Thē MRTC®

1. Thē MRTC® Providing in Vivo Preclinical Testing for Radiosensitization Research

2. Thē MRTC®[The Murine Radiation Treatment Center] • A device and animal care strategy with unprecedented preclinical capabilities • All solid tumor malignancies can be studied • Broad spectrum anti-cancer screening • High-throughput focal irradiation • Over 100 mice/hour • Statistically robust • Large-number sample generation • Clinically relevant dosing and treatment schedules • Up to 50 Gy delivered in 25 daily treatments • Treatment associated mortality <0.3% over 4 months • Multiple efficacy and toxicity metrics

3. A B C D Back: 2.2% Throat: 2.0% Abdomen: 4.2% Xenograft: 100%

4. The reality of drug development • Costly with high failure rate • Discovering, developing and launching a new drug (along with the prospective drugs that fail) >$4B • 1/10,000 discovered compounds actually becomes an approved drug for sale • 1/3 approved drugs bring in sufficient revenue to cover their developmental cost • 3/20 approved drugs bring in sufficient revenue to cover previous failures • Unknown full clinical potential • Indications for radiosensitization remain untested

5. Deficiencies in radiosensitization research • In vitro screens • Tumor biology absent • False discovery rate enormous • Requires in vivo validation or “jump to clinic” • Failure, lost revenue, wasted time • Delivery short cuts • Give large fraction sizes • Entirely different radiobiology • Lethal whole-animal radiation • No follow-up possible • No high throughput in vivo alternatives • SARRP excellent for specialized biologic studies

6. Profound knowledge gap in radiobiology • Very few resistance mechanisms are known • It goes beyond the known DNA repair mechanisms • Resistance mechanisms vary from one malignancy to another • Accept these unknowns as a rationale for empirical discovery

7. Efficacy metrics • Tumor growth kinetics • Response rates • Progression/recurrence rates • Disease free survival rates • Radiation enhancement ratio calculation • Proprietary method

8. Toxicity metrics • Skin reaction • Femoral bone density • Mobility • End-organ toxicity

9. MRTC project scenarios • To determine radio-sensitization efficacy and/or toxicity of new drugs in development • A screening across a board spectrum of malignancies, to capture potential clinical indications early in the R&D phase

10. MRTC project scenarios • To determine radio-sensitization efficacy and/or toxicity of drugs that have failed clinically or pre-clinically, as monotherapy or chemotherapy adjunct • Identifies novel indications (concurrent administration with radiotherapy) • potentially recoup R&D costs

11. MRTC project scenarios • To determine radio-sensitization efficacy and/or toxicity of clinically successful anti-cancer drugs • Optimizes their clinical performance • Identifies any untoward interactions in the setting of radiotherapy administration

12. MRTC project scenarios • Perform “murine clinical trials” in which the optimal timing of radiotherapy administration relative to systemic agent dosing can be determined • Neo-adjuvant, concurrent or adjuvant

13. The brass tacks • Cost benefit ratio • A drug + radiation screen against 20 different tumor lines (lung, breast, colon, etc.) ≈ $500K • $500K/4B = 0.0125% • For 0.0125% additional R&D cost • Robust, clinically relevant biologic data generated • New clinical indications discovered • Approved uses = more sales

14. Fishing expedition? • How do you catch the big fish? You Thē MRTC® GO FISHING!!!

15. Key Principals [3+ years working together] • Mamata Singh, PhD – co-partner, director of marketing and customer relations (Expertise in both molecular biology and clinical trials research) • Kathryn Bondra, BS – co-partner, director of animal operations (15 years of experience in animal care, co-inventor of the MRTC device/process) • Christopher Pelloski, MD – co-partner, director of experimental design and analysis (American Board of Radiology certified clinical radiation oncologist, co-inventor of the MRTC device/process)

16. Advisory Board • Peter Houghton, PhD – scientific advisor (Director of the Pediatric Preclinical Testing Program (PPTP)) • KP Singh, MS – financial advisor (Kellogg School of Business, OSU) • Jim Sommerfeld, BS – technical advisor (30 years material fabrication specialist, co-inventor of the MRTC device/process) • JaimiBlakeman, JD – legal advisor (healthcare law, Loyola University, Chicago 2001)

17. Track record of excellence • Patent • Rodent Ionizing Radiation Treatment Device. (U.S. Patent Pending: Application No.:13/834,025) • Grants, Contracts & Projects • RachidDrissi, PhD, Cincinnati Children’s Hospital “The Investigation of Telomerase Inhibition as a Radiosensitizer in High-Grade Pediatric Brain Tumors” 2013 • RFA-RM-09-3011 (NIH R01) “Therapeutic Exploitation of Mutant BRAF for Astrocytoma” 2013 • The Roche Group “The Investigation of MDM2 Inhibition as a Radiosensitizer in Pediatric Rhabdomyosarcoma” 2012 • AstraZeneca “Investigation of mTORkinase inhibition as a Radiosensitizer in Pediatric Rhabdomyosarcoma” 2011

18. Track record of excellence • Publications • “FANCD2 is a Potential Therapeutic Target and Biomarker in Alveolar Rhabdomyosarcoma Harboring the PAX3/FOXO1 Fusion Gene.”Singh M, Leasure J, Chronowski C, Geier B, Bondra K, Duan W, Hensley L, Villalona-Calero M, Li N, Vergis A, Kurmasheva R, Shen C, Woods G, Sebastian N, Fabian D, Kaplon R, Hammond S, Palanichamy K, Chakravarti A, HoughtonPJ. Clinical Cancer Research(In press) • Using NanoDotdosimetry to study the RS 2000 X-ray Biological Irradiator.” Lu L, Bondra K, Gupta N, Sommerfeld J, Chronowski C, Leasure J, Singh M,Pelloski CE. Int J Radiat Biol.2013 Jul 29. PMID: 23786571 • “Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks.” Shen C, Oswald D, Phelps D, Cam H, Pelloski CE, Pang Q, Houghton PJ. Cancer Res. 2013 Jun 1;73(11):3393-401. PMID: 23633493 • “The application of radiation therapy to the Pediatric Preclinical Testing Program (PPTP): results of a pilot study in rhabdomyosarcoma.” Kaplon R, Hadziahmetovic M, Sommerfeld J, Bondra K, Lu L, Leasure J, Nguyen P, McHugh K, Li N, Chronowski C, Sebastian N, Singh M, Kurmasheva R, Houghton P, Pelloski CE. Pediatr Blood Cancer. 2013 Mar;60(3):377-82. PMID: 22692929

19. Unprecedented competative advantage • We have developed a high throughput mouse-flank irradiator, delivering full intended doses to flank xenografts, while our custom shielding blocks 95-99% of the non-targeted animal • We can irradiate >100 mice per hour • We have designed our system to deliver any clinically relevant dosing schemes which faithfully recapitulate the clinical experience • Our model is based upon a living system, recreating “real-world” tumor conditions limiting the number of false-positive and false-negative findings seen in the setting of irrelevant in vitro biology • Our endpoints provide more comprehensive interpretation of data due to prolonged post treatment observation periods • Our results provide an unprecedented insight into radiosensitizerperformance before initiating costly and public clinical trials or to identify new indications to recoup lost R&D costs • We have an experienced team of experts

20. We hope to share our future with you Please set up a project for any compound/drug that could benefit from our services!

21. Thē MRTC® Thank you for your time and attention!