2014 Holiday Fundraiser The KressWorks Foundation

COPYRIGHT © The KressWorks Foundation 2014 THE DAWN OF THE THIRD REVOLUTION IN MEDICINE BEGINS WITH YOU THE KRESSWORKS FOUNDATION IS A MICHIGAN NONPROFIT, IRS DESIGNATED 501C3 CHARITABLE CORPORATION

AGENDA • KWF Background • Summary of Current Status in Cancer Treatment • KWF Approach and Project Accomplishments To Date – Root Cause Analysis: DNA Double Strand Break Simulation – Pathways and Data Analysis – Systematic Treatment Methodology • Next Steps – 2015 Projects – Projected Financial Requirements • Questions COPYRIGHT © The KressWorks Foundation 2014

WHAT WE WILL ACHIEVE A Clinically Applicable Systematic Treatment Methodology that will be used to treat and cure people suffering from cancer. COPYRIGHT © The KressWorks Foundation 2014

BACKGROUND • The KressWorks Foundation was started following the death of my younger Sister from Ewing’s Sarcoma – Ewing’s sarcoma – 2 most frequent bone tumor in children & young adults nd – She contracted Ewing’s first in her early 20’s – She was repeatedly declared “Cancer Free” for the following 25 years – Her Ewing’s recurred in her mid 50’s and she died from it • Her treatment was not Systematic, Targeted, Effective or Efficient COPYRIGHT © The KressWorks Foundation 2014

WHO WE ARE • Governing Boa rd – James Kress (President) PhD (Physical Chemistry), Member of ASCO, AACR, ACS, APS, IEEE – Henriette Eles (Treasurer) BS (Computer Engineering), BS (Electrical Engineering), MS (EE) – Joseph Giachino (Director) IEEE Fellow, Visiting Scholar and Past Director of External Programs, WIMS ERC - University of Michigan, MS (Physics), BS (Physics) – Dave Brown (Director) President of Mobility Transportation Systems located in Canton, MI • Technical Advisory Board – Dr. Alexander A. Granovsky, PhD in Chemistry, Moscow State University, Moscow, Russia – Dr. Sorin Draghici, PhD, Robert J. Sokol MD Endowed Chair in Systems Biology, head of the Intelligent Systems and Bioinformatics Laboratory at Wayne State University – Dr. Adri van Duin, PhD, Delft University of Technology, the Netherlands, Associate Professor, Department of Mechanical & Nuclear Engineering, Pennsylvania State University – Dr. Patrick J. Grohar, M.D., PhD, Wayne State University, Assistant Professor at Vanderbilt University School of Medicine specializing in Pediatric Hematology/Oncology – Dr. James Bosley, PhD is founder of Clermont, Bosley LLC. which supports drug development in pharma with disease modeling. Senior technical and management roles with leading modeling firms. PhD, BS degrees In Chemical Engineering from Texas & Wisconsin, MS in Electrical Engineering from UC-Irvine. • Partners – Advaita Bioinformatics – Rosa & Co., LLC (Contractor – work for hire) • Additional – Dr. Elizabeth Lawlor M.D., PhD, University of Michigan, Pediatrics-Hematology/Oncology COPYRIGHT © The KressWorks Foundation 2014

CURRENT STATUS IN TREATMENT • There have been a number of successes: – The effectiveness and expansion of available therapies has seen some significant improvements since the 1970s. – E.g. Gleevec now cures most pediatric Chronic Myeloid Leukemia patients. – The cancer death rate, adjusted for the size and age of the population, has decreased by only 5 percent between 1950 and 2010 (Gina Kolata science columnist for The New York Times) • The Institute of Medicine (IOM) has noted disconnect between the billions of dollars spent on cancer initiatives and to what that money has actually translated. • DNA pioneer and Nobel Laureate James Watson – “New therapies work for just a few months and we have nothing for major cancers such as the lung, colon and breast that have become metastatic.” – “We must overcome the inherently conservative nature of today's cancer research establishments.“ • Cancer Biologist Robert Weinberg of MIT – The main reason drugs that target genetic glitches are not cures is that cancer cells have a work-around. COPYRIGHT © The KressWorks Foundation 2014

FRAGMENTED DEVELOPMENT Cancer Centers/ Physicians Hospitals New Drugs Pharmaceutical Companies Government (FDA, NIH, NSF, NCI, etc) Bioinformatics Genomics/ Metabolomics Molecular Biology Biochemistry Biophysics COPYRIGHT © The KressWorks Foundation 2014

WE NEED A BETTER APPROACH Cancer is extremely complex • Multiple genetic types, disease states, and history • The disease changes with time (mutations, tumor size) • Many chemo-, radio-, surgical and other treatment options • Infinite variety of dose and treatment timing options • Science is reductionist. Focuses on small parts • The disease is systemic. Interaction of many small parts. The KressWorks Foundation is Pioneering a New Approach COPYRIGHT © The KressWorks Foundation 2014

THE KRESSWORKS NEW APPROACH Implement the Third Revolution in Medicine • The 3rd Revolution in Medicine is the Convergence Of Science, Mathematics & Engineering via Systems Engineering. • Using Systems Engineering to develop a Clinically Applicable, Targeted, Effective and Efficient Systematic Treatment Methodology (STM). • The STM provides the framework that – Allows us to perceive Cancer as complex dynamical and evolvable systems. – Consolidates and Integrates the fragmented pieces of Science to make Nature work for us. – Facilitates methodical and personalized treatments and cures. – Allows outcome predictions for complex treatments – Provides for the patient to be an active participant in their treatment: • Aware of the choices they have. • The consequences of their choices. • The progress being made. COPYRIGHT © The KressWorks Foundation 2014

