Thē MRTC®Providing in Vivo Preclinical Testing for

Radiosensitization Research

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

Thē MRTC®[The Murine Radiation Treatment Center]

A B

C D

Abdomen: 4.2%

Throat: 2.0%

Back: 2.2%

Xenograft: 100%

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

The reality of drug development

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

Deficiencies in radiosensitization research

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

Profound knowledge gap in radiobiology

Tumor growth kinetics Response rates Progression/recurrence rates Disease free survival rates Radiation enhancement ratio calculation

◦ Proprietary method

Efficacy metrics

Skin reaction Femoral bone density Mobility End-organ toxicity

Toxicity metrics

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

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

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

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

MRTC project scenarios

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

The brass tacks

How do you catch the big fish?

Fishing expedition?

Thē MRTC®You

GO FISHING!!!

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)

Key Principals [3+ years working together]

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)

Jaimi Blakeman, JD – legal advisor (healthcare law, Loyola University, Chicago 2001)

Advisory Board

Patent◦ Rodent Ionizing Radiation Treatment Device. (U.S. Patent Pending: Application

No.:13/834,025)

Grants, Contracts & Projects ◦ Rachid Drissi, 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 mTOR kinase inhibition as a Radiosensitizer in Pediatric Rhabdomyosarcoma” 2011

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, Houghton PJ. Clinical Cancer Research (In press)

◦ Using NanoDot dosimetry 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

Track record of excellence

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 radiosensitizer performance 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

Unprecedented competative advantage

We hope to share our future with you

Please set up a project for any compound/drug that could benefit from our services!

Thē MRTC®

Thank you for your time and attention!