview Nestin-Cre Ink4ab-/-;Arf f/f PTEN f/+ Nestin-Cre Ink4a+/+;Arf +/+ Nestin-Cre Ink4a/Arf f/f Nestin-Cre Ink4ab-/-;Arf f/f Mock-IR 40 40 40 40 40 40 1Gy Fe (600 MeV/n) 40 40 40 4Gy Gamma-rays 40 40 40 HZE particles vs Gamma-rays RNA Expression Profiling Whole Genome aCGH Copy Number Analysis Molecular Profiling and Validation 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 Thesis Committee Robert M Bachoo, MD, PhD David A Boothman, PhD Chaitanya S Nirodi, PhD 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.) Past Members Brandon Hahm, MD NandiniPichamoorthy KaushikAmancherla Katherine Deland BNL/ NSRL Peter Guida, PhD Adam Rusek, PhD Funding CBP Training Grant (PI: Jerry Shay, PhD) NASA

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