PROGRESS HAS BEEN MADE • Root Cause Analysis – can we can simulate and affect this? – Mahdi Golkaram, Dr. Adri van Duin (both at Penn State University) and Dr. Jim Kress (The KressWorks Foundation) • How does Cancer (Ewing’s) work in Nature? – Experimental data from Dr. Patrick Grohar, MD (Vanderbilt) and Dr. Elizabeth Lawlor, MD (University of Michigan) – Pathway analysis by Dr. Jim Kress with assistance from Dr. Sorin Draghici (Advaita Bioinformatics) • How do we make Nature work to cure Cancer (Ewing’s)? – Dr. Jim Kress, Dr. Jim Bosley (Clermont, Bosley LLC) and Contractor Rosa & Co. COPYRIGHT © The KressWorks Foundation 2014

CHROMOSOMAL TRANSLOCATION THE ROOT CAUSE – CANCER GENE FORMATION COPYRIGHT © The KressWorks Foundation 2014

DNA DOUBLE STRAND BREAK SIMULATION THE FIRST STEP IN CANCER GENE FORMATION 100 80 60 % 40 Strain 20 EWSR1 EWSR1*(a) EWSR1*(b) Thermal Fluctuation 0 ‐20 ‐40 Sequence EWSR1 gene DSBs. (Blue line) DSBs in EWSR1 without oxidative stress can be observed. (Green and purple lines) Oxidative stress accelerates DSBs in EWSR1. COPYRIGHT © The KressWorks Foundation 2014

PATIENT PATHWAY ANALYSIS HOW NATURE USES THE CANCER GENE TO STIMULATE AND INHIBIT OTHER GENES KRESSWORKS ANALYSIS RESULTS COPYRIGHT © The KressWorks Foundation 2014

SYSTEMATIC TREATMENT METHODOLOGY MAKING NATURE WORK FOR US The Systems Engineering coordinated framework Tailor model to patient for personalization of treatment Using the tailored model, determine the best possible treatment regimen, including quality of life and cost, for the patient Apply the treatment regimen. Monitor the patient and use the model to react quickly if cancer adapts or resists. COPYRIGHT © The KressWorks Foundation 2014

DISEASE PROGRESSION MODEL MAKING NATURE WORK FOR US Systems Engineering Process: 1. Ewing’s Sarcoma is complex and Disease Progression Model helps understand that complexity 2. A Mechanistic Computer Model is optimal for this purpose 3. The first step is to create an architectural blueprint of the cancer system COPYRIGHT © The KressWorks Foundation 2014

INITIAL PROTOTYPE – VEGF MAKING NATURE WORK FOR US Mechanistic model by X-Y Zhang, MR Birtwistle and JM Gallo, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, Pharmacometrics & Systems Pharmacology (2014) 3, e92, 15 Jan 2014 COPYRIGHT © The KressWorks Foundation 2014

SYSTEMATIC TREATMENT METHODOLOGY MAKING NATURE WORK FOR US COPYRIGHT © The KressWorks Foundation 2014

STM TREATMENT ALTERNATIVES MAKING NATURE WORK FOR US COPYRIGHT © The KressWorks Foundation 2014

TREATMENT DECISION REVIEW MAKING NATURE WORK FOR US COPYRIGHT © The KressWorks Foundation 2014

SUMMARY • We have designed and done initial prototyping of the first Systematic Treatment Methodology to provide a Targeted, Effective and Efficient methodology for treating Cancer (Ewing’s) and other diseases. • We are developing a Disease Progression Model for Ewing's Sarcoma – The first architectural blueprint of Ewing's – An initial prototype of a mechanistic model for Ewing’s • Are the first to successfully simulate the DNA Double Strand Breakage process, the initial step in Chromosomal Translocation, the root cause for Ewing’s and other Cancers. COPYRIGHT © The KressWorks Foundation 2014

NEXT STEPS AND FINANCIAL NEEDS • Make Nature Work for Us - STM Development and Application – 2015: $405,000 • $250,000; $50,000 per Hallmark Model • $50,000; DDI analysis, Pathway Prioritization & Adaptation (Post Doc) • $30,000; Optimization of STM process and associated computer code • $60,000; Biomarker ID (3 year Grad Student commitment @ $60K/yr) • $15,000; Software – Overall: $2 Million – Produces: Complete STM Prototype ready for FDA approval cycle • Solve the Root Cause – 2015: $160,000 • $50,000; Transport Modeling in Nucleus (Post Doc) • $50,000; RMD Modeling of Gene Fusion Process (Post Doc) • $10,000; Software • $50,000; Hardware (leased – 3 year commitment @ $50K/yr) – Overall: $350,000 – Produces: • Complete understanding of Chromosomal Translocation for Ewing's • Candidates for therapeutic intervention at the gene level COPYRIGHT © The KressWorks Foundation 2014

THANK YOU ANY QUESTIONS? COPYRIGHT © The KressWorks Foundation 2014

COPYRIGHT © The KressWorks Foundation 2014 PLEASE CONTRIBUTE TONIGHT OR AT THE DONATE TAB OF OUR WEBSITE HTTP://WWW.KRESSWORKS.ORG THE DAWN OF THE THIRD REVOLUTION IN MEDICINE BEGINS WITH YOU THE KRESSWORKS FOUNDATION IS A MICHIGAN NONPROFIT, IRS DESIGNATED 501C3 CHARITABLE CORPORATION