Download MRTC project scenarios

Providing in Vivo Preclinical Testing for
Radiosensitization Research
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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%
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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
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Unknown full clinical potential
◦ Indications for radiosensitization remain untested
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In vitro screens
◦ Tumor biology absent
◦ False discovery rate enormous
 Requires in vivo validation or “jump to clinic”
 Failure, lost revenue, wasted time
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Delivery short cuts
◦ Give large fraction sizes
 Entirely different radiobiology
◦ Lethal whole-animal radiation
 No follow-up possible
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No high throughput in vivo alternatives
◦ SARRP excellent for specialized biologic studies
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Very few resistance mechanisms are known
◦ It goes beyond the known DNA repair mechanisms
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Resistance mechanisms vary from one
malignancy to another
Accept these unknowns as a rationale for
empirical discovery
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Tumor growth kinetics
Response rates
Progression/recurrence rates
Disease free survival rates
Radiation enhancement ratio calculation
◦ Proprietary method
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Skin reaction
Femoral bone density
Mobility
End-organ toxicity
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To determine radio-sensitization efficacy
and/or toxicity of new drugs in development
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A screening across a board spectrum of
malignancies, to capture potential clinical
indications early in the R&D phase
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To determine radio-sensitization efficacy and/or
toxicity of drugs that have failed clinically or preclinically, as monotherapy or chemotherapy adjunct
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Identifies novel indications (concurrent administration
with radiotherapy)
potentially recoup R&D costs
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To determine radio-sensitization efficacy and/or
toxicity of clinically successful anti-cancer drugs
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Optimizes their clinical performance
Identifies any untoward interactions in the setting of
radiotherapy administration
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Perform “murine clinical trials” in which the optimal
timing of radiotherapy administration relative to
systemic agent dosing can be determined
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Neo-adjuvant, concurrent or adjuvant
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Cost benefit ratio
◦ A drug + radiation screen against 20 different
tumor lines (lung, breast, colon, etc.) ≈ $500K
◦ $500K/4B = 0.0125%
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For 0.0125% additional R&D cost
◦ Robust, clinically relevant biologic data generated
◦ New clinical indications discovered
 Approved uses = more sales
Thē MRTC®
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You
How do you catch
the big fish?
GO FISHING!!!
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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)
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Peter Houghton, PhD – scientific advisor (Director of the
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KP Singh, MS – financial advisor (Kellogg School of Business,
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Jim Sommerfeld, BS – technical advisor (30 years material
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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)
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Patent
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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
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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
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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!