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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 A B C D Back: 2.2% Throat: 2.0% Abdomen: 4.2% 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 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 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 Tumor growth kinetics Response rates Progression/recurrence rates Disease free survival rates Radiation enhancement ratio calculation ◦ Proprietary method Skin reaction Femoral bone density Mobility End-organ toxicity 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 To determine radio-sensitization efficacy and/or toxicity of drugs that have failed clinically or preclinically, as monotherapy or chemotherapy adjunct Identifies novel indications (concurrent administration with radiotherapy) potentially recoup R&D costs 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 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 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 Thē MRTC® You How do you catch the big fish? 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, coinventor of the MRTC device/process) Christopher Pelloski, MD – co-partner, director of experimental design and analysis (American Board of Radiology certified clinical radiation oncologist, coinventor of the MRTC device/process) Peter Houghton, PhD – scientific advisor (Director of the KP Singh, MS – financial advisor (Kellogg School of Business, Jim Sommerfeld, BS – technical advisor (30 years material Jaimi Blakeman, JD – legal advisor (healthcare law, Loyola Pediatric Preclinical Testing Program (PPTP)) OSU) fabrication specialist, co-inventor of the MRTC device/process) University, Chicago 2001) Patent Grants, Contracts & Projects ◦ Rodent Ionizing Radiation Treatment Device. (U.S. Patent Pending: Application No.:13/834,025) ◦ 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 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 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 Please set up a project for any compound/drug that could benefit from our services! Thank you for your time and attention!